慢性间歇性低压低氧对癫痫大鼠的脑保护作用和机制探讨
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摘要
癫痫是一种常见的神经系统综合征。国内流行病学调查结果显示，我国目前约有900多万癫痫患者，其中25％-40％为难治性癫痫，颞叶癫痫（temporal lobe epilepsy，TLE）是最常见的难治性癫痫类型，主要特点是逐渐进展的原发性癫痫反复发作（spontaneous recurrent epileptic seizure，SRS）和海马硬化，伴有明显的药物抵抗性。临床调查表明，超过一半的癫痫患者具有不同程度的认知功能障碍，有的因癫痫发作频繁不能坚持服药，有的因长期服用抗癫痫药物（药物本身可致不同程度的认知功能障碍）所致，这无疑给个人、家庭及社会带来了沉重的负担。
匹鲁卡品（pilocarpine，PILO）致痫大鼠的行为学、海马神经元损伤的病理形态学及神经电生理学等改变均与人类的TLE相似，因此该模型是目前研究癫痫持续状态（status epilepticus，SE）和TLE的经典模型之一。
SE的致病机制较为复杂，目前尚未完全阐明，主要包括：苔藓纤维芽生假说；Ca2+内流引发的细胞毒性；谷氨酸和γ-氨基丁酸及其受体结构和功能异常；氧化应激损伤及凋亡等。氧化应激是指体内活性氧簇（reactive oxygen species，ROS）产生增多或体内的抗氧化系统出现障碍，体内氧自由基代谢就会失衡，蓄积过多的ROS易导致组织受损。ROS通过直接或间接氧化损伤DNA、诱发基因突变，导致蛋白质和脂质过氧化，激活非选择性钙通道，调节细胞凋亡相关基因，诱导海马神经元发生凋亡。另外，SE时常伴严重的缺氧，易致ROS的增加，而ROS也可直接或间接堆积于线粒体，损伤线粒体膜，降低膜电位，造成线粒体的结构和功能异常，使线粒体内的细胞色素C（Cytochrome c）释放入细胞质，引发caspase级联效应，诱导细胞凋亡。因此，对如何减少氧化应激ROS的产生、保护线粒体并抑制细胞凋亡具有重要的研究意义，探索难治性癫痫的替代治疗或辅助治疗措施便成为当务之急。
目前已发现多种预处理方法可以诱导组织细胞对缺氧产生耐受，包括缺血、高压氧、高温、低温、睡眠剥夺等，这些方法由于本身存在明显的副作用，在临床实际应用方面受到限制。众所周知，低氧容易改变机体的生理功能，严重的低氧往往引起的是一种损伤的病理改变，而最近研究发现适度的低氧预处理对机体则起到一定的保护效应。
研究已证实，低氧预处理可通过抑制肿瘤坏死因子α、上调促红细胞生成素、血管内皮生长因子及Bcl-2抗凋亡蛋白等在海马CA1和CA3区的表达，改善脑缺血缺氧后脑组织的损伤及其导致的认知功能障碍。越来越多的研究报道，慢性间歇性低压低氧（chronic intermittent hypobarichypoxia，CIHH）对机体多种组织、器官均有明显的保护作用，例如增强机体对缺血缺氧的耐受性，对抗缺血/再灌注所致的心脏功能损伤、抑制心肌超微结构受损及钙离子超载、保持钙稳态，并能够有效抗心律失常，保护神经、肝脏、肾脏等组织器官；而且CIHH还具有降压、抗氧化应激、抗凋亡、增强免疫功能等作用。在缺血性脑血管病方面的研究中，CIHH通过上调大鼠脑内的谷氨酸转运体-1（glutamate transporter-1，GLT-1）诱导其产生缺氧耐受性。而CIHH预处理是否对癫痫也具有一定的脑保护作用？目前尚未见报道。有鉴于此，本实验通过制备氯化锂-匹鲁卡品诱导的SE大鼠模型，观察CIHH对致痫大鼠的行为学、脑组织形态学及分子生物学等方面的影响，评价CIHH预处理的保护作用并进一步探讨其可能的作用机制，为此主要致力于以下四个部分的研究：
第一部分CIHH预处理对匹鲁卡品致痫大鼠的脑保护效应
目的：建立匹鲁卡品（pilocarpine，PILO）诱导的SE大鼠模型，研究CIHH预处理对PILO致痫大鼠的脑损伤是否具有保护作用，分别从行为学、形态学及分子生物学等方面进行评价，并初步探讨其作用机制。
方法：
（实验一）将成年健康雄性Sprague-Dawley（SD）大鼠随机分为6组：正常对照组（CON组）和PILO模型组（SE组），根据SE发作后不同的时间点分为SE3h、SE12h、SE24h、SE72h和SE7d五个亚组，每组各10只。应用Nissl染色法和流式细胞仪动态观察SE后不同时间点大鼠的海马神经元凋亡情况，检测该模型制备是否成功。
（实验二）根据目前文献报道：SE后脑组织损伤程度最严重的时间多为发作后72h，我们选取SE72h进行研究，将动物随机分为4组：CON组（n=7），SE组（n=13），CIHH+SE组（n=13），CIHH组（n=7）。利用脑电图观察大鼠的痫性发作潜伏期和癫痫波发放的频率，并记录死亡率；对脑组织一部分行Nissl染色计数海马组织中存活的神经元；另一部分应用流式细胞仪定量分析海马神经元的凋亡情况。
结果：
（实验一）
150只大鼠中，41只被诱发SE，成功率为82％，实验过程中共死亡9只（包括诱发SE成功后的7只），最终可纳入实验的大鼠共34只。CON组无大鼠死亡，10只均可纳入实验。
2Nissl染色：CON组大鼠海马CA1区和CA3区神经元结构完整，无神经元丢失；SE3h组和SE12h组大鼠海马CA1区和CA3区结构相对完整，未见到明显的神经元丢失；SE24h组可见大鼠海马CA1区和CA3区神经元部分丢失；SE72h组神经元丢失明显，且CA1区更严重。而SE7d组海马CA1区神经元的丢失较SE72h组有所减少。
与CON组相比，SE3h组、SE12h组大鼠海马CA1区和CA3区神经元数量几乎无减少（P>0.05）；SE24h组、SE72h组和SE7d组大鼠海马CA1区和CA3区的神经元数量均明显减少（P<0.05）。与SE72h组相比，其它组大鼠海马CA1区和CA3区神经元数量均明显增加（P<0.05）。
3细胞凋亡率：与CON组相比，SE3h组、SE12h组的海马细胞凋亡率均无明显增加（P>0.05），而SE24h组、SE72h组和SE7d的细胞凋亡率有不同程度的增加（P<0.05）。与SE72h组相比，SE24h组和SE7d组海马细胞的凋亡率均有所下降（P<0.05），但后两者间无明显的统计学差异（P>0.05）。与Nissl染色及以往的文献报道结果一致，证明本实验模型制备是成功的、可行的。
(实验二)
1SE组、CIHH+SE组大鼠的死亡率分别为23.1%和0%。与SE组相比，CIHH+SE组的潜伏期延长（33.9±2.3min vs.24.5±1.7min，P<0.05）；癫痫波发放的频率更少（100.5±2.9HZ vs.118.3±4.0HZ，P<0.05）。CON组和CIHH预处理组中大鼠均无SE发作及死亡。
2Nissl染色：CON组大鼠的海马CA1区和CA3区神经元结构完整，几乎无神经元丢失。与CON组相比，SE组大鼠神经元丢失明显；CIHH+SE组神经元结构部分完整，尼氏小体数量较SE组显著增加。CIHH组大鼠的海马区神经元结构相对完整，偶见神经元丢失。
海马神经元存活数：与CON组相比，SE组大鼠海马CA1区和CA3区神经元数量均明显减少（P<0.05）；经CIHH预处理后明显增加了神经元的存活数量（P<0.05）。单纯行CIHH预处理组存活的神经元数量虽然少于CON组，但两者间无明显的统计学差异（P>0.05）。
3细胞凋亡率：与CON组相比，SE组和CIHH+SE组的海马细胞凋亡率均明显增加（P<0.05）；单纯行CIHH组细胞凋亡率虽然稍高于CON组，但两者无明显的统计学差异（P>0.05）。与SE组相比，CIHH+SE组的细胞凋亡率明显减低（P<0.05）。
结论：PILO诱导的SE大鼠模型能较好的动态观察脑损伤后神经元凋亡情况。SE发作后72h时，海马组织CA1区损伤最为严重；CIHH预处理可能通过延长SE大鼠的脑电图痫性放电潜伏期、降低痫性波发放频率来抑制癫痫发作，降低海马神经元的凋亡率。第二部分不同的低氧预处理对匹鲁卡品致痫大鼠的海马损伤作用
目的：已有研究表明，慢性间歇性常压低氧（chronic intermittentnormobaric hypoxia，CINH）对大鼠的脑组织损伤发挥着一定的保护作用。本研究分别从PILO诱导的SE大鼠的SRS、胞浆内钙离子浓度及细胞凋亡率等方面比较两种不同的预处理方式（CIHH和CINH）对大鼠海马损伤的保护作用。
方法：将成年雄性SD大鼠随机分为4组：正常对照组（CON组，n=18），PILO模型组（SE组，n=34），CIHH预处理+SE组（CIHH-Pre组，n=24）和CINH预处理+SE组（CINH-Pre组，n=24）。将每组大鼠分为两部分：一部分应用视频脑电图(V-EEG)观察大鼠SE后自发性癫痫反复发作（SRS）情况（包括SRS的频率、发作级别及持续时间）；另一部分于SE72h时分别应用Nissl和FJB染色法观察大鼠海马的神经元凋亡和变性情况；流式细胞仪检测海马胞浆内钙离子浓度（[Ca2+]i）和细胞凋亡率。
结果：
1PILO诱导的SE大鼠死亡率为47.1%，而CIHH-Pre组和CINH-Pre组SE大鼠的死亡率分别为16.7%和20.8%。
V-EEG记录SRS的情况：CIHH-Pre组和CINH-Pre组出现SRS的频率、严重程度和持续时间均较SE组明显降低（P<0.05）。与CINH-Pre组相比，CIHH-Pre组出现SRS的频率更少（P<0.05），发作级别更低（P<0.05）。CON组大鼠无SRS发作和死亡。
2与CON组相比，SE组海马胞浆内[Ca2+]i明显升高（2.16±0.06vs.1.19±0.03，P<0.05）。与SE组相比，CIHH-Pre组大鼠海马胞浆内[Ca2+]i（1.51±0.03）和CINH-Pre组（1.74±0.03）均明显的降低（P<0.05）；且CIHH-Pre组海马胞浆内[Ca2+]i低于CINH-Pre组（P<0.05）。
3与CON组相比，SE组大鼠海马的神经元丢失明显；而CIHH-Pre组和CINH-Pre组神经元丢失的程度较SE组减轻。SE组大鼠海马CA1区和CA3区的存活神经元数量均较CON组明显减少（P<0.05）。与SE组相比，CIHH-Pre组和CINH-Pre组均明显地增加了大鼠海马CA1区和CA3区的神经元数量（P<0.05）；而CINH-Pre组CA1区的存活神经元数量仍低于CIHH-Pre组（55.00±1.07vs.74.83±1.40，P<0.05）。
4CON组未见明显的FJB阳性细胞。与CON组相比，PILO诱导的SE组海马CA1区和CA3区可见呈黄绿色荧光的FJB阳性细胞明显增多。CIHH-Pre组和CINH-Pre组大鼠海马CA1区和CA3区均明显减少了FJB阳性细胞（P<0.05）,且CIHH-Pre组CA1区的FJB阳性细胞数少于CINH-Pre组（P<0.05）。
5PILO诱导的SE组大鼠海马细胞早期凋亡率（Q4）和总的凋亡率（Q2+Q4）均明显高于CON组（P<0.05）。与SE组相比，CIHH-Pre组和CINH-Pre组均明显地降低了海马细胞的凋亡率（P<0.05），且CIHH-Pre组的凋亡率低于CINH-Pre组（P<0.05）。
结论：PILO诱导的SE大鼠容易出现SRS行为，使海马组织细胞内[Ca2+]i升高，导致神经元损伤。CIHH和CINH预处理均可通过有效地抑制SE大鼠的SRS行为和胞浆内钙离子超载来营救损伤的海马神经元，且CIHH预处理措施可能更有效。
第三部分CIHH对匹鲁卡品致痫大鼠的海马抗氧化防御体系的影响
目的：研究CIHH预处理是否对癫痫发作产生的氧化应激及线粒体损伤具有一定的保护作用，并探讨可能的作用机制。
方法：将成年雄性SD大鼠随机分为3组：正常对照组（CON组），PILO模型组（SE组）和CIHH预处理+SE组（CIHH+SE组），每组各20只。于SE发作后72h时，首先制作大鼠海马组织的匀浆液，根据试剂盒说明分别检测MDA含量、总SOD、SOD1、SOD2及GSH的活力；然后应用流式细胞仪检测海马组织细胞内ROS、线粒体膜电位（mitochondrial transmembranepotential，△Ψm）的水平；Western Blot检测胞浆中Cytochrome c、Caspase3、Bcl-2、Bax蛋白的表达；并结合透射电镜观察线粒体的超微结构。
结果：
1与CON组相比，SE组大鼠海马内MDA的水平明显升高（P<0.05）；总的SOD和SOD2的活力均明显降低（P<0.05），GSH的含量也明显降低（P<0.05），而CIHH+SE组可不同程度地逆转上述指标的异常改变（P<0.05）。SODl在各实验组间则无明显差异（P>0.05）。
2与SE组相比， CIHH+SE组能明显降低海马细胞内ROS的水平（P<0.05），明显升高△Ψ的水平（P<0.05）。
3与CON组相比，SE组大鼠海马组织胞浆内Cytochrome c，Caspase3，Bax，及Bax/Bcl-2蛋白的水平均明显升高（P<0.05），而Bcl-2蛋白水平显著降低（P<0.05）。CIHH预处理后均可不同程度地逆转上述蛋白的表达水平（P<0.05）。
4与CON组相比，SE组中线粒体的超微结构发生明显改变，表现为广泛的空泡化、严重的嵴断裂伴膜破坏；而CIHH+SE组可部分改善线粒体的结构变化。
结论：SE发作后线粒体可能是自由基攻击的靶点。CIHH预处理可通过增强大鼠海马组织的抗氧化应激能力，改善线粒体的结构和功能来发挥神经元的保护作用。第四部分CIHH对匹鲁卡品致痫大鼠认知功能的改善作用和机制探讨
目的：研究CIHH预处理对SE大鼠的认知功能障碍、海马组织中突触的超微结构和突触相关蛋白的表达有何影响，进一步探讨相关的作用机制。
方法：将成年雄性SD大鼠随机分为3组：正常对照组（CON组，n=10）和PILO模型组（SE组，n=20）和CIHH预处理+SE组（CIHH+SE组，n=20）。根据文献报道及我们前期的实验结果表明：SE发作后多于14-42d出现SRS行为，由此我们选取SE发作后42d时，进行Morris水迷宫行认知功能检测；结束后分别应用透射电镜观察海马CA1区突触的超微结构；WesternBlot法检测胞浆中PSD-95和Kalirin-7蛋白的表达。
结果：由于大鼠经SE发作后部分出现死亡，本部分实验中SE发作后42d时，各组大鼠的存活情况：CON组10只，PILO诱导的SE组9只，CIHH+SE组14只。
1水迷宫检测：随着训练时间的延长，从第3d开始，各组大鼠寻找平台的潜伏期均逐渐缩短（P<0.05）。CIHH预处理组较SE组的潜伏期明显缩短（P<0.05）。在空间探索试验中，与CON组相比，SE组大鼠的穿台次数明显减低（5.33±0.58vs.11.8±0.76，P<0.05），在目标象限停留时间也明显缩短（52.78±2.00s vs.86.80±1.67s，P<0.05）；而CIHH+SE组大鼠的穿台次数（7.86±0.44）较SE组有所增加（P<0.05），在目标象限停留时间（67.36±2.06s）也明显延长（P<0.05）。在可视平台试验中，各组间大鼠的逃避潜伏期和游泳速度均无明显的统计学差异（P>0.05）。
2突触间隙宽度:与CON组相比（20.27±0.45nm），SE组和CIHH+SE组大鼠海马的突触间隙均显著增宽（P<0.05）。虽然CIHH+SE组的突触间隙较SE缩窄，但两者无明显的统计学差异（23.13±0.89nm vs.25.20±0.78nm，P>0.05）。
突触后致密物厚度：与CON组相比（30.27±0.69nm），SE组和CIHH+SE组大鼠海马的突触后致密物厚度均显著降低（P<0.05）；而CIHH+SE组较SE组明显增加（27.87±0.77nm vs.22.67±0.76nm，P<0.05）。
3PSD-95蛋白：与CON组相比（0.72±0.02），SE组和CIHH+SE组中大鼠海马的胞浆内PSD-95蛋白的表达水平均显著降低（P<0.05）；而CIHH+SE组中表达的水平明显高于SE组（0.40±0.02vs.0.21±0.02，P<0.05）。
Kalirin-7蛋白：与CON组相比(0.68±0.02)，SE组和CIHH+SE组中大鼠海马胞浆内Kalirin-7蛋白水平均显著降低（P<0.05）；而CIHH+SE组的表达水平高于SE组（0.34±0.02vs.0.26±0.02，P<0.05）。
结论： PILO诱导的SE大鼠长期反复发作可出现明显的认知功能障碍和海马突触结构的损伤。CIHH预处理可有效改善受损的突触超微结构并上调突触相关蛋白的表达，这可能是CIHH改善癫痫发作后认知功能障碍的机制之一。
Epilepsy is one of the most common neurological disorders, afflictingmore than9million individuals in China according to domesticepidemiological investigations. Among patients with epilepsy, about25%-40%suffers from intractable epilepsy resistant to currently available antiepilepticdrugs (AEDs). Many such cases are of temporal lobe epilepsy (TLE),characterized by spontaneous recurrent seizures (SRS) and progressivehippocampal sclerosis. Clinical investigations have shown that over half ofepilepsy patients suffer from cognitive impairments due to neurologicaldamage associated with frequent seizures and (or) the side-effects oflong-term AED use. This cognitive dysfunction imposes an even heavierburden on epileptic individuals, their families, and society.
The rat pilocarpine (PILO)-induced seizure model exhibits many of theclinical, behavioral, and neuropathological hallmarks of TLE and statusepilepticus (SE), and so is advantageous for preclinical testing of noveltreatment strategies.
The pathogenesis of TLE is complex and may involve a combination ofrecurrent mossy fiber sprouting, excitotoxicity induced by neuronal calciuminflux, abnormal glutamate and γ-aminobutyric acid (GABA) receptorstructure and function, and oxidative stress with ensuing apoptosis. Oxidativestress occurs when production of reactive oxygen species (ROS) exceeds thecapacity of endogenous cellular antioxidant defense systems, resulting inmitochondrial dysfunction and destruction of macromolecules such asmembrane lipids. Status epilepticus is often associated with severe brainhypoxia. Reperfusion of hypoxic tissue is associated with ROS accumulationin mitochondria, which can damage mitochondrial membranes, decreasing the mitochondrial transmembrane potential, inducing mitochondrial cytochrome crelease into the neuronal cytoplasm, and activating the caspase cascadeleading to apoptosis. Reducing ROS production during SE to protectmitochondria and inhibit neuronal apoptosis is a possible replacement oradjuvant therapy for intractable epilepsy.
A variety of pretreatment or preconditioning methods can induce hypoxicand oxidative stress tolerance, including mild transient ischemia, hyperbaricoxygen, hyperthermia, hypothermia, sleep deprivation. However, clinicalapplication of many of these methods is limited by potential side effects.Severe hypoxia often leads to pathological changes, but recent studies havethat shown moderate transient hypoxia is a physiologically importantmechanism for maintaining or enhancing endogenous cytoprotection.
Hypoxic preconditioning can inhibit tumor necrosis factor alphaexpression while raising erythropoietin, vascular endothelial growth factor,and anti-apoptotic Bcl-2expression in hippocampal CA1and CA3subfields.In vivo, hypoxic preconditioning can prevent hippocampal damage fromischemia/hypoxia and prevent associated cognitive dysfunction. Accumulatingevidence indicates that chronic intermittent hypobaric hypoxia (CIHH)enhances cardiac tolerance against subsequent ischemia/hypoxia, reducesheart damaged due to ischemia/reperfusion, inhibits ultrastructural damageand calcium overload in cardiac myocytes, maintains myocyte calciumhomeostasis, and prevents arrhythmia. In addition, CIHH has been shown toprotect nerve, liver, kidney, and other organs against subsequent severehypoxic insults. Furthermore, CIHH lowers blood pressure, reduces oxidativestress and apoptosis, and enhances immune function. In a rat model ofischemic cerebrovascular disease, CIHH enhanced ischemic resistance byupregulating brain expression of glutamate transporter-1(GLT-1). However,whether CIHH preconditioning may protect against SE or not, there was noreported. In this study, we examined the effects of CIHH preconditioning onbehavioristics of rat lithium-pilocarpine model of TLE, hippocampal neuronsurvival (morphology), and molecular biology in order to further explore the underling mechanisms.
PartⅠ Neuroprotective effect of CIHH preconditioning on pilocarpine-induced seizures in rats
Objective: To establish a pilocarpine (PILO)-induced SE rat model andevaluate the efficacy of CIHH preconditioning for preventing SE-associateddeath of hippocampal neurons and preserving hippocampal function.
Methods:(Experiment1) Healthy adult male Sprague-Dawley rats wererandomly divided into six groups of10: a normal control (CON group) and5PILO groups (SE groups) sacrificed3h,12h,24h,72h, and7days post-SE(SE3h, SE12h, SE24h, SE72h and SE7d groups, respectively). Nissl stainingand flow cytometry were used to assess morphological damage and apoptosisof hippocampal neurons post-SE.(Experiment2) According to previousreports,72h post-SE is the peak time of SE-associated brain damage, so thistime point was selected to examine the neuroprotective effects of CIHHpreconditioning. Animals were randomly divided into four groups: CON (n=7),SE (n=13), CIHH+SE (n=13), CIHH (n=7). Rat mortality from0-72h post-SEwas determined and electroencephalograms (EEGs) were recorded to measurethe frequency, severity, and duration of epileptiform discharges. Hippocampaltissues were then isolated to assess morphological damage and neuronalsurvival by Nissl staining and neuronal apoptosis rate by flow cytometery.
Results:
(Experiment1)
1Status epilepticus was induced by PILO in41of50rats (success rate,82%). Seven SE group rats died during the procedure. The remaining34PILO-treated rats were analyzed and compared to the10(surviving) CONgroup rats.
2Nissl staining: In the CON group, there was almost no visible neuronalloss in CA1and CA3subfields. Similarly, SE3h and SE12h groups showed noobvious neuronal loss and neuronal morphology resembled that of the CONgroup. Neuronal loss was apparent in the CA1and CA3regions of the SE24hgroup. In the SE72h group, neuron loss appeared even greater, especially in CA1. Neuronal loss in the CA1of the SE7d group was clearly lower than inthe SE72h group. Cell counting revealed that the numbers of survivingneurons in the SE3h and SE12h groups were not significantly different fromthe CON group (P>0.05), while significant reductions were observed in theSE24h, SE72h, and SE7d groups compared to the CON group (P<0.05).Neuronal survival was significantly higher in all other SE groups compared tothe SE72h group (P<0.05).
3Flow cytometry: Compared to the CON group, neuronal apoptosis rateswere significantly higher in the SE24h, SE72h, and SE7d groups (P<0.05), butnot in the SE3h and SE12h groups (P>0.05). Apoptosis rates in SE24h andSE7d groups were not significantly different (P>0.05) but were bothsignificantly lower compared than in the SE72h group (P<0.05). Thus, PILOinduced neuronal death in the hippocampus, peaking at72h post-SE.
(Experiment2)
1Mortality was23.1%in the SE group, while no deaths were observed inthe CIHH+SE group. Compared to the SE group, the latency to reach SE waslonger (P<0.05) and the frequency of EEG-defined epileptic discharges lower(P<0.05) in the CIHH+SE group. There was no mortality or seizures in theCON and CIHH groups.
2Nissl staining: Neurons in CA1and CA3subfields of the CON groupwere clearly stained and there was almost no neuronal loss, while neuronal losswas clearly visible in the SE group. Neuronal cell death was partially reversedin the CIHH+SE group and fewer neurons showed morphological signs ofdamage in both CA1and CA3subfields compared to the SE group. There wasvery slight neuronal loss in the CIHH group. Cell counting revealed asignificant decrease in neuronal survival in the SE group compared to the CONgroup (P<0.05), while the number of surviving neurons was significantlyhigher in the CIHH+SE group compared to the SE group (P<0.05). Althoughthe number of surviving hippocampal neurons was lower in the CIHH groupthan the CON group, there was no significant statistical difference (P>0.05).
3Flow cytometry: The numbers of apoptotic neurons were significantly higher in the SE and SE+CIHH groups compared to the CON group (P<0.05).However, apoptotic rate was significantly lower in the CIHH+SE groupcompared to the SE group (P<0.05), indicating partial rescue from apoptosisby CIHH preconditioning. The rate of neuronal apoptosis was slightly higher inthe CIHH group compared to the CON group, but the difference was notstatistically significant (P>0.05).
Conclusion: The PILO-induced SE rat model allows for dynamicobservation of progressive hippocampal neuronal injury and apoptosis. At72hafter SE, damage was more severe in the CA1. Preconditioning with CIHHprolonged SE latency and reduced seizure frequency, PILO-induced mortality,morphological signs of hippocampal neuronal damage, and neuronalapoptosis.PartⅡ Effects of different hypoxic preconditioning protocols on thehippocampal damage of status epileptic rats
Objective: Chronic intermittent normobaric hypoxia (CINH）has beenproved playing an important role in protecting the damaged brain of rats. Inthis study, we compared the effects of different hypoxic preconditioningprotocols (CIHH and CINH) on spontaneous recurrent seizures (SRS),intracellular free calcium concentration ([Ca2+]i), and apoptosis rate followingPILO-induced status epilepticus (SE).
Methods: Adult male Sprague-Dawley rats were randomly divided intofour groups: normal control group (CON group, n=18), PILO group (SE group,n=34), CIHH+SE group (CIHH-Pre, n=24) and CINH+SE group (CINH-Pre,n=24). The rats in each group were divided into two parts: a part of that wascompared by video monitoring of behavioral seizure activity (frequency, rank,and duration); another part of that were used to examine changes in themorphology of hippocampal pyramidal neurons by menas of Nissl stainingand Fluoro-Jade B (FJB) staining, and further to detect the quantification of[Ca2+]i and cell apoptosis by means of flow cytometry at SE72hour.
Results:
1Mortality and SRS of rats induced by PILO: In the SE group, mortality rate was47.1%, while in the CIHH-Pre group and CINH-Pre group, mortalityrate was16.7%and20.8%, respectively.
SRS by the V-EEG: There was a significant decrease in the number,mean severity, and duration of seizures in both CIHH-treated andCINH-treated SE rats compared to those treated by PILO (P<0.05). However,the CIHH-Pre protocol induced a greater reduction in both seizure frequencyand severity compared to the CINH-Pre group (P<0.05). There was no SRSseizures and animal died in the CON group.
2Comparation of the [Ca2+]i: A substantial increase was measured in theSE group compared to the CON group (P<0.05), while both CIHH-Pre andCINH-Pre significantly reduced the post-SE [Ca2+]i elevation compared to theSE group (P<0.05). Hippocampal [Ca2+]i was lower in the CIHH-Pre groupthan that of the CINH-Pre group (P<0.05).
3Nissl staining: There was a marked loss of neurons in CA1and CA3subfields of SE group compared to the CON group. Compared to the SE group,there was a significantly reduced neuronal loss in the CIHH-Pre andCINH-Pre groups.
The number of surviving neurons in both subfields of the hippocampus inSE group obviously decrease compared to the CON group (P<0.05).Compared to the SE group, the number of neurons was significantly increasein the CIHH-Pre and CINH-Pre groups (P<0.05), while the average CA1pyramidal neuron density was lower in the CINH-Pre group than in theCIHH-Pre group (P<0.05).
4FJB staining: No FJB-positive cell was observed in the CON group.Many FJB-positive cells with kelly fluorescent were observed in the CA1andCA3subfields in the SE group. CIHH-Pre and CINH-Pre groups showed asignificant reduction in the number of FJB-positive cells in the CA1and CA3subfiels (P<0.05). The average numbers of FJB-positive cells in the CA1subfield was lower in the CIHH-Pre group than in the CINH-Pre group(P<0.05).
5Apoptosis rate of the hippocampus: Both the number of cells in early apoptosis (Q4) and total apoptotic cells (Q2+Q4) were significantly higher inthe SE group than in the CON group (P<0.05). Both the CIHH-Pre group andthe CINH-Pre group exhibited markedly reduced apoptosis rate compared tothe SE group (P<0.05). Moreover, apoptosis rate was lower in the CIHH-Pregroup than in the CINH-Pre group (P<0.05).
Conclusion: SE rats induced by PILO prone to SRS leads to neuronaldamage of hippocampus by increasing the [Ca2+]i. CIHH-Pre and CINH-Precan effectively inhibit the SRS behavior and reduce the post-SE [Ca2+]i so asto rescue the hippocampal neurons. What’s more, hypobaric preconditioningmay be more effective.Part Ⅲ Effect of CIHH on the antioxidant defense system of thehippocampus in epileptic rats
Objective: To examine whether CIHH preconditioning protects againstoxidative stress and mitochondrial damage induced by SE and to explore theunderlying mechanisms.
Methods: Animals were randomly divided into three groups: CON(n=20), SE (n=20), and CIHH+SE (n=20). Following these treatments,homogenates were prepared from hippocampus to measure MDAaccumulation, an index of oxidative stress, as well as the activities of theantioxidants superoxide dismutase (SOD) isoforms and glutathione (GSH)using commercial assay kits72hour post-SE. Second, levels of ROS and themitochondrial transmembrane potential (△Ψm) in the hippocampus weremeasured by flow cytometry. Third, Cytochrome c, activated Caspase3, Bcl-2,and Bax proteins in cytoplasm were measured by Western Blot. Theultrastructure of mitochondria under the three experimental conditions wasexamined by transmission electron microscopy.
Results:
1Compared to the CON group, the level of MDA was significantlyhigher (P<0.05), total SOD and SOD2activities lower (P<0.05), and GSHconcentration lower (P<0.05) in the SE group. These “pro-oxidant” changes inthe SE group were partially reversed in the CIHH+SE group (P<0.05). There were no significant group differences in SOD1activity (P>0.05).
2Compared to the SE group, ROS was significantly lower (P<0.05) and△Ψm significantly greater (P<0.05) in the hippocampus of the CIHH+SEgroup.
3Compared to the CON group, the protein expression levels ofCytochrome c, Caspase3, and Bax, as well as the Bax/Bcl-2ratio weresignificantly higher in the SE group (P<0.05), while expression of Bcl-2wassignificantly lower (P<0.05). These pro-apoptotic changes were partiallyreversed by CIHH preconditioning prior to SE (CIHH+SE group)(P<0.05).
4Compared to the CON group, mitochondria from the SE groupexhibited obvious morphological abnormalities, such as vacuolization, ridgefracture, and membrane damage, effects partially reversed by CIHHpreconditioning.
Conclusion: Mitochondria were damaged by SE, possibly due to freeradical generation and oxidative stress. Preconditioning by CIHH inhibitedoxidative stress and maintained mitochondrial structure and function, possiblyaccounting for the neuroprotection and inhibition of apoptosis observed in theCIHH+SE group compared to the SE group.Part Ⅳ Effect of CIHH on cognitive impairment in SE rats
Objective: To examine if CIHH can reduce cognitive impairments inSE-treated rats with spontaneous recurrent seizures (SRSs) and to determinethe underlying mechanisms.
Methods: Animals were randomly divided into three groups: CON(n=10), SE (n=20), and CIHH+SE (n=20). According to results of ourpreliminary study, SRSs occur1442days after SE. Thus, the Morris watermaze (MWM) test of hippocampus-dependent spatial reference memory wasperformed at day42post-SE. After the MWM test, synaptic ultrastructure inthe hippocampal CA1was examined by electron microscopy and theexpression levels of synaptic proteins PSD-95and Kalirin-7were detected byWestern Blot.
Results: As some rats in the SE group died, the numbers of rats examined by the MWM on day42post-SE were as follows: CON group(n=10), PILO-induced SE group (n=9), CIHH+SE group (n=14).
1In the Morris water maze, all animals exhibited a progressive decline inescape latency starting on the third day of training (P<0.05). Rats in theCIHH+SE group exhibited a significantly shorter escape latency than the SEgroup (P<0.05). On the probe trial, the number of platform crossing wasmarkedly lower (P<0.05) in the SE group and these rats spent significantlyless time in the target quadrant compared to the CON and CIHH+SE group(P<0.05). Thus, SE group rats demonstrated both impaired (hippocampus-dependent) spatial learning during training and poor spatial reference memory.These deficits were partially reversed in the CIHH+SE group as indicated bysignificantly shorter escape latencies and a longer mean time in the targetquadrant compared to the SE group (P<0.05). There were no significant groupdifferences in escape latency and swimming speed in the visible platformversion of the MWM test (P>0.05), indicating that motor and sensory effectscannot account for the effects of CIHH preconditioning on cognition.
2The width of synaptic cleft: The PILO-treated rats exhibitedsignificantly wider synaptic clefts compared to the CON group (P<0.05)(SE:25.20±0.78nm, CIHH+SE:23.13±0.89nm, CON:20.27±0.45nm). AlthoughCIHH reduced the synaptic cleft width, there was no statistical differencebetween SE and CIHH+SE groups (P>0.05).
The thickness of the postsynaptic density (PSD): PILO-treated ratsexhibited a significant decrease in PSD compared to the CON group (P<0.05)(SE:22.67±0.76nm,CIHH+SE:27.87±0.77nm,CON:30.27±0.69nm). However,PSD thickness was significantly greater in the CIHH+SE group compared tothe SE group (P<0.05).
3Expression levels of synaptic proteins: Compared to the CON group(mean density,0.72±0.02), expression levels of PSD-95were significantlylower in the SE and CIHH+SE groups (P<0.05), but expression wassignificantly higher in the CIHH+SE group compared to the SE group(0.40±0.02vs.0.21±0.02, P<0.05). Similarly, compared to the CON group (0.68±0.02), protein expression levels of kalirin-7were significantly lower inthe SE and CIHH+SE groups (P<0.05), but higher in the CIHH+SE groupthan SE group (0.34±0.02vs.0.26±0.02, P<0.05).
Conclusion: PILO-induced SE rats demonstrated significant cognitiveimpairments and changes in hippocampal synaptic ultrastructure.Preconditioning by CIHH partially ameliorated hippocampus-dependentlearning and memory deficits, changes in synaptic ultrastructure, and impairedexpression levels of PSD-95and kalirin-7in the hippocampus. Rescue ofsynaptic dysfunction by CIHH preconditioning may be one of the underlyingmechanisms for improved cognition function.
匹鲁卡品（pilocarpine，PILO）致痫大鼠的行为学、海马神经元损伤的病理形态学及神经电生理学等改变均与人类的TLE相似，因此该模型是目前研究癫痫持续状态（status epilepticus，SE）和TLE的经典模型之一。
SE的致病机制较为复杂，目前尚未完全阐明，主要包括：苔藓纤维芽生假说；Ca2+内流引发的细胞毒性；谷氨酸和γ-氨基丁酸及其受体结构和功能异常；氧化应激损伤及凋亡等。氧化应激是指体内活性氧簇（reactive oxygen species，ROS）产生增多或体内的抗氧化系统出现障碍，体内氧自由基代谢就会失衡，蓄积过多的ROS易导致组织受损。ROS通过直接或间接氧化损伤DNA、诱发基因突变，导致蛋白质和脂质过氧化，激活非选择性钙通道，调节细胞凋亡相关基因，诱导海马神经元发生凋亡。另外，SE时常伴严重的缺氧，易致ROS的增加，而ROS也可直接或间接堆积于线粒体，损伤线粒体膜，降低膜电位，造成线粒体的结构和功能异常，使线粒体内的细胞色素C（Cytochrome c）释放入细胞质，引发caspase级联效应，诱导细胞凋亡。因此，对如何减少氧化应激ROS的产生、保护线粒体并抑制细胞凋亡具有重要的研究意义，探索难治性癫痫的替代治疗或辅助治疗措施便成为当务之急。
目前已发现多种预处理方法可以诱导组织细胞对缺氧产生耐受，包括缺血、高压氧、高温、低温、睡眠剥夺等，这些方法由于本身存在明显的副作用，在临床实际应用方面受到限制。众所周知，低氧容易改变机体的生理功能，严重的低氧往往引起的是一种损伤的病理改变，而最近研究发现适度的低氧预处理对机体则起到一定的保护效应。
研究已证实，低氧预处理可通过抑制肿瘤坏死因子α、上调促红细胞生成素、血管内皮生长因子及Bcl-2抗凋亡蛋白等在海马CA1和CA3区的表达，改善脑缺血缺氧后脑组织的损伤及其导致的认知功能障碍。越来越多的研究报道，慢性间歇性低压低氧（chronic intermittent hypobarichypoxia，CIHH）对机体多种组织、器官均有明显的保护作用，例如增强机体对缺血缺氧的耐受性，对抗缺血/再灌注所致的心脏功能损伤、抑制心肌超微结构受损及钙离子超载、保持钙稳态，并能够有效抗心律失常，保护神经、肝脏、肾脏等组织器官；而且CIHH还具有降压、抗氧化应激、抗凋亡、增强免疫功能等作用。在缺血性脑血管病方面的研究中，CIHH通过上调大鼠脑内的谷氨酸转运体-1（glutamate transporter-1，GLT-1）诱导其产生缺氧耐受性。而CIHH预处理是否对癫痫也具有一定的脑保护作用？目前尚未见报道。有鉴于此，本实验通过制备氯化锂-匹鲁卡品诱导的SE大鼠模型，观察CIHH对致痫大鼠的行为学、脑组织形态学及分子生物学等方面的影响，评价CIHH预处理的保护作用并进一步探讨其可能的作用机制，为此主要致力于以下四个部分的研究：
第一部分CIHH预处理对匹鲁卡品致痫大鼠的脑保护效应
目的：建立匹鲁卡品（pilocarpine，PILO）诱导的SE大鼠模型，研究CIHH预处理对PILO致痫大鼠的脑损伤是否具有保护作用，分别从行为学、形态学及分子生物学等方面进行评价，并初步探讨其作用机制。
方法：
（实验一）将成年健康雄性Sprague-Dawley（SD）大鼠随机分为6组：正常对照组（CON组）和PILO模型组（SE组），根据SE发作后不同的时间点分为SE3h、SE12h、SE24h、SE72h和SE7d五个亚组，每组各10只。应用Nissl染色法和流式细胞仪动态观察SE后不同时间点大鼠的海马神经元凋亡情况，检测该模型制备是否成功。
（实验二）根据目前文献报道：SE后脑组织损伤程度最严重的时间多为发作后72h，我们选取SE72h进行研究，将动物随机分为4组：CON组（n=7），SE组（n=13），CIHH+SE组（n=13），CIHH组（n=7）。利用脑电图观察大鼠的痫性发作潜伏期和癫痫波发放的频率，并记录死亡率；对脑组织一部分行Nissl染色计数海马组织中存活的神经元；另一部分应用流式细胞仪定量分析海马神经元的凋亡情况。
结果：
（实验一）
150只大鼠中，41只被诱发SE，成功率为82％，实验过程中共死亡9只（包括诱发SE成功后的7只），最终可纳入实验的大鼠共34只。CON组无大鼠死亡，10只均可纳入实验。
2Nissl染色：CON组大鼠海马CA1区和CA3区神经元结构完整，无神经元丢失；SE3h组和SE12h组大鼠海马CA1区和CA3区结构相对完整，未见到明显的神经元丢失；SE24h组可见大鼠海马CA1区和CA3区神经元部分丢失；SE72h组神经元丢失明显，且CA1区更严重。而SE7d组海马CA1区神经元的丢失较SE72h组有所减少。
与CON组相比，SE3h组、SE12h组大鼠海马CA1区和CA3区神经元数量几乎无减少（P>0.05）；SE24h组、SE72h组和SE7d组大鼠海马CA1区和CA3区的神经元数量均明显减少（P<0.05）。与SE72h组相比，其它组大鼠海马CA1区和CA3区神经元数量均明显增加（P<0.05）。
3细胞凋亡率：与CON组相比，SE3h组、SE12h组的海马细胞凋亡率均无明显增加（P>0.05），而SE24h组、SE72h组和SE7d的细胞凋亡率有不同程度的增加（P<0.05）。与SE72h组相比，SE24h组和SE7d组海马细胞的凋亡率均有所下降（P<0.05），但后两者间无明显的统计学差异（P>0.05）。与Nissl染色及以往的文献报道结果一致，证明本实验模型制备是成功的、可行的。
(实验二)
1SE组、CIHH+SE组大鼠的死亡率分别为23.1%和0%。与SE组相比，CIHH+SE组的潜伏期延长（33.9±2.3min vs.24.5±1.7min，P<0.05）；癫痫波发放的频率更少（100.5±2.9HZ vs.118.3±4.0HZ，P<0.05）。CON组和CIHH预处理组中大鼠均无SE发作及死亡。
2Nissl染色：CON组大鼠的海马CA1区和CA3区神经元结构完整，几乎无神经元丢失。与CON组相比，SE组大鼠神经元丢失明显；CIHH+SE组神经元结构部分完整，尼氏小体数量较SE组显著增加。CIHH组大鼠的海马区神经元结构相对完整，偶见神经元丢失。
海马神经元存活数：与CON组相比，SE组大鼠海马CA1区和CA3区神经元数量均明显减少（P<0.05）；经CIHH预处理后明显增加了神经元的存活数量（P<0.05）。单纯行CIHH预处理组存活的神经元数量虽然少于CON组，但两者间无明显的统计学差异（P>0.05）。
3细胞凋亡率：与CON组相比，SE组和CIHH+SE组的海马细胞凋亡率均明显增加（P<0.05）；单纯行CIHH组细胞凋亡率虽然稍高于CON组，但两者无明显的统计学差异（P>0.05）。与SE组相比，CIHH+SE组的细胞凋亡率明显减低（P<0.05）。
结论：PILO诱导的SE大鼠模型能较好的动态观察脑损伤后神经元凋亡情况。SE发作后72h时，海马组织CA1区损伤最为严重；CIHH预处理可能通过延长SE大鼠的脑电图痫性放电潜伏期、降低痫性波发放频率来抑制癫痫发作，降低海马神经元的凋亡率。第二部分不同的低氧预处理对匹鲁卡品致痫大鼠的海马损伤作用
目的：已有研究表明，慢性间歇性常压低氧（chronic intermittentnormobaric hypoxia，CINH）对大鼠的脑组织损伤发挥着一定的保护作用。本研究分别从PILO诱导的SE大鼠的SRS、胞浆内钙离子浓度及细胞凋亡率等方面比较两种不同的预处理方式（CIHH和CINH）对大鼠海马损伤的保护作用。
方法：将成年雄性SD大鼠随机分为4组：正常对照组（CON组，n=18），PILO模型组（SE组，n=34），CIHH预处理+SE组（CIHH-Pre组，n=24）和CINH预处理+SE组（CINH-Pre组，n=24）。将每组大鼠分为两部分：一部分应用视频脑电图(V-EEG)观察大鼠SE后自发性癫痫反复发作（SRS）情况（包括SRS的频率、发作级别及持续时间）；另一部分于SE72h时分别应用Nissl和FJB染色法观察大鼠海马的神经元凋亡和变性情况；流式细胞仪检测海马胞浆内钙离子浓度（[Ca2+]i）和细胞凋亡率。
结果：
1PILO诱导的SE大鼠死亡率为47.1%，而CIHH-Pre组和CINH-Pre组SE大鼠的死亡率分别为16.7%和20.8%。
V-EEG记录SRS的情况：CIHH-Pre组和CINH-Pre组出现SRS的频率、严重程度和持续时间均较SE组明显降低（P<0.05）。与CINH-Pre组相比，CIHH-Pre组出现SRS的频率更少（P<0.05），发作级别更低（P<0.05）。CON组大鼠无SRS发作和死亡。
2与CON组相比，SE组海马胞浆内[Ca2+]i明显升高（2.16±0.06vs.1.19±0.03，P<0.05）。与SE组相比，CIHH-Pre组大鼠海马胞浆内[Ca2+]i（1.51±0.03）和CINH-Pre组（1.74±0.03）均明显的降低（P<0.05）；且CIHH-Pre组海马胞浆内[Ca2+]i低于CINH-Pre组（P<0.05）。
3与CON组相比，SE组大鼠海马的神经元丢失明显；而CIHH-Pre组和CINH-Pre组神经元丢失的程度较SE组减轻。SE组大鼠海马CA1区和CA3区的存活神经元数量均较CON组明显减少（P<0.05）。与SE组相比，CIHH-Pre组和CINH-Pre组均明显地增加了大鼠海马CA1区和CA3区的神经元数量（P<0.05）；而CINH-Pre组CA1区的存活神经元数量仍低于CIHH-Pre组（55.00±1.07vs.74.83±1.40，P<0.05）。
4CON组未见明显的FJB阳性细胞。与CON组相比，PILO诱导的SE组海马CA1区和CA3区可见呈黄绿色荧光的FJB阳性细胞明显增多。CIHH-Pre组和CINH-Pre组大鼠海马CA1区和CA3区均明显减少了FJB阳性细胞（P<0.05）,且CIHH-Pre组CA1区的FJB阳性细胞数少于CINH-Pre组（P<0.05）。
5PILO诱导的SE组大鼠海马细胞早期凋亡率（Q4）和总的凋亡率（Q2+Q4）均明显高于CON组（P<0.05）。与SE组相比，CIHH-Pre组和CINH-Pre组均明显地降低了海马细胞的凋亡率（P<0.05），且CIHH-Pre组的凋亡率低于CINH-Pre组（P<0.05）。
结论：PILO诱导的SE大鼠容易出现SRS行为，使海马组织细胞内[Ca2+]i升高，导致神经元损伤。CIHH和CINH预处理均可通过有效地抑制SE大鼠的SRS行为和胞浆内钙离子超载来营救损伤的海马神经元，且CIHH预处理措施可能更有效。
第三部分CIHH对匹鲁卡品致痫大鼠的海马抗氧化防御体系的影响
目的：研究CIHH预处理是否对癫痫发作产生的氧化应激及线粒体损伤具有一定的保护作用，并探讨可能的作用机制。
方法：将成年雄性SD大鼠随机分为3组：正常对照组（CON组），PILO模型组（SE组）和CIHH预处理+SE组（CIHH+SE组），每组各20只。于SE发作后72h时，首先制作大鼠海马组织的匀浆液，根据试剂盒说明分别检测MDA含量、总SOD、SOD1、SOD2及GSH的活力；然后应用流式细胞仪检测海马组织细胞内ROS、线粒体膜电位（mitochondrial transmembranepotential，△Ψm）的水平；Western Blot检测胞浆中Cytochrome c、Caspase3、Bcl-2、Bax蛋白的表达；并结合透射电镜观察线粒体的超微结构。
结果：
1与CON组相比，SE组大鼠海马内MDA的水平明显升高（P<0.05）；总的SOD和SOD2的活力均明显降低（P<0.05），GSH的含量也明显降低（P<0.05），而CIHH+SE组可不同程度地逆转上述指标的异常改变（P<0.05）。SODl在各实验组间则无明显差异（P>0.05）。
2与SE组相比， CIHH+SE组能明显降低海马细胞内ROS的水平（P<0.05），明显升高△Ψ的水平（P<0.05）。
3与CON组相比，SE组大鼠海马组织胞浆内Cytochrome c，Caspase3，Bax，及Bax/Bcl-2蛋白的水平均明显升高（P<0.05），而Bcl-2蛋白水平显著降低（P<0.05）。CIHH预处理后均可不同程度地逆转上述蛋白的表达水平（P<0.05）。
4与CON组相比，SE组中线粒体的超微结构发生明显改变，表现为广泛的空泡化、严重的嵴断裂伴膜破坏；而CIHH+SE组可部分改善线粒体的结构变化。
结论：SE发作后线粒体可能是自由基攻击的靶点。CIHH预处理可通过增强大鼠海马组织的抗氧化应激能力，改善线粒体的结构和功能来发挥神经元的保护作用。第四部分CIHH对匹鲁卡品致痫大鼠认知功能的改善作用和机制探讨
目的：研究CIHH预处理对SE大鼠的认知功能障碍、海马组织中突触的超微结构和突触相关蛋白的表达有何影响，进一步探讨相关的作用机制。
方法：将成年雄性SD大鼠随机分为3组：正常对照组（CON组，n=10）和PILO模型组（SE组，n=20）和CIHH预处理+SE组（CIHH+SE组，n=20）。根据文献报道及我们前期的实验结果表明：SE发作后多于14-42d出现SRS行为，由此我们选取SE发作后42d时，进行Morris水迷宫行认知功能检测；结束后分别应用透射电镜观察海马CA1区突触的超微结构；WesternBlot法检测胞浆中PSD-95和Kalirin-7蛋白的表达。
结果：由于大鼠经SE发作后部分出现死亡，本部分实验中SE发作后42d时，各组大鼠的存活情况：CON组10只，PILO诱导的SE组9只，CIHH+SE组14只。
1水迷宫检测：随着训练时间的延长，从第3d开始，各组大鼠寻找平台的潜伏期均逐渐缩短（P<0.05）。CIHH预处理组较SE组的潜伏期明显缩短（P<0.05）。在空间探索试验中，与CON组相比，SE组大鼠的穿台次数明显减低（5.33±0.58vs.11.8±0.76，P<0.05），在目标象限停留时间也明显缩短（52.78±2.00s vs.86.80±1.67s，P<0.05）；而CIHH+SE组大鼠的穿台次数（7.86±0.44）较SE组有所增加（P<0.05），在目标象限停留时间（67.36±2.06s）也明显延长（P<0.05）。在可视平台试验中，各组间大鼠的逃避潜伏期和游泳速度均无明显的统计学差异（P>0.05）。
2突触间隙宽度:与CON组相比（20.27±0.45nm），SE组和CIHH+SE组大鼠海马的突触间隙均显著增宽（P<0.05）。虽然CIHH+SE组的突触间隙较SE缩窄，但两者无明显的统计学差异（23.13±0.89nm vs.25.20±0.78nm，P>0.05）。
突触后致密物厚度：与CON组相比（30.27±0.69nm），SE组和CIHH+SE组大鼠海马的突触后致密物厚度均显著降低（P<0.05）；而CIHH+SE组较SE组明显增加（27.87±0.77nm vs.22.67±0.76nm，P<0.05）。
3PSD-95蛋白：与CON组相比（0.72±0.02），SE组和CIHH+SE组中大鼠海马的胞浆内PSD-95蛋白的表达水平均显著降低（P<0.05）；而CIHH+SE组中表达的水平明显高于SE组（0.40±0.02vs.0.21±0.02，P<0.05）。
Kalirin-7蛋白：与CON组相比(0.68±0.02)，SE组和CIHH+SE组中大鼠海马胞浆内Kalirin-7蛋白水平均显著降低（P<0.05）；而CIHH+SE组的表达水平高于SE组（0.34±0.02vs.0.26±0.02，P<0.05）。
结论： PILO诱导的SE大鼠长期反复发作可出现明显的认知功能障碍和海马突触结构的损伤。CIHH预处理可有效改善受损的突触超微结构并上调突触相关蛋白的表达，这可能是CIHH改善癫痫发作后认知功能障碍的机制之一。
Epilepsy is one of the most common neurological disorders, afflictingmore than9million individuals in China according to domesticepidemiological investigations. Among patients with epilepsy, about25%-40%suffers from intractable epilepsy resistant to currently available antiepilepticdrugs (AEDs). Many such cases are of temporal lobe epilepsy (TLE),characterized by spontaneous recurrent seizures (SRS) and progressivehippocampal sclerosis. Clinical investigations have shown that over half ofepilepsy patients suffer from cognitive impairments due to neurologicaldamage associated with frequent seizures and (or) the side-effects oflong-term AED use. This cognitive dysfunction imposes an even heavierburden on epileptic individuals, their families, and society.
The rat pilocarpine (PILO)-induced seizure model exhibits many of theclinical, behavioral, and neuropathological hallmarks of TLE and statusepilepticus (SE), and so is advantageous for preclinical testing of noveltreatment strategies.
The pathogenesis of TLE is complex and may involve a combination ofrecurrent mossy fiber sprouting, excitotoxicity induced by neuronal calciuminflux, abnormal glutamate and γ-aminobutyric acid (GABA) receptorstructure and function, and oxidative stress with ensuing apoptosis. Oxidativestress occurs when production of reactive oxygen species (ROS) exceeds thecapacity of endogenous cellular antioxidant defense systems, resulting inmitochondrial dysfunction and destruction of macromolecules such asmembrane lipids. Status epilepticus is often associated with severe brainhypoxia. Reperfusion of hypoxic tissue is associated with ROS accumulationin mitochondria, which can damage mitochondrial membranes, decreasing the mitochondrial transmembrane potential, inducing mitochondrial cytochrome crelease into the neuronal cytoplasm, and activating the caspase cascadeleading to apoptosis. Reducing ROS production during SE to protectmitochondria and inhibit neuronal apoptosis is a possible replacement oradjuvant therapy for intractable epilepsy.
A variety of pretreatment or preconditioning methods can induce hypoxicand oxidative stress tolerance, including mild transient ischemia, hyperbaricoxygen, hyperthermia, hypothermia, sleep deprivation. However, clinicalapplication of many of these methods is limited by potential side effects.Severe hypoxia often leads to pathological changes, but recent studies havethat shown moderate transient hypoxia is a physiologically importantmechanism for maintaining or enhancing endogenous cytoprotection.
Hypoxic preconditioning can inhibit tumor necrosis factor alphaexpression while raising erythropoietin, vascular endothelial growth factor,and anti-apoptotic Bcl-2expression in hippocampal CA1and CA3subfields.In vivo, hypoxic preconditioning can prevent hippocampal damage fromischemia/hypoxia and prevent associated cognitive dysfunction. Accumulatingevidence indicates that chronic intermittent hypobaric hypoxia (CIHH)enhances cardiac tolerance against subsequent ischemia/hypoxia, reducesheart damaged due to ischemia/reperfusion, inhibits ultrastructural damageand calcium overload in cardiac myocytes, maintains myocyte calciumhomeostasis, and prevents arrhythmia. In addition, CIHH has been shown toprotect nerve, liver, kidney, and other organs against subsequent severehypoxic insults. Furthermore, CIHH lowers blood pressure, reduces oxidativestress and apoptosis, and enhances immune function. In a rat model ofischemic cerebrovascular disease, CIHH enhanced ischemic resistance byupregulating brain expression of glutamate transporter-1(GLT-1). However,whether CIHH preconditioning may protect against SE or not, there was noreported. In this study, we examined the effects of CIHH preconditioning onbehavioristics of rat lithium-pilocarpine model of TLE, hippocampal neuronsurvival (morphology), and molecular biology in order to further explore the underling mechanisms.
PartⅠ Neuroprotective effect of CIHH preconditioning on pilocarpine-induced seizures in rats
Objective: To establish a pilocarpine (PILO)-induced SE rat model andevaluate the efficacy of CIHH preconditioning for preventing SE-associateddeath of hippocampal neurons and preserving hippocampal function.
Methods:(Experiment1) Healthy adult male Sprague-Dawley rats wererandomly divided into six groups of10: a normal control (CON group) and5PILO groups (SE groups) sacrificed3h,12h,24h,72h, and7days post-SE(SE3h, SE12h, SE24h, SE72h and SE7d groups, respectively). Nissl stainingand flow cytometry were used to assess morphological damage and apoptosisof hippocampal neurons post-SE.(Experiment2) According to previousreports,72h post-SE is the peak time of SE-associated brain damage, so thistime point was selected to examine the neuroprotective effects of CIHHpreconditioning. Animals were randomly divided into four groups: CON (n=7),SE (n=13), CIHH+SE (n=13), CIHH (n=7). Rat mortality from0-72h post-SEwas determined and electroencephalograms (EEGs) were recorded to measurethe frequency, severity, and duration of epileptiform discharges. Hippocampaltissues were then isolated to assess morphological damage and neuronalsurvival by Nissl staining and neuronal apoptosis rate by flow cytometery.
Results:
(Experiment1)
1Status epilepticus was induced by PILO in41of50rats (success rate,82%). Seven SE group rats died during the procedure. The remaining34PILO-treated rats were analyzed and compared to the10(surviving) CONgroup rats.
2Nissl staining: In the CON group, there was almost no visible neuronalloss in CA1and CA3subfields. Similarly, SE3h and SE12h groups showed noobvious neuronal loss and neuronal morphology resembled that of the CONgroup. Neuronal loss was apparent in the CA1and CA3regions of the SE24hgroup. In the SE72h group, neuron loss appeared even greater, especially in CA1. Neuronal loss in the CA1of the SE7d group was clearly lower than inthe SE72h group. Cell counting revealed that the numbers of survivingneurons in the SE3h and SE12h groups were not significantly different fromthe CON group (P>0.05), while significant reductions were observed in theSE24h, SE72h, and SE7d groups compared to the CON group (P<0.05).Neuronal survival was significantly higher in all other SE groups compared tothe SE72h group (P<0.05).
3Flow cytometry: Compared to the CON group, neuronal apoptosis rateswere significantly higher in the SE24h, SE72h, and SE7d groups (P<0.05), butnot in the SE3h and SE12h groups (P>0.05). Apoptosis rates in SE24h andSE7d groups were not significantly different (P>0.05) but were bothsignificantly lower compared than in the SE72h group (P<0.05). Thus, PILOinduced neuronal death in the hippocampus, peaking at72h post-SE.
(Experiment2)
1Mortality was23.1%in the SE group, while no deaths were observed inthe CIHH+SE group. Compared to the SE group, the latency to reach SE waslonger (P<0.05) and the frequency of EEG-defined epileptic discharges lower(P<0.05) in the CIHH+SE group. There was no mortality or seizures in theCON and CIHH groups.
2Nissl staining: Neurons in CA1and CA3subfields of the CON groupwere clearly stained and there was almost no neuronal loss, while neuronal losswas clearly visible in the SE group. Neuronal cell death was partially reversedin the CIHH+SE group and fewer neurons showed morphological signs ofdamage in both CA1and CA3subfields compared to the SE group. There wasvery slight neuronal loss in the CIHH group. Cell counting revealed asignificant decrease in neuronal survival in the SE group compared to the CONgroup (P<0.05), while the number of surviving neurons was significantlyhigher in the CIHH+SE group compared to the SE group (P<0.05). Althoughthe number of surviving hippocampal neurons was lower in the CIHH groupthan the CON group, there was no significant statistical difference (P>0.05).
3Flow cytometry: The numbers of apoptotic neurons were significantly higher in the SE and SE+CIHH groups compared to the CON group (P<0.05).However, apoptotic rate was significantly lower in the CIHH+SE groupcompared to the SE group (P<0.05), indicating partial rescue from apoptosisby CIHH preconditioning. The rate of neuronal apoptosis was slightly higher inthe CIHH group compared to the CON group, but the difference was notstatistically significant (P>0.05).
Conclusion: The PILO-induced SE rat model allows for dynamicobservation of progressive hippocampal neuronal injury and apoptosis. At72hafter SE, damage was more severe in the CA1. Preconditioning with CIHHprolonged SE latency and reduced seizure frequency, PILO-induced mortality,morphological signs of hippocampal neuronal damage, and neuronalapoptosis.PartⅡ Effects of different hypoxic preconditioning protocols on thehippocampal damage of status epileptic rats
Objective: Chronic intermittent normobaric hypoxia (CINH）has beenproved playing an important role in protecting the damaged brain of rats. Inthis study, we compared the effects of different hypoxic preconditioningprotocols (CIHH and CINH) on spontaneous recurrent seizures (SRS),intracellular free calcium concentration ([Ca2+]i), and apoptosis rate followingPILO-induced status epilepticus (SE).
Methods: Adult male Sprague-Dawley rats were randomly divided intofour groups: normal control group (CON group, n=18), PILO group (SE group,n=34), CIHH+SE group (CIHH-Pre, n=24) and CINH+SE group (CINH-Pre,n=24). The rats in each group were divided into two parts: a part of that wascompared by video monitoring of behavioral seizure activity (frequency, rank,and duration); another part of that were used to examine changes in themorphology of hippocampal pyramidal neurons by menas of Nissl stainingand Fluoro-Jade B (FJB) staining, and further to detect the quantification of[Ca2+]i and cell apoptosis by means of flow cytometry at SE72hour.
Results:
1Mortality and SRS of rats induced by PILO: In the SE group, mortality rate was47.1%, while in the CIHH-Pre group and CINH-Pre group, mortalityrate was16.7%and20.8%, respectively.
SRS by the V-EEG: There was a significant decrease in the number,mean severity, and duration of seizures in both CIHH-treated andCINH-treated SE rats compared to those treated by PILO (P<0.05). However,the CIHH-Pre protocol induced a greater reduction in both seizure frequencyand severity compared to the CINH-Pre group (P<0.05). There was no SRSseizures and animal died in the CON group.
2Comparation of the [Ca2+]i: A substantial increase was measured in theSE group compared to the CON group (P<0.05), while both CIHH-Pre andCINH-Pre significantly reduced the post-SE [Ca2+]i elevation compared to theSE group (P<0.05). Hippocampal [Ca2+]i was lower in the CIHH-Pre groupthan that of the CINH-Pre group (P<0.05).
3Nissl staining: There was a marked loss of neurons in CA1and CA3subfields of SE group compared to the CON group. Compared to the SE group,there was a significantly reduced neuronal loss in the CIHH-Pre andCINH-Pre groups.
The number of surviving neurons in both subfields of the hippocampus inSE group obviously decrease compared to the CON group (P<0.05).Compared to the SE group, the number of neurons was significantly increasein the CIHH-Pre and CINH-Pre groups (P<0.05), while the average CA1pyramidal neuron density was lower in the CINH-Pre group than in theCIHH-Pre group (P<0.05).
4FJB staining: No FJB-positive cell was observed in the CON group.Many FJB-positive cells with kelly fluorescent were observed in the CA1andCA3subfields in the SE group. CIHH-Pre and CINH-Pre groups showed asignificant reduction in the number of FJB-positive cells in the CA1and CA3subfiels (P<0.05). The average numbers of FJB-positive cells in the CA1subfield was lower in the CIHH-Pre group than in the CINH-Pre group(P<0.05).
5Apoptosis rate of the hippocampus: Both the number of cells in early apoptosis (Q4) and total apoptotic cells (Q2+Q4) were significantly higher inthe SE group than in the CON group (P<0.05). Both the CIHH-Pre group andthe CINH-Pre group exhibited markedly reduced apoptosis rate compared tothe SE group (P<0.05). Moreover, apoptosis rate was lower in the CIHH-Pregroup than in the CINH-Pre group (P<0.05).
Conclusion: SE rats induced by PILO prone to SRS leads to neuronaldamage of hippocampus by increasing the [Ca2+]i. CIHH-Pre and CINH-Precan effectively inhibit the SRS behavior and reduce the post-SE [Ca2+]i so asto rescue the hippocampal neurons. What’s more, hypobaric preconditioningmay be more effective.Part Ⅲ Effect of CIHH on the antioxidant defense system of thehippocampus in epileptic rats
Objective: To examine whether CIHH preconditioning protects againstoxidative stress and mitochondrial damage induced by SE and to explore theunderlying mechanisms.
Methods: Animals were randomly divided into three groups: CON(n=20), SE (n=20), and CIHH+SE (n=20). Following these treatments,homogenates were prepared from hippocampus to measure MDAaccumulation, an index of oxidative stress, as well as the activities of theantioxidants superoxide dismutase (SOD) isoforms and glutathione (GSH)using commercial assay kits72hour post-SE. Second, levels of ROS and themitochondrial transmembrane potential (△Ψm) in the hippocampus weremeasured by flow cytometry. Third, Cytochrome c, activated Caspase3, Bcl-2,and Bax proteins in cytoplasm were measured by Western Blot. Theultrastructure of mitochondria under the three experimental conditions wasexamined by transmission electron microscopy.
Results:
1Compared to the CON group, the level of MDA was significantlyhigher (P<0.05), total SOD and SOD2activities lower (P<0.05), and GSHconcentration lower (P<0.05) in the SE group. These “pro-oxidant” changes inthe SE group were partially reversed in the CIHH+SE group (P<0.05). There were no significant group differences in SOD1activity (P>0.05).
2Compared to the SE group, ROS was significantly lower (P<0.05) and△Ψm significantly greater (P<0.05) in the hippocampus of the CIHH+SEgroup.
3Compared to the CON group, the protein expression levels ofCytochrome c, Caspase3, and Bax, as well as the Bax/Bcl-2ratio weresignificantly higher in the SE group (P<0.05), while expression of Bcl-2wassignificantly lower (P<0.05). These pro-apoptotic changes were partiallyreversed by CIHH preconditioning prior to SE (CIHH+SE group)(P<0.05).
4Compared to the CON group, mitochondria from the SE groupexhibited obvious morphological abnormalities, such as vacuolization, ridgefracture, and membrane damage, effects partially reversed by CIHHpreconditioning.
Conclusion: Mitochondria were damaged by SE, possibly due to freeradical generation and oxidative stress. Preconditioning by CIHH inhibitedoxidative stress and maintained mitochondrial structure and function, possiblyaccounting for the neuroprotection and inhibition of apoptosis observed in theCIHH+SE group compared to the SE group.Part Ⅳ Effect of CIHH on cognitive impairment in SE rats
Objective: To examine if CIHH can reduce cognitive impairments inSE-treated rats with spontaneous recurrent seizures (SRSs) and to determinethe underlying mechanisms.
Methods: Animals were randomly divided into three groups: CON(n=10), SE (n=20), and CIHH+SE (n=20). According to results of ourpreliminary study, SRSs occur1442days after SE. Thus, the Morris watermaze (MWM) test of hippocampus-dependent spatial reference memory wasperformed at day42post-SE. After the MWM test, synaptic ultrastructure inthe hippocampal CA1was examined by electron microscopy and theexpression levels of synaptic proteins PSD-95and Kalirin-7were detected byWestern Blot.
Results: As some rats in the SE group died, the numbers of rats examined by the MWM on day42post-SE were as follows: CON group(n=10), PILO-induced SE group (n=9), CIHH+SE group (n=14).
1In the Morris water maze, all animals exhibited a progressive decline inescape latency starting on the third day of training (P<0.05). Rats in theCIHH+SE group exhibited a significantly shorter escape latency than the SEgroup (P<0.05). On the probe trial, the number of platform crossing wasmarkedly lower (P<0.05) in the SE group and these rats spent significantlyless time in the target quadrant compared to the CON and CIHH+SE group(P<0.05). Thus, SE group rats demonstrated both impaired (hippocampus-dependent) spatial learning during training and poor spatial reference memory.These deficits were partially reversed in the CIHH+SE group as indicated bysignificantly shorter escape latencies and a longer mean time in the targetquadrant compared to the SE group (P<0.05). There were no significant groupdifferences in escape latency and swimming speed in the visible platformversion of the MWM test (P>0.05), indicating that motor and sensory effectscannot account for the effects of CIHH preconditioning on cognition.
2The width of synaptic cleft: The PILO-treated rats exhibitedsignificantly wider synaptic clefts compared to the CON group (P<0.05)(SE:25.20±0.78nm, CIHH+SE:23.13±0.89nm, CON:20.27±0.45nm). AlthoughCIHH reduced the synaptic cleft width, there was no statistical differencebetween SE and CIHH+SE groups (P>0.05).
The thickness of the postsynaptic density (PSD): PILO-treated ratsexhibited a significant decrease in PSD compared to the CON group (P<0.05)(SE:22.67±0.76nm,CIHH+SE:27.87±0.77nm,CON:30.27±0.69nm). However,PSD thickness was significantly greater in the CIHH+SE group compared tothe SE group (P<0.05).
3Expression levels of synaptic proteins: Compared to the CON group(mean density,0.72±0.02), expression levels of PSD-95were significantlylower in the SE and CIHH+SE groups (P<0.05), but expression wassignificantly higher in the CIHH+SE group compared to the SE group(0.40±0.02vs.0.21±0.02, P<0.05). Similarly, compared to the CON group (0.68±0.02), protein expression levels of kalirin-7were significantly lower inthe SE and CIHH+SE groups (P<0.05), but higher in the CIHH+SE groupthan SE group (0.34±0.02vs.0.26±0.02, P<0.05).
Conclusion: PILO-induced SE rats demonstrated significant cognitiveimpairments and changes in hippocampal synaptic ultrastructure.Preconditioning by CIHH partially ameliorated hippocampus-dependentlearning and memory deficits, changes in synaptic ultrastructure, and impairedexpression levels of PSD-95and kalirin-7in the hippocampus. Rescue ofsynaptic dysfunction by CIHH preconditioning may be one of the underlyingmechanisms for improved cognition function.
引文
1Ding D, Hong Z, Chen GS, et al. Primary care treatment of epilepsy withphenobarbital in rural China: cost-outcome analysis from the WHO/ILAE/IBE global campaign against epilepsy demonstration project. Epilepsia,2008,49(3):535-9
2Antonucci F, Bozzi Y, Caleo M. Intrahippocampal infusion of botulinumneurotoxin E (BoNT/E) reduces spontaneous recurrent seizures in a mousemodel of mesial temporal lobe epilepsy. Epilepsia,2009,50(4):963-6
3Zhang HD, Xie YC, Weng L, et al. Rapamycin improves learning andmemory ability in ICR mice with pilocarpine-induced temporal lobeepilepsy. Journal of Zhejiang University. Medical sciences,2013,42(6):602-8
4Smeland OB, Hadera MG, McDonald TS, et al. Brain mitochondrialmetabolic dysfunction and glutamate level reduction in the pilocarpinemodel of temporal lobe epilepsy in mice. J Cereb Blood Flow Metab,2013,33(7):1090-7
5Aur D. Understanding the physical mechanism of transition to epilepticseizures. J Neurosci Methods,2011,200(1):80-5
6Deepa D, Jayakumari N, Thomas SV. Oxidative stress is increased inwomen with epilepsy: Is it a potential mechanism of anti-epilepticdrug-induced teratogenesis. Ann Indian Acad Neurol,2012,15(4):281-6
7Dayton C, Yamaguchi T, Warren A, et al. Ischemic preconditioningprevents postischemic arteriolar, capillary, and postcapillary venulardysfunction: signaling pathways mediating the adaptive metamorphosis toa protected phenotype in preconditioned endothelium. Microcirculation,2002,9(2):73-89
8Li J, Liu W, Ding S, et al. Hyperbaric oxygen preconditioning inducestolerance against brain ischemia-reperfusion injury by upregulation ofantioxidant enzymes in rats. Brain Res,2008,1210:223-9
9Kim SM, Kim H, Lee JS, et al. Intermittent hypoxia can aggravate motorneuronal loss and cognitive dysfunction in ALS mice. PLoS One,2013,8(11): e81808
10Bourque SL, Kuny S, Reyes LM, et al. Prenatal hypoxia is associated withlong-term retinal dysfunction in rats. PLoS One,2013,8(4): e61861
11Churilova AV, Rybnikova EA, Glushchenko TS, et al. Effects of moderatehypobaric hypoxic preconditioning on the expression of the transcriptionfactors pCREB and NF-kappaB in the rat hippocampus before and aftersevere hypoxia. Neurosci Behav Physiol,2010,40(8):852-7
12Guner I,Yelmen N,Sahin G,et al. Respiratory alterations due to chroniclong-term intermittent hypobaric hypoxia in rabbits: importance ofperipheral chemoreceptors. Arch Med Res,2007,38(7):739-45
13Zhou JJ, Wei Y, Zhang L, et al. Chronic intermittent hypobaric hypoxiaprevents cardiac dysfunction through enhancing antioxidation infructose-fed rats. Can J Physiol Pharmacol,2013,91(5):332-7
14Guo HC, Guo F, Zhang LN, et al. Enhancement of Na/K pump activity bychronic intermittent hypobaric hypoxia protected against reperfusioninjury. Am J Physiol Heart Circ Physiol,2011,300(6): H2280-7
15Guo HC, Zhang Z, Zhang LN, et al. Chronic intermittent hypobarichypoxia protects the heart against ischemia/reperfusion injury throughupregulation of antioxidant enzymes in adult guinea pigs. Acta PharmacolSin,2009,30(7):947-55
16Shi M, Cui F, Yang CY, et al. Effects of chronic intermittent hypobarichypoxia on immune function in rat. Chinese journal of applied physiology,2009,25(4):433-8
17Guner I, Uzun DD, Yaman MO, et al. The effect of chronic long-termintermittent hypobaric hypoxia on bone mineral density in rats: role ofnitric oxide. Biol Trace Elem Res,2013,154(2):262-7
18Shi M, Cui F, Liu AJ, et al. Protection of chronic intermittent hypobarichypoxia against collagen-induced arthritis in rat through increasingapoptosis. Acta physiologica Sinica,2011,63(2):115-23
19Gamdzyk M, Makarewicz D, Slomka M, et al. Hypobaric HypoxiaPostconditioning Reduces Brain Damage and Improves AntioxidativeDefense in the Model of Birth Asphyxia in7-Day-Old Rats. NeurochemRes,2014,39(1):68-75
20Gong SJ, Chen LY, Zhang M, et al. Intermittent hypobaric hypoxiapreconditioning induced brain ischemic tolerance by up-regulating glialglutamate transporter-1in rats. Neurochem Res,2012,37(3):527-37
21Jones NM, Lee EM, Brown TG, et al. Hypoxic preconditioning producesdifferential expression of hypoxia-inducible factor-1alpha (HIF-1alpha)and its regulatory enzyme HIF prolyl hydroxylase2in neonatal rat brain.Neurosci Lett,2006,404(1-2):72-7
22Racine RJ. Modification of seizure activity by electrical stimulation. II.Motor seizure. Electroencephalography and clinical neurophysiology,1972,32(3):281-94
23Li LY, Li JL, Zhang HM, et al. TGFbeta1treatment reduces hippocampaldamage, spontaneous recurrent seizures, and learning memory deficits inpilocarpine-treated rats. J Mol Neurosci,2013,50(1):109-23
24Gao F, Liu Y, Li X, et al. Fingolimod (FTY720) inhibits neuroinflamm-ation and attenuates spontaneous convulsions in lithium-pilocarpineinduced status epilepticus in rat model. Pharmacol Biochem Behav,2012,103(2):187-96
25da SVG, da SRS, de Paula Cognato G, et al. A ketogenic diet did notprevent effects on the ectonucleotidases pathway promoted by lithium-pilocarpine-induced status epilepticus in rat hippocampus. Metab BrainDis,2012,27(4):471-8
26Savolainen KM, Hirvonen MR. Second messengers in cholinergic-induced convulsions and neuronal injury. Toxicol Lett,1992,64-65SpecNo:437-45
27Einat H, Kofman O, Itkin O, et al. Augmentation of lithium's behavioraleffect by inositol uptake inhibitors. Journal of neural transmission,1998,105(1):31-8
28Arisi GM, Ruch M, Foresti ML, et al. Astrocyte Alterations in theHippocampus Following Pilocarpine-induced Seizures in Aged Rats.Aging Dis,2011,2(4):294-300
29Smilin BAG, Sivasudha T, Suganya M, et al. Trichosanthes tricuspidatamodulates oxidative toxicity in brain hippocampus against pilocarpineinduced status epilepticus in mice. Neurochem Res,2013,38(8):1715-25
30Scholl EA, Dudek FE, Ekstrand JJ. Neuronal degeneration is observed inmultiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat. Neuroscience,2013,252:45-59
31Xia Y, Luo C, Dai S, et al. Increased EphA/ephrinA expression inhippocampus of pilocarpine treated mouse. Epilepsy Res,2013,105(1-2):20-9
32Liu J, Wang A, Li L, et al. Oxidative stress mediates hippocampal neurondeath in rats after lithium-pilocarpine-induced status epilepticus. Seizure,2010,19(3):165-72
33Atanasova M, Petkova Z, Pechlivanova D, et al. Strain-dependent effectsof long-term treatment with melatonin on kainic acid-induced statusepilepticus, oxidative stress and the expression of heat shock proteins.Pharmacol Biochem Behav,2013,111:44-50
34Ahmad M. Protective effects of curcumin against lithium-pilocarpineinduced status epilepticus, cognitive dysfunction and oxidative stress inyoung rats. Saudi journal of biological sciences,2013,20(2):155-62
35Gao CJ, Niu L, Ren PC, et al. Hypoxic preconditioning attenuates globalcerebral ischemic injury following asphyxial cardiac arrest throughregulation of delta opioid receptor system. Neuroscience,2012,202:352-62
36Tokunaga H, Hiramatsu K, Sakaki T. Effect of preceding in vivo sublethalischemia on the evoked potentials during secondary in vitro hypoxiaevaluated with gerbil hippocampal slices. Brain Res,1998,784(1-2):316-20
37Wick A, Wick W, Waltenberger J, et al. Neuroprotection by hypoxicpreconditioning requires sequential activation of vascular endothelialgrowth factor receptor and Akt. The Journal of neuroscience: the officialjournal of the Society for Neuroscience,2002,22(15):6401-7
38Emerson MR, Nelson SR, Samson FE, et al. Hypoxia preconditioningattenuates brain edema associated with kainic acid-induced statusepilepticus in rats. Brain Res,1999,825(1-2):189-93
39Churilova AV, Rybnikova EA, Glushchenko TS, et al. Effect of mildhypobaric hypoxia in the preconditioning regime on expression of pCREBand NF-kappaB transcription factors in the rat hippocampus before andafter severe hypoxia. Morfologiia,2009,136(6):38-42
40Lee DS, Ryu HJ, Kim JE, et al. The effect of levetiracetam on statusepilepticus-induced neuronal death in the rat hippocampus. Seizure,2013,22(5):368-77
41Costa DC, Alva N, Trigueros L, et al. Intermittent hypobaric hypoxiainduces neuroprotection in kainate-induced oxidative stress in rats. J MolNeurosci,2013,50(3):402-10
1Vorob'ev LP, AIa C, Potievskaia VI. The possibilities of using intermittentnormobaric hypoxia for treating hypertension patients. Terapevticheskiiarkhiv,1994,66(8):12-5
2Ragozin ON, Balykin MV, Charikova EI. The biorhythmologicalregulation of external breathing in bronchial asthma patients by usingintermittent normobaric hypoxia therapy. Voprosy kurortologii,2000,(4):45-6
3Starykh EV, Fedin AI. Computer-assisted EEG in epileptic patients treatedwith intermittent normobaric hypoxic therapy in combined treatment ofepilepsy. Vserossiiskoe obshchestvo psikhiatrov,2002,102(3):27-9
4Bailey DM, Davies B, Baker J. Training in hypoxia: modulation ofmetabolic and cardiovascular risk factors in men. Med Sci Sports Exerc,2000,32(6):1058-66
5Berezovskii VA, Levashov MI. The build-up of human reserve potentialby exposure to intermittent normobaric hypoxia. Aerospace andenvironmental medicine,2000,34(2):39-43
6Wilber RL. Current trends in altitude training. Sports medicine,2001,31(4):249-65
7吕国蔚,崔秀玉,赵兰峰,等。低氧预适应的脑机制。中国应用生理学杂志,2004,(01):99-104
8Phillis JW, Ren J, O'Regan MH. Transporter reversal as a mechanism ofglutamate release from the ischemic rat cerebral cortex: studies withDL-threo-beta-benzyloxyaspartate. Brain Res,2000,880(1-2):224
9Delcamp TJ, Dales C, Ralenkotter L, et al. Intramitochondrial [Ca2+] andmembrane potential in ventricular myocytes exposed to anoxia-reoxygenation. Am J Physiol,1998,275(2Pt2): H484-94
10Weinberg JM, Venkatachalam MA, Roeser NF, et al. Mitochondrialdysfunction during hypoxia/reoxygenation and its correction by anaerobicmetabolism of citric acid cycle intermediates. Proc Natl Acad Sci U S A,2000,97(6):2826-31
11LoPachin RM, Gaughan CL, Lehning EJ, et al. Effects of ion channelblockade on the distribution of Na, K, Ca and other elements inoxygen-glucose deprived CA1hippocampal neurons. Neuroscience,2001,103(4):971-83
12Singh BK, Tripathi M, Pandey PK, et al. Alteration in mitochondrial thiolenhances calcium ion dependent membrane permeability transition anddysfunction in vitro: a cross-talk between mtThiol, Ca2+, and ROS. MolCell Biochem,2011,357(1-2):373-85
13Li LY, Li JL, Zhang HM, et al. TGFbeta1treatment reduces hippocampaldamage, spontaneous recurrent seizures, and learning memory deficits inpilocarpine-treated rats. J Mol Neurosci,2013,50(1):109-23
14Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol,2003,16(2):165-70
15Xiang J, Jiang Y. Long-term VEEG monitoring and intracranial electrodeEEG monitoring in the surgical treatment of temporal lobe epilepsy.Journal of Central South University. Medical sciences,2013,38(1):31-5
16Si Y, Liu L, Fang JJ, et al. Evaluation of the efficiency of inpatient24-hourVEEG combined with MRI in consecutive patients with newly diagnosedepilepsies. Epilepsy Behav,2011,20(4):633-7
17Geinisman Y, Detoledo-Morrell L, Morrell F, et al. Synapse restructuringassociated with the maintenance phase of hippocampal long-termpotentiation. J Comp Neurol,1996,368(3):413-23
18Jones OT. Ca2+channels and epilepsy. Eur J Pharmacol,2002,447(2-3):211-25
19Broicher T, Seidenbecher T, Meuth P, et al. T-current related effects ofantiepileptic drugs and a Ca2+channel antagonist on thalamic relay andlocal circuit interneurons in a rat model of absence epilepsy.Neuropharmacology,2007,53(3):431-46
20Shin HS, Lee J, Song I. Genetic studies on the role of T-type Ca2+channelsin sleep and absence epilepsy. CNS Neurol Disord Drug Targets,2006,5(6):629-38
21Weiergraber M, Stephani U, Kohling R. Voltage-gated calcium channels inthe etiopathogenesis and treatment of absence epilepsy. Brain researchreviews,2010,62(2):245-71
22Shin HS. T-type Ca2+channels and absence epilepsy. Cell Calcium,2006,40(2):191-6
23Felix R. Insights from mouse models of absence epilepsy into Ca2+channelphysiology and disease etiology. Cell Mol Neurobiol,2002,22(2):103-20
24Gurkoff GG, Shahlaie K, Lyeth BG. In vitro mechanical strain traumaalters neuronal calcium responses: Implications for posttraumatic epilepsy.Epilepsia,2012,53Suppl1:53-60
25Steinbeck JA, Henke N, Opatz J, et al. Store-operated calcium entrymodulates neuronal network activity in a model of chronic epilepsy. ExpNeurol,2011,232(2):185-94
26Thom M, Eriksson S, Martinian L, et al. Temporal lobe sclerosisassociated with hippocampal sclerosis in temporal lobe epilepsy:neuropathological features. J Neuropathol Exp Neurol,2009,68(8):928-38
27Acharya MM, Hattiangady B, Shetty AK. Progress in neuroprotectivestrategies for preventing epilepsy. Prog Neurobiol,2008,84(4):363-404
28de Araujo Furtado M, Lumley LA, Robison C, et al. Spontaneous recurrentseizures after status epilepticus induced by soman in Sprague-Dawley rats.Epilepsia,2010,51(8):1503-10
29Rybnikova E, Vataeva L, Tyulkova E, et al. Mild hypoxia preconditioningprevents impairment of passive avoidance learning and suppression ofbrain NGFI-A expression induced by severe hypoxia. Behav Brain Res,2005,160(1):107-14
30Gong SJ, Chen LY, Zhang M, et al. Intermittent hypobaric hypoxiapreconditioning induced brain ischemic tolerance by up-regulating glialglutamate transporter-1in rats. Neurochem Res,2012,37(3):527-37
1Liu H, Zhang X, Du Y, et al. Leonurine protects brain injury by increasedactivities of UCP4, SOD, CAT and Bcl-2, decreased levels of MDA andBax, and ameliorated ultrastructure of mitochondria in experimental stroke.Brain Res,2012,1474:73-81
2Hua JS, Li LP, Zhu XM. Effects of moxibustion pretreating on SOD andMDA in the rat of global brain ischemia. Journal of traditional Chinesemedicine,2008,28(4):289-92
3Tripanichkul W, Sripanichkulchai K, Duce JA, et al.17Beta-estradiolreduces nitrotyrosine immunoreactivity and increases SOD1and SOD2immunoreactivity in nigral neurons in male mice following MPTP insult.Brain Res,2007,1164:24-31
4Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: acomparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD(SOD3) gene structures, evolution, and expression. Free Radic Biol Med,2002,33(3):337-49
5Fukui M, Zhu BT. Mitochondrial superoxide dismutase SOD2, but notcytosolic SOD1, plays a critical role in protection against glutamate-induced oxidative stress and cell death in HT22neuronal cells. Free RadicBiol Med,2010,48(6):821-30
6Cardenas-Rodriguez N, Huerta-Gertrudis B, Rivera-Espinosa L, et al.Role of oxidative stress in refractory epilepsy: evidence in patients andexperimental models. Int J Mol Sci,2013,14(1):1455-76
7Rowley S, Patel M. Mitochondrial involvement and oxidative stress intemporal lobe epilepsy. Free Radic Biol Med,2013,62:121-31
8Azam F, Prasad MV, Thangavel N. Targeting oxidative stress componentin the therapeutics of epilepsy. Curr Top Med Chem,2012,12(9):994-1007
9Waldbaum S, Patel M. Mitochondria, oxidative stress, and temporal lobeepilepsy. Epilepsy Res,2010,88(1):23-45
10Liang LP, Waldbaum S, Rowley S, et al. Mitochondrial oxidative stressand epilepsy in SOD2deficient mice: attenuation by a lipophilicmetalloporphyrin. Neurobiol Dis,2012,45(3):1068-76
11Skemiene K, Rakauskaite G, Trumbeckaite S, et al. Anthocyanins blockischemia-induced apoptosis in the perfused heart and supportmitochondrial respiration potentially by reducing cytosolic cytochrome c.Int J Biochem Cell Biol,2013,45(1):23-9
12Yang RF, Zhao GW, Liang ST, et al. Mitofilin regulates cytochrome crelease during apoptosis by controlling mitochondrial cristae remodeling.Biochem Biophys Res Commun,2012,428(1):93-8
13Lin HI, Lee YJ, Chen BF, et al. Involvement of Bcl-2family, cytochrome cand caspase3in induction of apoptosis by beauvericin in human non-smallcell lung cancer cells. Cancer Lett.2005,230(2):248-59
14Chae IH, Park KW, Kim HS, et al. Nitric oxide-induced apoptosis ismediated by Bax/Bcl-2gene expression, transition of cytochrome c, andactivation of caspase-3in rat vascular smooth muscle cells. Clin ChimActa,2004,341(1-2):83-91
15Zhao H, Yenari MA, Cheng D, et al. Bcl-2overexpression protects againstneuron loss within the ischemic margin following experimental stroke andinhibits cytochrome c translocation and caspase-3activity. J Neurochem,2003,85(4):1026-36
16Dong GX, Singh DK, Dendle P, et al. Regional expression of Bcl-2mRNAand mitochondrial cytochrome c release after experimental brain injury inthe rat. Brain Res,2001,903(1-2):45-52
17Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissuesby thiobarbituric acid reaction. Anal Biochem,1979,95(2):351-8
18Schmidt PJ, Ramos-Gomez M, Culotta VC. A gain of superoxidedismutase (SOD) activity obtained with CCS, the copper metallochap-erone for SOD1. J Biol Chem,1999,274(52):36952-6
19ELLMAN GL. Tissue sulfhydryl groups. Arch Biochem Biophys,1959,82(1):70-7
20Dringen R. Metabolism and functions of glutathione in brain. ProgNeurobiol,2000,62(6):649-71
21Liang LP, Waldbaum S, Rowley S, et al. Mitochondrial oxidative stressand epilepsy in SOD2deficient mice: attenuation by a lipophilicmetalloporphyrin. Neurobiol Dis,2012,45(3):1068-76
22Liang LP, Patel M. Mitochondrial oxidative stress and increased seizuresusceptibility in Sod2(-/+) mice. Free Radic Biol Med,2004,36(5):542-54
23Dal-Pizzol F, Klamt F, Vianna MM, et al. Lipid peroxidation inhippocampus early and late after status epilepticus induced by pilocarpineor kainic acid in Wistar rats. Neurosci Lett,2000,291(3):179-82
24Ng CF, Schafer FQ, Buettner GR, et al. The rate of cellular hydrogenperoxide removal shows dependency on GSH: mathematical insight into invivo H2O2and GPx concentrations. Free Radic Res,2007,41(11):1201-11
25Bruce AJ, Baudry M. Oxygen free radicals in rat limbic structures afterkainate-induced seizures. Free Radic Biol Med,1995,18(6):993-1002
26Erakovic V, Zupan G, Varljen J, et al. Lithium plus pilocarpine inducedstatus epilepticus-biochemical changes. Neurosci Res,2000,36(2):157-66
27Bellissimo MI, Amado D, Abdalla DS, et al. Superoxide dismutase,glutathione peroxidase activities and the hydroperoxide concentration aremodified in the hippocampus of epileptic rats. Epilepsy Res,2001,46(2):121-8
28Shin EJ, Ko KH, Kim WK, et al. Role of glutathione peroxidase in theontogeny of hippocampal oxidative stress and kainate seizure sensitivity inthe genetically epilepsy-prone rats. Neurochem Int,2008,52(6):1134-47
29Gamdzyk M, Makarewicz D, Slomka M, et al. Hypobaric HypoxiaPostconditioning Reduces Brain Damage and Improves AntioxidativeDefense in the Model of Birth Asphyxia in7-Day-Old Rats. NeurochemRes,2014,39(1):68-75
30Zhou JJ, Wei Y, Zhang L, et al. Chronic intermittent hypobaric hypoxiaprevents cardiac dysfunction through enhancing antioxidation infructose-fed rats. Can J Physiol Pharmacol,2013,91(5):332-7
31Mukherjee N, Mukherjee S, Saini P, et al. Antifilarial effects of polyphenolrich ethanolic extract from the leaves of Azadirachta indica throughmolecular and biochemical approaches describing reactive oxygen species(ROS) mediated apoptosis of Setaria cervi. Exp Parasitol,2014,136:41-58
32Cortassa S, O'Rourke B, Aon MA. Redox-Optimized ROS Balance andthe relationship between mitochondrial respiration and ROS. BiochimBiophys Acta,2014,1837(2):287-95
33Lin B, Chen Z, Xu Y, et al.7-b, a novel amonafide analogue, cause growthinhibition and apoptosis in Raji cells via a ROS-mediated mitochondrialpathway. Leuk Res,2011,35(5):646-56
34Martinez-Abundis E, Rajapurohitam V, Haist JV, et al. The obesity-relatedpeptide leptin sensitizes cardiac mitochondria to calcium-inducedpermeability transition pore opening and apoptosis. PLoS One,2012,7(7):e41612
35Haeberlein SL. Mitochondrial function in apoptotic neuronal cell death.Neurochem Res,2004,29(3):521-30
36Chen W, Zhao Z, Li L, et al. Hispolon induces apoptosis in human gastriccancer cells through a ROS-mediated mitochondrial pathway. Free RadicBiol Med,2008,45(1):60-72
37Waldbaum S, Patel M. Mitochondrial dysfunction and oxidative stress: acontributing link to acquired epilepsy. J Bioenerg Biomembr,2010,42(6):449-55
38Rowley S, Patel M. Mitochondrial involvement and oxidative stress intemporal lobe epilepsy. Free Radic Biol Med,2013,62:121-31
39Polster BM, Fiskum G. Mitochondrial mechanisms of neural cell apoptosis.J Neurochem,2004,90(6):1281-9
40Christensen ME, Jansen ES, Sanchez W, et al. Flow cytometry basedassays for the measurement of apoptosis-associated mitochondrialmembrane depolarisation and cytochrome c release. Methods (San Diego,Calif.),2013,61(2):138-45
41Smeland OB, Hadera MG, McDonald TS, et al. Brain mitochondrialmetabolic dysfunction and glutamate level reduction in the pilocarpinemodel of temporal lobe epilepsy in mice. J Cereb Blood Flow Metab,2013,33(7):1090-7
42Kluck RM, Bossy-Wetzel E, Green DR, et al. The release of cytochrome cfrom mitochondria: a primary site for Bcl-2regulation of apoptosis.Science (New York, N.Y.),1997,275(5303):1132-6
43Henshall DC, Clark RS, Adelson PD, et al. Alterations in bcl-2andcaspase gene family protein expression in human temporal lobe epilepsy.Neurology,2000,55(2):250-7
44Narkilahti S, Pirttila TJ, Lukasiuk K, et al. Expression and activation ofcaspase3following status epilepticus in the rat. Eur J Neurosci,2003,18(6):1486-96
45Xu J, Wang S, Lin Y, et al. Ghrelin protects against cell death ofhippocampal neurons in pilocarpine-induced seizures in rats. NeurosciLett,2009,453(1):58-61
1Pinabiaux C, Bulteau C, Fohlen M, et al. Impaired emotional memoryrecognition after early temporal lobe epilepsy surgery: the fearful faceexception. Cortex,2013,49(5):1386-93
2Duncan JS. Seizure-induced neuronal injury: human data. Neurology,2002,59(9Suppl5): S15-20
3Tobimatsu S, Hiromatsu M, Kato M, et al. Adverse effect of antiepilepticdrugs on the visual recognition--a contrast sensitivity function study.Clinical neurology,1992,32(7):713-7
4Berberich S, Jensen V, Hvalby O, et al. The role of NMDAR subtypes andcharge transfer during hippocampal LTP induction. Neuropharmacology,2007,52(1):77-86
5Geinisman Y, Disterhoft JF, Gundersen HJ, et al. Remodeling ofhippocampal synapses after hippocampus-dependent associative learning.J Comp Neurol,2000,417(1):49-59
6Nagura H, Ishikawa Y, Kobayashi K, et al. Impaired synaptic clustering ofpostsynaptic density proteins and altered signal transmission inhippocampal neurons, and disrupted learning behavior in PDZ1and PDZ2ligand binding-deficient PSD-95knockin mice. Mol Brain,2012,5:43
7Gandhi RM, Kogan CS, Messier C, et al. Visual-spatial learningimpairments are associated with hippocampal PSD-95proteindysregulation in a mouse model of fragile X syndrome. Neuroreport,2014,25(4):255-61
8Mishima K, Ikeda T, Aoo N, et al. Hypoxia-ischemic insult in neonatal ratsinduced slowly progressive brain damage related to memory impairment.Neurosci Lett,2005,376(3):194-9
9Mecklinger A, von CDY, Matthes-von CG. Event-related potentialevidence for a specific recognition memory deficit in adult survivors ofcerebral hypoxia. Brain,1998,121(Pt10):1919-35
10Virues-Ortega J, Garrido E, Javierre C, et al. Human behaviour anddevelopment under high-altitude conditions. Dev Sci,2006,9(4):400-10
11Gong SJ, Chen LY, Zhang M, et al. Intermittent hypobaric hypoxiapreconditioning induced brain ischemic tolerance by up-regulating glialglutamate transporter-1in rats. Neurochem Res,2012,37(3):527-37
12Churilova AV, Rybnikova EA, Glushchenko TS, et al. Effects of moderatehypobaric hypoxic preconditioning on the expression of the transcriptionfactors pCREB and NF-kappaB in the rat hippocampus before and aftersevere hypoxia. Neurosci Behav Physiol,2010,40(8):852-7
13Zhang JX, Chen XQ, Du JZ, et al. Neonatal exposure to intermittenthypoxia enhances mice performance in water maze and8-arm radial mazetasks. Journal of neurobiology,2005,65(1):72-84
14Xie T, Wang WP, Mao ZF, et al. Effects of epigallocatechin-3-gallate onpentylenetetrazole-induced kindling, cognitive impairment and oxidativestress in rats. Neurosci Lett,2012,516(2):237-41
15Geinisman Y, Ganeshina O, Yoshida R, et al. Aging, spatial learning, andtotal synapse number in the rat CA1stratum radiatum. Neurobiol Aging,2004,25(3):407-16
16Guldner FH, Ingham CA. Increase in postsynaptic density material in optictarget neurons of the rat suprachiasmatic nucleus after bilateral enucleation.Neurosci Lett,1980,17(1-2):27-31
17Kozyrev SA, Nikitin VP. Different mechanisms of long-term synapticfacilitation during associative learning and sensitization. Rossiiskaiaakademiia nauk,2013,99(5):599-611
18Kennedy MB. Synaptic Signaling in Learning and Memory. Cold SpringHarb Perspect Biol,2013
19Cavazos JE, Jones SM, Cross DJ. Sprouting and synaptic reorganization inthe subiculum and CA1region of the hippocampus in acute and chronicmodels of partial-onset epilepsy. Neuroscience,2004,126(3):677-88
20Babanejad S, Naghdi N, Haeri RSA. Microinjection of Dihydrotestos-terone as a5alpha-Reduced Metabolite of Testosterone into CA1Regionof Hippocampus Could Improve Spatial Learning in the Adult Male Rats.Iranian journal of pharmaceutical research: IJPR,2012,11(2):661-9
21Talebi A, Naghdi N, Sepehri H, et al. The Role of Estrogen Receptors onSpatial Learning and Memory in CA1Region of Adult Male RatHippocampus. Iranian journal of pharmaceutical research: IJPR,2010,9(2):183-91
22Gallagher M, Burwell R, Burchinal M. Severity of spatial learningimpairment in aging: development of a learning index for performance inthe Morris water maze. Behav Neurosci,1993,107(4):618-26
23Fiore M, Korf J, Antonelli A, et al. Long-lasting effects of prenatal MAMtreatment on water maze performance in rats: associations with alteredbrain development and neurotrophin levels. Neurotoxicol Teratol,2002,24(2):179-91
24Karabeg MM, Grauthoff S, Kollert SY, et al.5-HTT deficiency affectsneuroplasticity and increases stress sensitivity resulting in altered spatiallearning performance in the Morris water maze but not in the Barnes maze.PLoS One,2013,8(10): e78238
25Bromley-Brits K, Deng Y, Song W. Morris water maze test for learningand memory deficits in Alzheimer's disease model mice. J Vis Exp,2011,(53):2920
26Bell BD. Route learning impairment in temporal lobe epilepsy. EpilepsyBehav,2012,25(2):256-62
27Zhang JX, Chen XQ, Du JZ, et al. Neonatal exposure to intermittenthypoxia enhances mice performance in water maze and8-arm radial mazetasks. Journal of neurobiology,2005,65(1):72-84
28Berberich S, Jensen V, Hvalby O, et al. The role of NMDAR subtypes andcharge transfer during hippocampal LTP induction. Neuropharmacology,2007,52(1):77-86
29Zhang Y, Wei J, Yang Z. Perinatal undernutrition attenuates fieldexcitatory postsynaptic potentials and influences dendritic spine densityand morphology in hippocampus of male rat offspring. Neuroscience,2013,244:31-41
30Ding J, Xi YD, Zhang DD, et al. Soybean isoflavone amelioratesbeta-amyloid1-42-induced learning and memory deficit in rats byprotecting synaptic structure and function. Synapse (New York, N.Y.),2013,67(12):856-64
31Volk L, Kim CH, Takamiya K, et al. Developmental regulation of proteininteracting with C kinase1(PICK1) function in hippocampal synapticplasticity and learning. Proc Natl Acad Sci U S A,2010,107(50):21784-9
32Yang SN, Liu CA, Chung MY, et al. Alterations of postsynaptic densityproteins in the hippocampus of rat offspring from the morphine-addictedmother: Beneficial effect of dextromethorphan. Hippocampus,2006,16(6):521-30
33Zhang Y, Wei J, Yang Z. Perinatal undernutrition attenuates fieldexcitatory postsynaptic potentials and influences dendritic spine densityand morphology in hippocampus of male rat offspring. Neuroscience,2013,244:31-41
34Chen X, Nelson CD, Li X, et al. PSD-95is required to sustain themolecular organization of the postsynaptic density. J Neurosci,2011,31(17):6329-38
35Di G, Zheng Y. Effects of high-speed railway noise on the synapticultrastructure and phosphorylated-CaMKII expression in the centralnervous system of SD rats. Environ Toxicol Pharmacol,2013,35(1):93-9
36Xie T, Wang WP, Jia LJ, et al. Environmental enrichment restorescognitive deficits induced by prenatal maternal seizure. Brain Res,2012,1470:80-8
37Yang J, Liu Q, Zhang L, et al. Lanthanum chloride impairs memory,decreases pCaMK IV, pMAPK and pCREB expression of hippocampus inrats. Toxicol Lett,2009,190(2):208-14
38Sharrad DF, Gai WP, Brookes SJ. Selective coexpression of synapticproteins, alpha-synuclein,cysteine string protein-alpha, synaptophysin,synaptotagmin-1,and synaptobrevin-2in vesicular acetylcholine transpor-ter-immunoreactive axons in the guinea pig ileum. J Comp Neurol,2013,521(11):2523-37
39Kiraly DD, Lemtiri-Chlieh F, Levine ES, et al. Kalirin binds the NR2Bsubunit of the NMDA receptor,altering its synaptic localization andfunction. J Neurosci,2011,31(35):12554-65
40Li Y, Hu J, Hofer K, et al. DHHC5interacts with PDZ domain3ofpost-synaptic density-95(PSD-95) protein and plays a role in learning andmemory. J Biol Chem,2010,285(17):13022-31
41Nagura H, Ishikawa Y, Kobayashi K, et al. Impaired synaptic clustering ofpostsynaptic density proteins and altered signal transmission inhippocampal neurons, and disrupted learning behavior in PDZ1and PDZ2ligand binding-deficient PSD-95knockin mice. Mol Brain,2012,5:43
42Rosas K, Parron I, Serrano P, et al. Spatial recognition memory in a virtualreality task is altered in refractory temporal lobe epilepsy. Epilepsy Behav,2013,28(2):227-31
43Penzes P, Johnson RC, Alam MR, et al. An isoform of kalirin, abrain-specific GDP/GTP exchange factor, is enriched in the postsynapticdensity fraction. J Biol Chem,2000,275(9):6395-403
44Schiller MR, Blangy A, Huang J, et al. Induction of lamellipodia byKalirin does not require its guanine nucleotide exchange factor activity.Exp Cell Res,2005,307(2):402-17
45Ma XM, Kiraly DD, Gaier ED, et al. Kalirin-7is required for synapticstructure and function. J Neurosci,2008,28(47):12368-82
46Nicholson DA, Cahill ME, Tulisiak CT, et al. Spatially restrictedactin-regulatory signaling contributes to synapse morphology. JNeurochem,2012,121(6):852-60
47Migaud M, Charlesworth P, Dempster M, et al. Enhanced long-termpotentiation and impaired learning in mice with mutant postsynapticdensity-95protein. Nature,1998,396(6710):433-9
48Chen WF, Chang H, Huang LT, et al. Alterations in long-term seizuresusceptibility and the complex of PSD-95with NMDA receptor fromanimals previously exposed to perinatal hypoxia. Epilepsia,2006,47(2):288-96
1Di MR, Mastroberardino PG, Hu X, et al. Thiol oxidation and alteredNR2B/NMDA receptor functions in in vitro and in vivo pilocarpinemodels: Implications for epileptogenesis. Neurobiol Dis,2012,49C:87-98
2Ashrafi MR, Shams S, Nouri M, et al. A probable causative factor for anold problem: selenium and glutathione peroxidase appear to playimportant roles in epilepsy pathogenesis. Epilepsia,2007,48(9):1750-5
3Khurana DS, Valencia I, Goldenthal MJ, et al. Mitochondrial dysfunctionin epilepsy. Semin Pediatr Neurol,2013,20(3):176-87
4Adebayo OL, Shallie PD, Salau BA, et al. Comparative study on theinfluence of fluoride on lipid peroxidation and antioxidants levels in thedifferent brain regions of well-fed and protein undernourished rats. Journalof trace elements in medicine and biology: organ of the Society forMinerals and Trace Elements (GMS),2013,27(4):370-4
5Butterick TA, Nixon JP, Billington CJ, et al. Orexin A decreases lipidperoxidation and apoptosis in a novel hypothalamic cell model. NeurosciLett,2012,524(1):30-4
6Smeland OB, Hadera MG, McDonald TS, et al. Brain mitochondrialmetabolic dysfunction and glutamate level reduction in the pilocarpinemodel of temporal lobe epilepsy in mice. Journal of cerebral blood flowand metabolism,2013,33(7):1090-7
7Rowley S, Patel M. Mitochondrial involvement and oxidative stress intemporal lobe epilepsy. Free Radic Biol Med,2013,62:121-31
8Menon B, Ramalingam K, Kumar RV. Oxidative stress in patients withepilepsy is independent of antiepileptic drugs. Seizure,2012,21(10):780-4
9Hong S, Xin Y, HaiQin W, et al. The PPARgamma agonist rosiglitazoneprevents cognitive impairment by inhibiting astrocyte activation andoxidative stress following pilocarpine-induced status epilepticus.Neurological sciences,2012,33(3):559-66
10Liu J, Wang A, Li L, et al. Oxidative stress mediates hippocampal neurondeath in rats after lithium-pilocarpine-induced status epilepticus. Seizure,2010,19(3):165-72
11dos SSIM, do NKG, Feitosa CM, et al. Caffeic acid effects on oxidativestress in rat hippocampus after pilocarpine-induced seizures. Neurologicalsciences: official journal of the Italian Neurological Society and of theItalian Society of Clinical Neurophysiology,2011,32(3):375-80
12Chuang YC, Chang AY, Lin JW, et al. Mitochondrial dysfunction andultrastructural damage in the hippocampus during kainic acid-inducedstatus epilepticus in the rat. Epilepsia,2004,45(10):1202-9
13Gao J, Chi ZF, Liu XW, et al. Mitochondrial dysfunction andultrastructural damage in the hippocampus of pilocarpine-inducedepileptic rat. Neurosci Lett,2007,411(2):152-7
14Ahmad M. Protective effects of curcumin against lithium-pilocarpineinduced status epilepticus, cognitive dysfunction and oxidative stress inyoung rats. Saudi journal of biological sciences,2013,20(2):155-62
15Naseer MI, Ullah I, Al-Qahtani MH, et al. Decreased GABABRexpression and increased neuronal cell death in developing rat brain afterPTZ-induced seizure. Neurological sciences: official journal of the ItalianNeurological Society and of the Italian Society of Clinical Neurophy-siology,2013,34(4):497-503
16Biagini G, D'Antuono M, Benini R, et al. Perirhinal cortex and temporallobe epilepsy. Front Cell Neurosci,2013,7:130
17Henshall DC. Apoptosis signalling pathways in seizure-induced neuronaldeath and epilepsy. Biochem Soc Trans,2007,35(Pt2):421-3
18Ewen CL, Kane KP, Bleackley RC. Granzyme H induces cell deathprimarily via a Bcl-2-sensitive mitochondrial cell death pathway that doesnot require direct Bid activation. Mol Immunol,2013,54(3-4):309-18
19Chen Q, Lesnefsky EJ. Blockade of electron transport during ischemiapreserves bcl-2and inhibits opening of the mitochondrial permeabilitytransition pore. FEBS Lett,2011,585(6):921-6
20Lu HF, Chie YJ, Yang MS, et al. Apigenin induces caspase-dependentapoptosis in human lung cancer A549cells through Bax-andBcl-2-triggered mitochondrial pathway. Int J Oncol,2010,36(6):1477-84
21Tomiyama A, Tachibana K, Suzuki K, et al. MEK-ERK-dependentmultiple caspase activation by mitochondrial proapoptotic Bcl-2familyproteins is essential for heavy ion irradiation-induced glioma cell death.Cell Death Dis,2010,1: e60
22Donovan M, Cotter TG. Control of mitochondrial integrity by Bcl-2familymembers and caspase-independent cell death. Biochim Biophys Acta,2004,1644(2-3):133-47
23Chen Q, Gong B, Almasan A. Distinct stages of cytochrome c release frommitochondria: evidence for a feedback amplification loop linking caspaseactivation to mitochondrial dysfunction in genotoxic stress inducedapoptosis. Cell Death Differ,2000,7(2):227-33
24Schindler CK, Pearson EG, Bonner HP, et al. Caspase-3cleavage andnuclear localization of caspase-activated DNase in human temporal lobeepilepsy. Journal of cerebral blood flow and metabolism,2006,26(4):583-9
25Hu K, Li SY, Xiao B, et al. Protective effects of quercetin against statusepilepticus induced hippocampal neuronal injury in rats: involvement ofX-linked inhibitor of apoptosis protein. Acta neurologica Belgica,2011,111(3):205-12
26Yuzefovych LV, Ledoux SP, Wilson GL, et al. Mitochondrial DNADamage via Augmented Oxidative Stress Regulates EndoplasmicReticulum Stress and Autophagy: Crosstalk, Links and Signaling. PLoSOne,2013,8(12): e83349
27Shi K, Wang D, Cao X, et al. Endoplasmic reticulum stress signaling isinvolved in mitomycin C (MMC)-induced apoptosis in human fibroblastsvia PERK pathway. PLoS One,2013,8(3): e59330
28Liu CY, Yang JS, Huang SM, et al. Smh-3induces G(2)/M arrest andapoptosis through calciummediated endoplasmic reticulum stress andmitochondrial signaling in human hepatocellular carcinoma Hep3B cells.Oncol Rep,2013,29(2):751-62
29Qu K, Shen NY, Xu XS, et al. Emodin induces human T cell apoptosis invitro by ROS-mediated endoplasmic reticulum stress and mitochondrialdysfunction. Acta Pharmacol Sin,2013,34(9):1217-28
30Yamamoto A, Murphy N, Schindler CK, et al. Endoplasmic reticulumstress and apoptosis signaling in human temporal lobe epilepsy. JNeuropathol Exp Neurol,2006,65(3):217-25
31Muzio M, Stockwell BR, Stennicke HR, et al. An induced proximitymodel for caspase-8activation. J Biol Chem,1998,273(5):2926-30
32Schug ZT, Gonzalvez F, Houtkooper RH, et al. BID is cleaved bycaspase-8within a native complex on the mitochondrial membrane. CellDeath Differ,2011,18(3):538-48
33Kim YJ, Jung EB, Seo SJ, et al. Quercetin-3-O-(2"-galloyl)-alpha-l-rhamnopyranoside prevents TRAIL-induced apoptosis in humankeratinocytes by suppressing the caspase-8-and Bid-pathways and themitochondrial pathway. Chem Biol Interact,2013,204(3):144-52
34El-Hodhod MA, Tomoum HY, Abd AMM, et al. Serum Fas and Bcl-2inpatients with epilepsy. Acta Neurol Scand,2006,113(5):315-21
35Henshall DC, Bonislawski DP, Skradski SL, et al. Cleavage of bid mayamplify caspase-8-induced neuronal death following focally evokedlimbic seizures. Neurobiol Dis,2001,8(4):568-80
36Larsen BD, Megeney LA. Parole terms for a killer: directingcaspase3/CAD induced DNA strand breaks to coordinate changes in geneexpression. Cell cycle (Georgetown, Tex.),2010,9(15):2940-5
37Chen N, Gao Y, Yan N, et al. High-frequency stimulation of thehippocampus protects against seizure activity and hippocampal neuronalapoptosis induced by kainic acid administration in macaques.Neuroscience,2014,256:370-8
38Henshall DC, Chen J, Simon RP. Involvement of caspase-3-like proteasein the mechanism of cell death following focally evoked limbic seizures. JNeurochem,2000,74(3):1215-23
39Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam,diazepam, and placebo for the treatment of out-of-hospital statusepilepticus. N Engl J Med Overseas Ed,2001,345(9):631-7
40Liefaard LC, Gunput RA, Danhof M, et al. Decreased Efficacy ofGABAA-receptor modulation by midazolam in the kainate model oftemporal lobe epilepsy. Epilepsia,2007,48(7):1378-87
41Holsti M, Dudley N, Schunk J, et al. Intranasal midazolam vs rectaldiazepam for the home treatment of acute seizures in pediatric patientswith epilepsy. Archives of pediatrics&adolescent medicine,2010,164(8):747-53
42Darrah SD, Chuang J, Mohler LM, et al. Dilantin therapy in anexperimental model of traumatic brain injury: effects of limited versusdaily treatment on neurological and behavioral recovery. J Neurotrauma,2011,28(1):43-55
43Inoue Y, Usui N, Hiroki T, et al. Bioavailability of intravenousfosphenytoin sodium in healthy Japanese volunteers. Eur J Drug MetabPharmacokinet,2013,38(2):139-48
44Karlovassitou-Koniari A, Alexiou D, Angelopoulos P, et al. Low dosesodium valproate in the treatment of juvenile myoclonic epilepsy. J Neurol,2002,249(4):396-9
45Wang W, Wu J, Li S, et al. Sodium valproate for epilepsy in rural China: anefficacy and safety assessment in primary care. Epilepsy Res,2012,102(3):201-5
46Cai YH, Wang H. Effects of valproate sodium on pituitary gonadotropin inadolescent girls with epilepsy. Chinese journal of contemporary pediatrics,2011,13(9):725-7
47Kanemura H, Sano F, Maeda Y, et al. Valproate sodium enhances bodyweight gain in patients with childhood epilepsy: a pathogenic mechanismsand open-label clinical trial of behavior therapy. Seizure,2012,21(7):496-500
48Monot R. Technique for venous general anesthesia using sodium pentothal.Annales francaises d'anesthesie et de reanimation,2008,27Suppl2: S310-22
49Schneider F, Herzer W, Schroeder HW, et al. Effects of propofol onelectrocorticography in patients with intractable partial epilepsy. JNeurosurg Anesthesiol,2011,23(2):150-5
50Agrawal N, Rao S, Nair R. A death associated with possible propofolinfusion syndrome. Indian J Surg,2013,75(Suppl1):407-8
51Power KN, Flaatten H, Gilhus NE, et al. Propofol treatment in adultrefractory status epilepticus. Mortality risk and outcome. Epilepsy Res,2011,94(1-2):53-60
52Kholin AA, Zavadenko NN, Il'ina ES, et al. Efficacy and safety oftopiramate depending on patient's age and forms of epilepsy.Vserossiiskoe obshchestvo psikhiatrov,2013,113(4Pt2):45-51
53Demir CF, Ozdemir HH, Mungen B. Efficacy of topiramate as add-ontherapy in two different types of progressive myoclonic epilepsy. Actamedica (Hradec Kralove)/Universitas Carolina, Facultas Medica HradecKralove,2013,56(1):36-8
54Kiviranta AM, Laitinen-Vapaavuori O, Hielm-Bjorkman A, et al.Topiramate as an add-on antiepileptic drug in treating refractory canineidiopathic epilepsy. J Small Anim Pract,2013,54(10):512-20
55Kremenchugskaia MR, Globa OV, Kuzenkova LM. The use of topiramatein the treatment of focal epilepsy in children. Vserossiiskoe obshchestvopsikhiatrov,2013,113(12):33-38
56Park KM, Kim SH, Nho SK, et al. A randomized open-label observationalstudy to compare the efficacy and tolerability between topiramate andvalproate in juvenile myoclonic epilepsy. Journal of clinical neuroscience,2013,20(8):1079-82
57Koo DL, Hwang KJ, Kim D, et al. Effects of levetiracetam monotherapyon the cognitive function of epilepsy patients. Eur Neurol,2013,70(1-2):88-94
58Kang BS, Moon HJ, Kim YS, et al. The long-term efficacy and safety oflevetiracetam in a tertiary epilepsy centre. Epileptic Disord,2013,15(3):302-10
59Goldberg-Stern H, Feldman L, Eidlitz-Markus T, et al. Levetiracetam inchildren, adolescents and young adults with intractable epilepsy: efficacy,tolerability and effect on electroencephalogram--a pilot study. EuropeanPaediatric Neurology Society,2013,17(3):248-53
60Kanemura H, Sano F, Sugita K, et al. Effects of levetiracetam on seizurefrequency and neuropsychological impairments in children with refractoryepilepsy with secondary bilateral synchrony. Seizure,2013,22(1):43-7
61Biton V, Berkovic SF, Abou-Khalil B, et al. Brivaracetam as adjunctivetreatment for uncontrolled partial epilepsy in adults: A phase IIIrandomized, double-blind, placebo-controlled trial. Epilepsia,2014,55(1):57-66
62Nicita F, Spalice A, Papetti L, et al. Efficacy of verapamil as an adjunctivetreatment in children with drug-resistant epilepsy: A pilot study. Seizure,2014,23(1):36-40
63Yamada J, Zhu G, Okada M, et al. A novel prophylactic effect offurosemide treatment on autosomal dominant nocturnal frontal lobeepilepsy (ADNFLE). Epilepsy Res,2013,107(1-2):127-37
64Petkova Z, Tchekalarova J, Pechlivanova D, et al. Treatment withmelatonin after status epilepticus attenuates seizure activity and neuronaldamage but does not prevent the disturbance in diurnal rhythms andbehavioral alterations in spontaneously hypertensive rats in kainate modelof temporal lobe epilepsy. Epilepsy Behav,2014,31C:198-208
65Maschio M, Dinapoli L, Sperati F, et al. Effect of pregabalin add-ontreatment on seizure control, quality of life, and anxiety in patients withbrain tumour-related epilepsy: a pilot study. Epileptic Disord,2012,14(4):388-97
66Ben-Menachem E. Medical management of refractory epilepsy-Practicaltreatment with novel antiepileptic drugs. Epilepsia,2014,55Suppl1:3-8
67Kissin MY, Bondarenko II. The experience treatment of adjunctivelacosamide for patients with drug-resistance partial epilepsy. Vserossiis-koe obshchestvo psikhiatrov,2013,113(9):23-8.
68Zaccara G, Giovannelli F, Cincotta M, et al. AMPA receptor inhibitors forthe treatment of epilepsy: the role of perampanel. Expert Rev Neurother,2013,13(6):647-55
69Craig D, Rice S, Paton F, et al. Retigabine for the adjunctive treatment ofadults with partial-onset seizures in epilepsy with and without secondarygeneralization: a NICE single technology appraisal. Pharmacoeconomics,2013,31(2):101-10
70Dhanushkodi A, Shetty AK. Is exposure to enriched environmentbeneficial for functional post-lesional recovery in temporal lobe epilepsy.Neurosci Biobehav Rev,2008,32(4):657-74
71Hu K, Xie YY, Zhang C, et al. MicroRNA expression profile of thehippocampus in a rat model of temporal lobe epilepsy andmiR-34a-targeted neuroprotection against hippocampal neurone cellapoptosis post-status epilepticus. BMC Neurosci,2012,13:115
72Perry MS, Duchowny M. Surgical versus medical treatment for refractoryepilepsy: outcomes beyond seizure control. Epilepsia,2013,54(12):2060-70
73Luan G, Zhao Y, Zhai F, et al. Ketogenic diet reduces Smac/Diablo andcytochrome c release and attenuates neuronal death in a mouse model oflimbic epilepsy. Brain Res Bull,2012,89(3-4):79-85
74Pablos-Sanchez T, Oliveros-Leal L, Nunez-Enamorado N, et al. The use ofthe ketogenic diet as treatment for refractory epilepsy in the paediatric age.Revista de neurologia,2014,58(2):55-62
75Cervenka MC, Kossoff EH. Dietary treatment of intractable epilepsy.Continuum (Minneapolis, Minn.),2013,19(3Epilepsy):756-66
76Sharma S, Sankhyan N, Gulati S, et al. Use of the modified Atkins diet fortreatment of refractory childhood epilepsy: a randomized controlled trial.Epilepsia,2013,54(3):481-6
77Morris GL3rd, Gloss D, Buchhalter J, et al. Evidence-based guidelineupdate: vagus nerve stimulation for the treatment of epilepsy: report of theguideline development subcommittee of the american academy ofneurology. Epilepsy currents/American Epilepsy Society,2013,13(6):297-303
78Roldan P, Brell M, Perla YPC, et al. Vagal nerve stimulation treatment inpatients with drug resistant epilepsy: Son Espases University Hospitalexperience. Neurocirugia (Asturias, Spain),2013,24(5):204-9
79Patel KS, Labar DR, Gordon CM, et al. Efficacy of vagus nervestimulation as a treatment for medically intractable epilepsy in brain tumorpatients. A case-controlled study using the VNS therapy Patient OutcomeRegistry. Seizure,2013,22(8):627-33
80Sun W, Mao W, Meng X, et al. Low-frequency repetitive transcranialmagnetic stimulation for the treatment of refractory partial epilepsy: acontrolled clinical study. Epilepsia,2012,53(10):1782-9
81Zhong K, Wu DC, Jin MM, et al. Wide therapeutic time-window oflow-frequency stimulation at the subiculum for temporal lobe epilepsytreatment in rats. Neurobiol Dis,2012,48(1):20-6
82Shen FZ, Wang F, Yang GM, et al. The effects of low-frequency electricstimulus on hippocampal of Effects of low-frequency electric stimulus onhippocampal of alpha5subunit of extra synapse GABAA receptor inkainic acid-induced epilepsy rats. Zhonghua yi xue za zhi,2013,93(7):550-3
83Ghotbedin Z, Janahmadi M, Mirnajafi-Zadeh J, et al. Electrical lowfrequency stimulation of the kindling site preserves the electrophysio-logical properties of the rat hippocampal CA1pyramidal neurons from thedestructive effects of amygdala kindling: the basis for a possible promisingepilepsy therapy. Brain Stimul,2013,6(4):515-23
84Li LY, Li JL, Zhang HM, et al. TGFbeta1treatment reduces hippocampaldamage, spontaneous recurrent seizures, and learning memory deficits inpilocarpine-treated rats. J Mol Neurosci,2013,50(1):109-23
1Hou ZH, Yu X. Activity-regulated somatostatin expression reducesdendritic spine density and lowers excitatory synaptic transmission viapostsynaptic somatostatin receptor4. J Biol Chem,2013,288(4):2501-9
2Sala C, Futai K, Yamamoto K, et al. Inhibition of dendritic spinemorphogenesis and synaptic transmission by activity-inducible proteinHomer1a. The Journal of neuroscience: the official journal of the Societyfor Neuroscience,2003,23(15):6327-37
3Hasan A, Nitsche MA, Rein B, et al. Dysfunctional long-termpotentiation-like plasticity in schizophrenia revealed by transcranial directcurrent stimulation. Behav Brain Res,2011,224(1):15-22
4Shi Y, Pontrello CG, DeFea KA, et al. Focal adhesion kinase actsdownstream of EphB receptors to maintain mature dendritic spines byregulating cofilin activity. The Journal of neuroscience: the official journalof the Society for Neuroscience,2009,29(25):8129-42
5Tetzlaff C, Kolodziejski C, Timme M, et al. Synaptic scaling enablesdynamically distinct short-and long-term memory formation. PLoSComput Biol,2013,9(10): e1003307
6Sharrad DF, Gai WP, Brookes SJ. Selective coexpression of synapticproteins, alpha-synuclein, cysteine string protein-alpha, synaptophysin,synaptotagmin-1, and synaptobrevin-2in vesicular acetylcholinetransporter-immunoreactive axons in the guinea pig ileum. J Comp Neurol,2013,521(11):2523-37
7Trovo L, Ahmed T, Callaerts-Vegh Z, et al. Low hippocampal PI(4,5)P(2)contributes to reduced cognition in old mice as a result of loss ofMARCKS. Nat Neurosci,2013,16(4):449-55
8Kiraly DD, Lemtiri-Chlieh F, Levine ES, et al. Kalirin binds the NR2Bsubunit of the NMDA receptor, altering its synaptic localization andfunction. The Journal of neuroscience: the official journal of the Societyfor Neuroscience,2011,31(35):12554-65
9Youn H, Jeoung M, Koo Y, et al. Kalirin is under-expressed in Alzheimer'sdisease hippocampus. J Alzheimers Dis,2007,11(3):385-97
10Kushima I, Nakamura Y, Aleksic B, et al. Resequencing and associationanalysis of the KALRN and EPHB1genes and their contribution toschizophrenia susceptibility. Schizophr Bull,2012,38(3):552-60
11Spires TL, Grote HE, Garry S, et al. Dendritic spine pathology and deficitsin experience-dependent dendritic plasticity in R6/1Huntington's diseasetransgenic mice. Eur J Neurosci,2004,19(10):2799-807
12Murray PS, Kirkwood CM, Gray MC, et al. beta-Amyloid42/40ratio andkalirin expression in Alzheimer disease with psychosis. Neurobiol Aging,2012,33(12):2807-16
13May V, Schiller MR, Eipper BA, et al. Kalirin Dbl-homology guaninenucleotide exchange factor1domain initiates new axon outgrowths viaRhoG-mediated mechanisms. The Journal of neuroscience: the officialjournal of the Society for Neuroscience,2002,22(16):6980-90
14Alam MR, Johnson RC, Darlington DN, et al. Kalirin, a cytosolic proteinwith spectrin-like and GDP/GTP exchange factor-like domains thatinteracts with peptidylglycine alpha-amidating monooxygenase, anintegral membrane peptide-processing enzyme. J Biol Chem,1997,272(19):12667-75
15Mandela P, Ma XM. Kalirin, a key player in synapse formation, isimplicated in human diseases. Neural Plast,2012,2012:728161
16Ma XM, Johnson RC, Mains RE, et al. Expression of kalirin, a neuronalGDP/GTP exchange factor of the trio family, in the central nervous systemof the adult rat. J Comp Neurol,2001,429(3):388-402
17Johnson RC, Penzes P, Eipper BA, et al. Isoforms of kalirin, a neuronalDbl family member, generated through use of different5'-and3'-endsalong with an internal translational initiation site. J Biol Chem,2000,275(25):19324-33
18Sommer JE, Budreck EC. Kalirin-7: linking spine plasticity and behavior.The Journal of neuroscience: the official journal of the Society forNeuroscience,2009,29(17):5367-9
19Mains RE, Alam MR, Johnson RC, et al. Kalirin, a multifunctional PAMCOOH-terminal domain interactor protein, affects cytoskeletalorganization and ACTH secretion from AtT-20cells. J Biol Chem,1999,274(5):2929-37
20Penzes P, Johnson RC, Alam MR, et al. An isoform of kalirin, abrain-specific GDP/GTP exchange factor, is enriched in the postsynapticdensity fraction. J Biol Chem,2000,275(9):6395-403
21Cahill ME, Xie Z, Day M, et al. Kalirin regulates cortical spinemorphogenesis and disease-related behavioral phenotypes. Proc Natl AcadSci U S A,2009,106(31):13058-63
22Cahill ME, Jones KA, Rafalovich I, et al. Control of interneuron dendriticgrowth through NRG1/erbB4-mediated kalirin-7disinhibition. MolPsychiatry,2012,17(1):1,99-107
23Penzes P, Beeser A, Chernoff J, et al. Rapid induction of dendritic spinemorphogenesis by trans-synaptic ephrinB-EphB receptor activation of theRho-GEF kalirin. Neuron,2003,37(2):263-74
24Xie Z, Cahill ME, Penzes P. Kalirin loss results in cortical morphologicalalterations. Mol Cell Neurosci,2010,43(1):81-9
25Ma XM, Huang J, Wang Y, et al. Kalirin, a multifunctional Rho guaninenucleotide exchange factor, is necessary for maintenance of hippocampalpyramidal neuron dendrites and dendritic spines. The Journal ofneuroscience: the official journal of the Society for Neuroscience,2003,23(33):10593-603
26Mazzone CM, Larese TP, Kiraly DD, et al. Analysis of kalirin-7knockoutmice reveals different effects in female mice. Mol Pharmacol,2012,82(6):1241-9
27Cahill ME, Remmers C, Jones KA, et al. Neuregulin1signaling promotesdendritic spine growth through kalirin. J Neurochem,2013,126(5):625-35
28Jones KA, Srivastava DP, Allen JA, et al. Rapid modulation of spinemorphology by the5-HT2A serotonin receptor through kalirin-7signaling.Proc Natl Acad Sci U S A,2009,106(46):19575-80
29Kiraly DD, Nemirovsky NE, LaRese TP, et al. Constitutive knockout ofKalirin-7leads to increased rates of cocaine self-administration. MolPharmacol,2013,84(4):582-90
30Wang X, Cahill ME, Werner CT, et al. Kalirin-7mediates cocaine-inducedAMPA receptor and spine plasticity, enabling incentive sensitization. TheJournal of neuroscience: the official journal of the Society forNeuroscience,2013,33(27):11012-22
31Schiller MR, Blangy A, Huang J, et al. Induction of lamellipodia byKalirin does not require its guanine nucleotide exchange factor activity.Exp Cell Res,2005,307(2):402-17
32Sousa N, Lukoyanov NV, Madeira MD, et al. Reorganization of themorphology of hippocampal neurites and synapses after stress-induceddamage correlates with behavioral improvement. Neuroscience,2000,97(2):253-66
33Inestrosa NC, Carvajal FJ, Zolezzi JM, et al. Peroxisome proliferatorsreduce spatial memory impairment, synaptic failure, andneurodegeneration in brains of a double transgenic mice model ofAlzheimer's disease. J Alzheimers Dis,2013,33(4):941-59
34Selkoe DJ. Alzheimer's disease is a synaptic failure. Science (New York,N.Y.),2002,298(5594):789-91
35Reddy PH, Tripathi R, Troung Q, et al. Abnormal mitochondrial dynamicsand synaptic degeneration as early events in Alzheimer's disease:implications to mitochondria-targeted antioxidant therapeutics. BiochimBiophys Acta,2012,1822(5):639-49
36Arendt T. Synaptic degeneration in Alzheimer's disease. Acta Neuropathol,2009,118(1):167-79
37Penzes P, Vanleeuwen JE. Impaired regulation of synaptic actincytoskeleton in Alzheimer's disease. Brain research reviews,2011,67(1-2):184-92
38Penzes P, Beeser A, Chernoff J, et al. Rapid induction of dendritic spinemorphogenesis by trans-synaptic ephrinB-EphB receptor activation of theRho-GEF kalirin. Neuron,2003,37(2):263-74
39Lacor PN, Buniel MC, Furlow PW, et al. Abeta oligomer-inducedaberrations in synapse composition, shape, and density provide amolecular basis for loss of connectivity in Alzheimer's disease. TheJournal of neuroscience: the official journal of the Society forNeuroscience,2007,27(4):796-807
40Zhao L, Ma QL, Calon F, et al. Role of p21-activated kinase pathwaydefects in the cognitive deficits of Alzheimer disease. Nat Neurosci,2006,9(2):234-42
41Youn H, Ji I, Ji HP, et al. Under-expression of Kalirin-7Increases iNOSactivity in cultured cells and correlates to elevated iNOS activity inAlzheimer's disease hippocampus. J Alzheimers Dis,2007,12(3):271-81
42Li W, Li QJ, An SC. Preventive effect of estrogen on depression-likebehavior induced by chronic restraint stress. Neurosci Bull,2010,26(2):140-6
43A novel gene containing a trinucleotide repeat that is expanded andunstable on Huntington's disease chromosomes. The Huntington's DiseaseCollaborative Research Group. Cell,1993,72(6):971-83
44Beresewicz M, Kowalczyk JE, Zablocka B. Kalirin-7, a protein enrichedin postsynaptic density, is involved in ischemic signal transduction.Neurochem Res,2008,33(9):1789-94
45Penzes P, Jones KA. Dendritic spine dynamics--a key role for kalirin-7.Trends Neurosci,2008,31(8):419-2
2Antonucci F, Bozzi Y, Caleo M. Intrahippocampal infusion of botulinumneurotoxin E (BoNT/E) reduces spontaneous recurrent seizures in a mousemodel of mesial temporal lobe epilepsy. Epilepsia,2009,50(4):963-6
3Zhang HD, Xie YC, Weng L, et al. Rapamycin improves learning andmemory ability in ICR mice with pilocarpine-induced temporal lobeepilepsy. Journal of Zhejiang University. Medical sciences,2013,42(6):602-8
4Smeland OB, Hadera MG, McDonald TS, et al. Brain mitochondrialmetabolic dysfunction and glutamate level reduction in the pilocarpinemodel of temporal lobe epilepsy in mice. J Cereb Blood Flow Metab,2013,33(7):1090-7
5Aur D. Understanding the physical mechanism of transition to epilepticseizures. J Neurosci Methods,2011,200(1):80-5
6Deepa D, Jayakumari N, Thomas SV. Oxidative stress is increased inwomen with epilepsy: Is it a potential mechanism of anti-epilepticdrug-induced teratogenesis. Ann Indian Acad Neurol,2012,15(4):281-6
7Dayton C, Yamaguchi T, Warren A, et al. Ischemic preconditioningprevents postischemic arteriolar, capillary, and postcapillary venulardysfunction: signaling pathways mediating the adaptive metamorphosis toa protected phenotype in preconditioned endothelium. Microcirculation,2002,9(2):73-89
8Li J, Liu W, Ding S, et al. Hyperbaric oxygen preconditioning inducestolerance against brain ischemia-reperfusion injury by upregulation ofantioxidant enzymes in rats. Brain Res,2008,1210:223-9
9Kim SM, Kim H, Lee JS, et al. Intermittent hypoxia can aggravate motorneuronal loss and cognitive dysfunction in ALS mice. PLoS One,2013,8(11): e81808
10Bourque SL, Kuny S, Reyes LM, et al. Prenatal hypoxia is associated withlong-term retinal dysfunction in rats. PLoS One,2013,8(4): e61861
11Churilova AV, Rybnikova EA, Glushchenko TS, et al. Effects of moderatehypobaric hypoxic preconditioning on the expression of the transcriptionfactors pCREB and NF-kappaB in the rat hippocampus before and aftersevere hypoxia. Neurosci Behav Physiol,2010,40(8):852-7
12Guner I,Yelmen N,Sahin G,et al. Respiratory alterations due to chroniclong-term intermittent hypobaric hypoxia in rabbits: importance ofperipheral chemoreceptors. Arch Med Res,2007,38(7):739-45
13Zhou JJ, Wei Y, Zhang L, et al. Chronic intermittent hypobaric hypoxiaprevents cardiac dysfunction through enhancing antioxidation infructose-fed rats. Can J Physiol Pharmacol,2013,91(5):332-7
14Guo HC, Guo F, Zhang LN, et al. Enhancement of Na/K pump activity bychronic intermittent hypobaric hypoxia protected against reperfusioninjury. Am J Physiol Heart Circ Physiol,2011,300(6): H2280-7
15Guo HC, Zhang Z, Zhang LN, et al. Chronic intermittent hypobarichypoxia protects the heart against ischemia/reperfusion injury throughupregulation of antioxidant enzymes in adult guinea pigs. Acta PharmacolSin,2009,30(7):947-55
16Shi M, Cui F, Yang CY, et al. Effects of chronic intermittent hypobarichypoxia on immune function in rat. Chinese journal of applied physiology,2009,25(4):433-8
17Guner I, Uzun DD, Yaman MO, et al. The effect of chronic long-termintermittent hypobaric hypoxia on bone mineral density in rats: role ofnitric oxide. Biol Trace Elem Res,2013,154(2):262-7
18Shi M, Cui F, Liu AJ, et al. Protection of chronic intermittent hypobarichypoxia against collagen-induced arthritis in rat through increasingapoptosis. Acta physiologica Sinica,2011,63(2):115-23
19Gamdzyk M, Makarewicz D, Slomka M, et al. Hypobaric HypoxiaPostconditioning Reduces Brain Damage and Improves AntioxidativeDefense in the Model of Birth Asphyxia in7-Day-Old Rats. NeurochemRes,2014,39(1):68-75
20Gong SJ, Chen LY, Zhang M, et al. Intermittent hypobaric hypoxiapreconditioning induced brain ischemic tolerance by up-regulating glialglutamate transporter-1in rats. Neurochem Res,2012,37(3):527-37
21Jones NM, Lee EM, Brown TG, et al. Hypoxic preconditioning producesdifferential expression of hypoxia-inducible factor-1alpha (HIF-1alpha)and its regulatory enzyme HIF prolyl hydroxylase2in neonatal rat brain.Neurosci Lett,2006,404(1-2):72-7
22Racine RJ. Modification of seizure activity by electrical stimulation. II.Motor seizure. Electroencephalography and clinical neurophysiology,1972,32(3):281-94
23Li LY, Li JL, Zhang HM, et al. TGFbeta1treatment reduces hippocampaldamage, spontaneous recurrent seizures, and learning memory deficits inpilocarpine-treated rats. J Mol Neurosci,2013,50(1):109-23
24Gao F, Liu Y, Li X, et al. Fingolimod (FTY720) inhibits neuroinflamm-ation and attenuates spontaneous convulsions in lithium-pilocarpineinduced status epilepticus in rat model. Pharmacol Biochem Behav,2012,103(2):187-96
25da SVG, da SRS, de Paula Cognato G, et al. A ketogenic diet did notprevent effects on the ectonucleotidases pathway promoted by lithium-pilocarpine-induced status epilepticus in rat hippocampus. Metab BrainDis,2012,27(4):471-8
26Savolainen KM, Hirvonen MR. Second messengers in cholinergic-induced convulsions and neuronal injury. Toxicol Lett,1992,64-65SpecNo:437-45
27Einat H, Kofman O, Itkin O, et al. Augmentation of lithium's behavioraleffect by inositol uptake inhibitors. Journal of neural transmission,1998,105(1):31-8
28Arisi GM, Ruch M, Foresti ML, et al. Astrocyte Alterations in theHippocampus Following Pilocarpine-induced Seizures in Aged Rats.Aging Dis,2011,2(4):294-300
29Smilin BAG, Sivasudha T, Suganya M, et al. Trichosanthes tricuspidatamodulates oxidative toxicity in brain hippocampus against pilocarpineinduced status epilepticus in mice. Neurochem Res,2013,38(8):1715-25
30Scholl EA, Dudek FE, Ekstrand JJ. Neuronal degeneration is observed inmultiple regions outside the hippocampus after lithium pilocarpine-induced status epilepticus in the immature rat. Neuroscience,2013,252:45-59
31Xia Y, Luo C, Dai S, et al. Increased EphA/ephrinA expression inhippocampus of pilocarpine treated mouse. Epilepsy Res,2013,105(1-2):20-9
32Liu J, Wang A, Li L, et al. Oxidative stress mediates hippocampal neurondeath in rats after lithium-pilocarpine-induced status epilepticus. Seizure,2010,19(3):165-72
33Atanasova M, Petkova Z, Pechlivanova D, et al. Strain-dependent effectsof long-term treatment with melatonin on kainic acid-induced statusepilepticus, oxidative stress and the expression of heat shock proteins.Pharmacol Biochem Behav,2013,111:44-50
34Ahmad M. Protective effects of curcumin against lithium-pilocarpineinduced status epilepticus, cognitive dysfunction and oxidative stress inyoung rats. Saudi journal of biological sciences,2013,20(2):155-62
35Gao CJ, Niu L, Ren PC, et al. Hypoxic preconditioning attenuates globalcerebral ischemic injury following asphyxial cardiac arrest throughregulation of delta opioid receptor system. Neuroscience,2012,202:352-62
36Tokunaga H, Hiramatsu K, Sakaki T. Effect of preceding in vivo sublethalischemia on the evoked potentials during secondary in vitro hypoxiaevaluated with gerbil hippocampal slices. Brain Res,1998,784(1-2):316-20
37Wick A, Wick W, Waltenberger J, et al. Neuroprotection by hypoxicpreconditioning requires sequential activation of vascular endothelialgrowth factor receptor and Akt. The Journal of neuroscience: the officialjournal of the Society for Neuroscience,2002,22(15):6401-7
38Emerson MR, Nelson SR, Samson FE, et al. Hypoxia preconditioningattenuates brain edema associated with kainic acid-induced statusepilepticus in rats. Brain Res,1999,825(1-2):189-93
39Churilova AV, Rybnikova EA, Glushchenko TS, et al. Effect of mildhypobaric hypoxia in the preconditioning regime on expression of pCREBand NF-kappaB transcription factors in the rat hippocampus before andafter severe hypoxia. Morfologiia,2009,136(6):38-42
40Lee DS, Ryu HJ, Kim JE, et al. The effect of levetiracetam on statusepilepticus-induced neuronal death in the rat hippocampus. Seizure,2013,22(5):368-77
41Costa DC, Alva N, Trigueros L, et al. Intermittent hypobaric hypoxiainduces neuroprotection in kainate-induced oxidative stress in rats. J MolNeurosci,2013,50(3):402-10
1Vorob'ev LP, AIa C, Potievskaia VI. The possibilities of using intermittentnormobaric hypoxia for treating hypertension patients. Terapevticheskiiarkhiv,1994,66(8):12-5
2Ragozin ON, Balykin MV, Charikova EI. The biorhythmologicalregulation of external breathing in bronchial asthma patients by usingintermittent normobaric hypoxia therapy. Voprosy kurortologii,2000,(4):45-6
3Starykh EV, Fedin AI. Computer-assisted EEG in epileptic patients treatedwith intermittent normobaric hypoxic therapy in combined treatment ofepilepsy. Vserossiiskoe obshchestvo psikhiatrov,2002,102(3):27-9
4Bailey DM, Davies B, Baker J. Training in hypoxia: modulation ofmetabolic and cardiovascular risk factors in men. Med Sci Sports Exerc,2000,32(6):1058-66
5Berezovskii VA, Levashov MI. The build-up of human reserve potentialby exposure to intermittent normobaric hypoxia. Aerospace andenvironmental medicine,2000,34(2):39-43
6Wilber RL. Current trends in altitude training. Sports medicine,2001,31(4):249-65
7吕国蔚,崔秀玉,赵兰峰,等。低氧预适应的脑机制。中国应用生理学杂志,2004,(01):99-104
8Phillis JW, Ren J, O'Regan MH. Transporter reversal as a mechanism ofglutamate release from the ischemic rat cerebral cortex: studies withDL-threo-beta-benzyloxyaspartate. Brain Res,2000,880(1-2):224
9Delcamp TJ, Dales C, Ralenkotter L, et al. Intramitochondrial [Ca2+] andmembrane potential in ventricular myocytes exposed to anoxia-reoxygenation. Am J Physiol,1998,275(2Pt2): H484-94
10Weinberg JM, Venkatachalam MA, Roeser NF, et al. Mitochondrialdysfunction during hypoxia/reoxygenation and its correction by anaerobicmetabolism of citric acid cycle intermediates. Proc Natl Acad Sci U S A,2000,97(6):2826-31
11LoPachin RM, Gaughan CL, Lehning EJ, et al. Effects of ion channelblockade on the distribution of Na, K, Ca and other elements inoxygen-glucose deprived CA1hippocampal neurons. Neuroscience,2001,103(4):971-83
12Singh BK, Tripathi M, Pandey PK, et al. Alteration in mitochondrial thiolenhances calcium ion dependent membrane permeability transition anddysfunction in vitro: a cross-talk between mtThiol, Ca2+, and ROS. MolCell Biochem,2011,357(1-2):373-85
13Li LY, Li JL, Zhang HM, et al. TGFbeta1treatment reduces hippocampaldamage, spontaneous recurrent seizures, and learning memory deficits inpilocarpine-treated rats. J Mol Neurosci,2013,50(1):109-23
14Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol,2003,16(2):165-70
15Xiang J, Jiang Y. Long-term VEEG monitoring and intracranial electrodeEEG monitoring in the surgical treatment of temporal lobe epilepsy.Journal of Central South University. Medical sciences,2013,38(1):31-5
16Si Y, Liu L, Fang JJ, et al. Evaluation of the efficiency of inpatient24-hourVEEG combined with MRI in consecutive patients with newly diagnosedepilepsies. Epilepsy Behav,2011,20(4):633-7
17Geinisman Y, Detoledo-Morrell L, Morrell F, et al. Synapse restructuringassociated with the maintenance phase of hippocampal long-termpotentiation. J Comp Neurol,1996,368(3):413-23
18Jones OT. Ca2+channels and epilepsy. Eur J Pharmacol,2002,447(2-3):211-25
19Broicher T, Seidenbecher T, Meuth P, et al. T-current related effects ofantiepileptic drugs and a Ca2+channel antagonist on thalamic relay andlocal circuit interneurons in a rat model of absence epilepsy.Neuropharmacology,2007,53(3):431-46
20Shin HS, Lee J, Song I. Genetic studies on the role of T-type Ca2+channelsin sleep and absence epilepsy. CNS Neurol Disord Drug Targets,2006,5(6):629-38
21Weiergraber M, Stephani U, Kohling R. Voltage-gated calcium channels inthe etiopathogenesis and treatment of absence epilepsy. Brain researchreviews,2010,62(2):245-71
22Shin HS. T-type Ca2+channels and absence epilepsy. Cell Calcium,2006,40(2):191-6
23Felix R. Insights from mouse models of absence epilepsy into Ca2+channelphysiology and disease etiology. Cell Mol Neurobiol,2002,22(2):103-20
24Gurkoff GG, Shahlaie K, Lyeth BG. In vitro mechanical strain traumaalters neuronal calcium responses: Implications for posttraumatic epilepsy.Epilepsia,2012,53Suppl1:53-60
25Steinbeck JA, Henke N, Opatz J, et al. Store-operated calcium entrymodulates neuronal network activity in a model of chronic epilepsy. ExpNeurol,2011,232(2):185-94
26Thom M, Eriksson S, Martinian L, et al. Temporal lobe sclerosisassociated with hippocampal sclerosis in temporal lobe epilepsy:neuropathological features. J Neuropathol Exp Neurol,2009,68(8):928-38
27Acharya MM, Hattiangady B, Shetty AK. Progress in neuroprotectivestrategies for preventing epilepsy. Prog Neurobiol,2008,84(4):363-404
28de Araujo Furtado M, Lumley LA, Robison C, et al. Spontaneous recurrentseizures after status epilepticus induced by soman in Sprague-Dawley rats.Epilepsia,2010,51(8):1503-10
29Rybnikova E, Vataeva L, Tyulkova E, et al. Mild hypoxia preconditioningprevents impairment of passive avoidance learning and suppression ofbrain NGFI-A expression induced by severe hypoxia. Behav Brain Res,2005,160(1):107-14
30Gong SJ, Chen LY, Zhang M, et al. Intermittent hypobaric hypoxiapreconditioning induced brain ischemic tolerance by up-regulating glialglutamate transporter-1in rats. Neurochem Res,2012,37(3):527-37
1Liu H, Zhang X, Du Y, et al. Leonurine protects brain injury by increasedactivities of UCP4, SOD, CAT and Bcl-2, decreased levels of MDA andBax, and ameliorated ultrastructure of mitochondria in experimental stroke.Brain Res,2012,1474:73-81
2Hua JS, Li LP, Zhu XM. Effects of moxibustion pretreating on SOD andMDA in the rat of global brain ischemia. Journal of traditional Chinesemedicine,2008,28(4):289-92
3Tripanichkul W, Sripanichkulchai K, Duce JA, et al.17Beta-estradiolreduces nitrotyrosine immunoreactivity and increases SOD1and SOD2immunoreactivity in nigral neurons in male mice following MPTP insult.Brain Res,2007,1164:24-31
4Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: acomparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD(SOD3) gene structures, evolution, and expression. Free Radic Biol Med,2002,33(3):337-49
5Fukui M, Zhu BT. Mitochondrial superoxide dismutase SOD2, but notcytosolic SOD1, plays a critical role in protection against glutamate-induced oxidative stress and cell death in HT22neuronal cells. Free RadicBiol Med,2010,48(6):821-30
6Cardenas-Rodriguez N, Huerta-Gertrudis B, Rivera-Espinosa L, et al.Role of oxidative stress in refractory epilepsy: evidence in patients andexperimental models. Int J Mol Sci,2013,14(1):1455-76
7Rowley S, Patel M. Mitochondrial involvement and oxidative stress intemporal lobe epilepsy. Free Radic Biol Med,2013,62:121-31
8Azam F, Prasad MV, Thangavel N. Targeting oxidative stress componentin the therapeutics of epilepsy. Curr Top Med Chem,2012,12(9):994-1007
9Waldbaum S, Patel M. Mitochondria, oxidative stress, and temporal lobeepilepsy. Epilepsy Res,2010,88(1):23-45
10Liang LP, Waldbaum S, Rowley S, et al. Mitochondrial oxidative stressand epilepsy in SOD2deficient mice: attenuation by a lipophilicmetalloporphyrin. Neurobiol Dis,2012,45(3):1068-76
11Skemiene K, Rakauskaite G, Trumbeckaite S, et al. Anthocyanins blockischemia-induced apoptosis in the perfused heart and supportmitochondrial respiration potentially by reducing cytosolic cytochrome c.Int J Biochem Cell Biol,2013,45(1):23-9
12Yang RF, Zhao GW, Liang ST, et al. Mitofilin regulates cytochrome crelease during apoptosis by controlling mitochondrial cristae remodeling.Biochem Biophys Res Commun,2012,428(1):93-8
13Lin HI, Lee YJ, Chen BF, et al. Involvement of Bcl-2family, cytochrome cand caspase3in induction of apoptosis by beauvericin in human non-smallcell lung cancer cells. Cancer Lett.2005,230(2):248-59
14Chae IH, Park KW, Kim HS, et al. Nitric oxide-induced apoptosis ismediated by Bax/Bcl-2gene expression, transition of cytochrome c, andactivation of caspase-3in rat vascular smooth muscle cells. Clin ChimActa,2004,341(1-2):83-91
15Zhao H, Yenari MA, Cheng D, et al. Bcl-2overexpression protects againstneuron loss within the ischemic margin following experimental stroke andinhibits cytochrome c translocation and caspase-3activity. J Neurochem,2003,85(4):1026-36
16Dong GX, Singh DK, Dendle P, et al. Regional expression of Bcl-2mRNAand mitochondrial cytochrome c release after experimental brain injury inthe rat. Brain Res,2001,903(1-2):45-52
17Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissuesby thiobarbituric acid reaction. Anal Biochem,1979,95(2):351-8
18Schmidt PJ, Ramos-Gomez M, Culotta VC. A gain of superoxidedismutase (SOD) activity obtained with CCS, the copper metallochap-erone for SOD1. J Biol Chem,1999,274(52):36952-6
19ELLMAN GL. Tissue sulfhydryl groups. Arch Biochem Biophys,1959,82(1):70-7
20Dringen R. Metabolism and functions of glutathione in brain. ProgNeurobiol,2000,62(6):649-71
21Liang LP, Waldbaum S, Rowley S, et al. Mitochondrial oxidative stressand epilepsy in SOD2deficient mice: attenuation by a lipophilicmetalloporphyrin. Neurobiol Dis,2012,45(3):1068-76
22Liang LP, Patel M. Mitochondrial oxidative stress and increased seizuresusceptibility in Sod2(-/+) mice. Free Radic Biol Med,2004,36(5):542-54
23Dal-Pizzol F, Klamt F, Vianna MM, et al. Lipid peroxidation inhippocampus early and late after status epilepticus induced by pilocarpineor kainic acid in Wistar rats. Neurosci Lett,2000,291(3):179-82
24Ng CF, Schafer FQ, Buettner GR, et al. The rate of cellular hydrogenperoxide removal shows dependency on GSH: mathematical insight into invivo H2O2and GPx concentrations. Free Radic Res,2007,41(11):1201-11
25Bruce AJ, Baudry M. Oxygen free radicals in rat limbic structures afterkainate-induced seizures. Free Radic Biol Med,1995,18(6):993-1002
26Erakovic V, Zupan G, Varljen J, et al. Lithium plus pilocarpine inducedstatus epilepticus-biochemical changes. Neurosci Res,2000,36(2):157-66
27Bellissimo MI, Amado D, Abdalla DS, et al. Superoxide dismutase,glutathione peroxidase activities and the hydroperoxide concentration aremodified in the hippocampus of epileptic rats. Epilepsy Res,2001,46(2):121-8
28Shin EJ, Ko KH, Kim WK, et al. Role of glutathione peroxidase in theontogeny of hippocampal oxidative stress and kainate seizure sensitivity inthe genetically epilepsy-prone rats. Neurochem Int,2008,52(6):1134-47
29Gamdzyk M, Makarewicz D, Slomka M, et al. Hypobaric HypoxiaPostconditioning Reduces Brain Damage and Improves AntioxidativeDefense in the Model of Birth Asphyxia in7-Day-Old Rats. NeurochemRes,2014,39(1):68-75
30Zhou JJ, Wei Y, Zhang L, et al. Chronic intermittent hypobaric hypoxiaprevents cardiac dysfunction through enhancing antioxidation infructose-fed rats. Can J Physiol Pharmacol,2013,91(5):332-7
31Mukherjee N, Mukherjee S, Saini P, et al. Antifilarial effects of polyphenolrich ethanolic extract from the leaves of Azadirachta indica throughmolecular and biochemical approaches describing reactive oxygen species(ROS) mediated apoptosis of Setaria cervi. Exp Parasitol,2014,136:41-58
32Cortassa S, O'Rourke B, Aon MA. Redox-Optimized ROS Balance andthe relationship between mitochondrial respiration and ROS. BiochimBiophys Acta,2014,1837(2):287-95
33Lin B, Chen Z, Xu Y, et al.7-b, a novel amonafide analogue, cause growthinhibition and apoptosis in Raji cells via a ROS-mediated mitochondrialpathway. Leuk Res,2011,35(5):646-56
34Martinez-Abundis E, Rajapurohitam V, Haist JV, et al. The obesity-relatedpeptide leptin sensitizes cardiac mitochondria to calcium-inducedpermeability transition pore opening and apoptosis. PLoS One,2012,7(7):e41612
35Haeberlein SL. Mitochondrial function in apoptotic neuronal cell death.Neurochem Res,2004,29(3):521-30
36Chen W, Zhao Z, Li L, et al. Hispolon induces apoptosis in human gastriccancer cells through a ROS-mediated mitochondrial pathway. Free RadicBiol Med,2008,45(1):60-72
37Waldbaum S, Patel M. Mitochondrial dysfunction and oxidative stress: acontributing link to acquired epilepsy. J Bioenerg Biomembr,2010,42(6):449-55
38Rowley S, Patel M. Mitochondrial involvement and oxidative stress intemporal lobe epilepsy. Free Radic Biol Med,2013,62:121-31
39Polster BM, Fiskum G. Mitochondrial mechanisms of neural cell apoptosis.J Neurochem,2004,90(6):1281-9
40Christensen ME, Jansen ES, Sanchez W, et al. Flow cytometry basedassays for the measurement of apoptosis-associated mitochondrialmembrane depolarisation and cytochrome c release. Methods (San Diego,Calif.),2013,61(2):138-45
41Smeland OB, Hadera MG, McDonald TS, et al. Brain mitochondrialmetabolic dysfunction and glutamate level reduction in the pilocarpinemodel of temporal lobe epilepsy in mice. J Cereb Blood Flow Metab,2013,33(7):1090-7
42Kluck RM, Bossy-Wetzel E, Green DR, et al. The release of cytochrome cfrom mitochondria: a primary site for Bcl-2regulation of apoptosis.Science (New York, N.Y.),1997,275(5303):1132-6
43Henshall DC, Clark RS, Adelson PD, et al. Alterations in bcl-2andcaspase gene family protein expression in human temporal lobe epilepsy.Neurology,2000,55(2):250-7
44Narkilahti S, Pirttila TJ, Lukasiuk K, et al. Expression and activation ofcaspase3following status epilepticus in the rat. Eur J Neurosci,2003,18(6):1486-96
45Xu J, Wang S, Lin Y, et al. Ghrelin protects against cell death ofhippocampal neurons in pilocarpine-induced seizures in rats. NeurosciLett,2009,453(1):58-61
1Pinabiaux C, Bulteau C, Fohlen M, et al. Impaired emotional memoryrecognition after early temporal lobe epilepsy surgery: the fearful faceexception. Cortex,2013,49(5):1386-93
2Duncan JS. Seizure-induced neuronal injury: human data. Neurology,2002,59(9Suppl5): S15-20
3Tobimatsu S, Hiromatsu M, Kato M, et al. Adverse effect of antiepilepticdrugs on the visual recognition--a contrast sensitivity function study.Clinical neurology,1992,32(7):713-7
4Berberich S, Jensen V, Hvalby O, et al. The role of NMDAR subtypes andcharge transfer during hippocampal LTP induction. Neuropharmacology,2007,52(1):77-86
5Geinisman Y, Disterhoft JF, Gundersen HJ, et al. Remodeling ofhippocampal synapses after hippocampus-dependent associative learning.J Comp Neurol,2000,417(1):49-59
6Nagura H, Ishikawa Y, Kobayashi K, et al. Impaired synaptic clustering ofpostsynaptic density proteins and altered signal transmission inhippocampal neurons, and disrupted learning behavior in PDZ1and PDZ2ligand binding-deficient PSD-95knockin mice. Mol Brain,2012,5:43
7Gandhi RM, Kogan CS, Messier C, et al. Visual-spatial learningimpairments are associated with hippocampal PSD-95proteindysregulation in a mouse model of fragile X syndrome. Neuroreport,2014,25(4):255-61
8Mishima K, Ikeda T, Aoo N, et al. Hypoxia-ischemic insult in neonatal ratsinduced slowly progressive brain damage related to memory impairment.Neurosci Lett,2005,376(3):194-9
9Mecklinger A, von CDY, Matthes-von CG. Event-related potentialevidence for a specific recognition memory deficit in adult survivors ofcerebral hypoxia. Brain,1998,121(Pt10):1919-35
10Virues-Ortega J, Garrido E, Javierre C, et al. Human behaviour anddevelopment under high-altitude conditions. Dev Sci,2006,9(4):400-10
11Gong SJ, Chen LY, Zhang M, et al. Intermittent hypobaric hypoxiapreconditioning induced brain ischemic tolerance by up-regulating glialglutamate transporter-1in rats. Neurochem Res,2012,37(3):527-37
12Churilova AV, Rybnikova EA, Glushchenko TS, et al. Effects of moderatehypobaric hypoxic preconditioning on the expression of the transcriptionfactors pCREB and NF-kappaB in the rat hippocampus before and aftersevere hypoxia. Neurosci Behav Physiol,2010,40(8):852-7
13Zhang JX, Chen XQ, Du JZ, et al. Neonatal exposure to intermittenthypoxia enhances mice performance in water maze and8-arm radial mazetasks. Journal of neurobiology,2005,65(1):72-84
14Xie T, Wang WP, Mao ZF, et al. Effects of epigallocatechin-3-gallate onpentylenetetrazole-induced kindling, cognitive impairment and oxidativestress in rats. Neurosci Lett,2012,516(2):237-41
15Geinisman Y, Ganeshina O, Yoshida R, et al. Aging, spatial learning, andtotal synapse number in the rat CA1stratum radiatum. Neurobiol Aging,2004,25(3):407-16
16Guldner FH, Ingham CA. Increase in postsynaptic density material in optictarget neurons of the rat suprachiasmatic nucleus after bilateral enucleation.Neurosci Lett,1980,17(1-2):27-31
17Kozyrev SA, Nikitin VP. Different mechanisms of long-term synapticfacilitation during associative learning and sensitization. Rossiiskaiaakademiia nauk,2013,99(5):599-611
18Kennedy MB. Synaptic Signaling in Learning and Memory. Cold SpringHarb Perspect Biol,2013
19Cavazos JE, Jones SM, Cross DJ. Sprouting and synaptic reorganization inthe subiculum and CA1region of the hippocampus in acute and chronicmodels of partial-onset epilepsy. Neuroscience,2004,126(3):677-88
20Babanejad S, Naghdi N, Haeri RSA. Microinjection of Dihydrotestos-terone as a5alpha-Reduced Metabolite of Testosterone into CA1Regionof Hippocampus Could Improve Spatial Learning in the Adult Male Rats.Iranian journal of pharmaceutical research: IJPR,2012,11(2):661-9
21Talebi A, Naghdi N, Sepehri H, et al. The Role of Estrogen Receptors onSpatial Learning and Memory in CA1Region of Adult Male RatHippocampus. Iranian journal of pharmaceutical research: IJPR,2010,9(2):183-91
22Gallagher M, Burwell R, Burchinal M. Severity of spatial learningimpairment in aging: development of a learning index for performance inthe Morris water maze. Behav Neurosci,1993,107(4):618-26
23Fiore M, Korf J, Antonelli A, et al. Long-lasting effects of prenatal MAMtreatment on water maze performance in rats: associations with alteredbrain development and neurotrophin levels. Neurotoxicol Teratol,2002,24(2):179-91
24Karabeg MM, Grauthoff S, Kollert SY, et al.5-HTT deficiency affectsneuroplasticity and increases stress sensitivity resulting in altered spatiallearning performance in the Morris water maze but not in the Barnes maze.PLoS One,2013,8(10): e78238
25Bromley-Brits K, Deng Y, Song W. Morris water maze test for learningand memory deficits in Alzheimer's disease model mice. J Vis Exp,2011,(53):2920
26Bell BD. Route learning impairment in temporal lobe epilepsy. EpilepsyBehav,2012,25(2):256-62
27Zhang JX, Chen XQ, Du JZ, et al. Neonatal exposure to intermittenthypoxia enhances mice performance in water maze and8-arm radial mazetasks. Journal of neurobiology,2005,65(1):72-84
28Berberich S, Jensen V, Hvalby O, et al. The role of NMDAR subtypes andcharge transfer during hippocampal LTP induction. Neuropharmacology,2007,52(1):77-86
29Zhang Y, Wei J, Yang Z. Perinatal undernutrition attenuates fieldexcitatory postsynaptic potentials and influences dendritic spine densityand morphology in hippocampus of male rat offspring. Neuroscience,2013,244:31-41
30Ding J, Xi YD, Zhang DD, et al. Soybean isoflavone amelioratesbeta-amyloid1-42-induced learning and memory deficit in rats byprotecting synaptic structure and function. Synapse (New York, N.Y.),2013,67(12):856-64
31Volk L, Kim CH, Takamiya K, et al. Developmental regulation of proteininteracting with C kinase1(PICK1) function in hippocampal synapticplasticity and learning. Proc Natl Acad Sci U S A,2010,107(50):21784-9
32Yang SN, Liu CA, Chung MY, et al. Alterations of postsynaptic densityproteins in the hippocampus of rat offspring from the morphine-addictedmother: Beneficial effect of dextromethorphan. Hippocampus,2006,16(6):521-30
33Zhang Y, Wei J, Yang Z. Perinatal undernutrition attenuates fieldexcitatory postsynaptic potentials and influences dendritic spine densityand morphology in hippocampus of male rat offspring. Neuroscience,2013,244:31-41
34Chen X, Nelson CD, Li X, et al. PSD-95is required to sustain themolecular organization of the postsynaptic density. J Neurosci,2011,31(17):6329-38
35Di G, Zheng Y. Effects of high-speed railway noise on the synapticultrastructure and phosphorylated-CaMKII expression in the centralnervous system of SD rats. Environ Toxicol Pharmacol,2013,35(1):93-9
36Xie T, Wang WP, Jia LJ, et al. Environmental enrichment restorescognitive deficits induced by prenatal maternal seizure. Brain Res,2012,1470:80-8
37Yang J, Liu Q, Zhang L, et al. Lanthanum chloride impairs memory,decreases pCaMK IV, pMAPK and pCREB expression of hippocampus inrats. Toxicol Lett,2009,190(2):208-14
38Sharrad DF, Gai WP, Brookes SJ. Selective coexpression of synapticproteins, alpha-synuclein,cysteine string protein-alpha, synaptophysin,synaptotagmin-1,and synaptobrevin-2in vesicular acetylcholine transpor-ter-immunoreactive axons in the guinea pig ileum. J Comp Neurol,2013,521(11):2523-37
39Kiraly DD, Lemtiri-Chlieh F, Levine ES, et al. Kalirin binds the NR2Bsubunit of the NMDA receptor,altering its synaptic localization andfunction. J Neurosci,2011,31(35):12554-65
40Li Y, Hu J, Hofer K, et al. DHHC5interacts with PDZ domain3ofpost-synaptic density-95(PSD-95) protein and plays a role in learning andmemory. J Biol Chem,2010,285(17):13022-31
41Nagura H, Ishikawa Y, Kobayashi K, et al. Impaired synaptic clustering ofpostsynaptic density proteins and altered signal transmission inhippocampal neurons, and disrupted learning behavior in PDZ1and PDZ2ligand binding-deficient PSD-95knockin mice. Mol Brain,2012,5:43
42Rosas K, Parron I, Serrano P, et al. Spatial recognition memory in a virtualreality task is altered in refractory temporal lobe epilepsy. Epilepsy Behav,2013,28(2):227-31
43Penzes P, Johnson RC, Alam MR, et al. An isoform of kalirin, abrain-specific GDP/GTP exchange factor, is enriched in the postsynapticdensity fraction. J Biol Chem,2000,275(9):6395-403
44Schiller MR, Blangy A, Huang J, et al. Induction of lamellipodia byKalirin does not require its guanine nucleotide exchange factor activity.Exp Cell Res,2005,307(2):402-17
45Ma XM, Kiraly DD, Gaier ED, et al. Kalirin-7is required for synapticstructure and function. J Neurosci,2008,28(47):12368-82
46Nicholson DA, Cahill ME, Tulisiak CT, et al. Spatially restrictedactin-regulatory signaling contributes to synapse morphology. JNeurochem,2012,121(6):852-60
47Migaud M, Charlesworth P, Dempster M, et al. Enhanced long-termpotentiation and impaired learning in mice with mutant postsynapticdensity-95protein. Nature,1998,396(6710):433-9
48Chen WF, Chang H, Huang LT, et al. Alterations in long-term seizuresusceptibility and the complex of PSD-95with NMDA receptor fromanimals previously exposed to perinatal hypoxia. Epilepsia,2006,47(2):288-96
1Di MR, Mastroberardino PG, Hu X, et al. Thiol oxidation and alteredNR2B/NMDA receptor functions in in vitro and in vivo pilocarpinemodels: Implications for epileptogenesis. Neurobiol Dis,2012,49C:87-98
2Ashrafi MR, Shams S, Nouri M, et al. A probable causative factor for anold problem: selenium and glutathione peroxidase appear to playimportant roles in epilepsy pathogenesis. Epilepsia,2007,48(9):1750-5
3Khurana DS, Valencia I, Goldenthal MJ, et al. Mitochondrial dysfunctionin epilepsy. Semin Pediatr Neurol,2013,20(3):176-87
4Adebayo OL, Shallie PD, Salau BA, et al. Comparative study on theinfluence of fluoride on lipid peroxidation and antioxidants levels in thedifferent brain regions of well-fed and protein undernourished rats. Journalof trace elements in medicine and biology: organ of the Society forMinerals and Trace Elements (GMS),2013,27(4):370-4
5Butterick TA, Nixon JP, Billington CJ, et al. Orexin A decreases lipidperoxidation and apoptosis in a novel hypothalamic cell model. NeurosciLett,2012,524(1):30-4
6Smeland OB, Hadera MG, McDonald TS, et al. Brain mitochondrialmetabolic dysfunction and glutamate level reduction in the pilocarpinemodel of temporal lobe epilepsy in mice. Journal of cerebral blood flowand metabolism,2013,33(7):1090-7
7Rowley S, Patel M. Mitochondrial involvement and oxidative stress intemporal lobe epilepsy. Free Radic Biol Med,2013,62:121-31
8Menon B, Ramalingam K, Kumar RV. Oxidative stress in patients withepilepsy is independent of antiepileptic drugs. Seizure,2012,21(10):780-4
9Hong S, Xin Y, HaiQin W, et al. The PPARgamma agonist rosiglitazoneprevents cognitive impairment by inhibiting astrocyte activation andoxidative stress following pilocarpine-induced status epilepticus.Neurological sciences,2012,33(3):559-66
10Liu J, Wang A, Li L, et al. Oxidative stress mediates hippocampal neurondeath in rats after lithium-pilocarpine-induced status epilepticus. Seizure,2010,19(3):165-72
11dos SSIM, do NKG, Feitosa CM, et al. Caffeic acid effects on oxidativestress in rat hippocampus after pilocarpine-induced seizures. Neurologicalsciences: official journal of the Italian Neurological Society and of theItalian Society of Clinical Neurophysiology,2011,32(3):375-80
12Chuang YC, Chang AY, Lin JW, et al. Mitochondrial dysfunction andultrastructural damage in the hippocampus during kainic acid-inducedstatus epilepticus in the rat. Epilepsia,2004,45(10):1202-9
13Gao J, Chi ZF, Liu XW, et al. Mitochondrial dysfunction andultrastructural damage in the hippocampus of pilocarpine-inducedepileptic rat. Neurosci Lett,2007,411(2):152-7
14Ahmad M. Protective effects of curcumin against lithium-pilocarpineinduced status epilepticus, cognitive dysfunction and oxidative stress inyoung rats. Saudi journal of biological sciences,2013,20(2):155-62
15Naseer MI, Ullah I, Al-Qahtani MH, et al. Decreased GABABRexpression and increased neuronal cell death in developing rat brain afterPTZ-induced seizure. Neurological sciences: official journal of the ItalianNeurological Society and of the Italian Society of Clinical Neurophy-siology,2013,34(4):497-503
16Biagini G, D'Antuono M, Benini R, et al. Perirhinal cortex and temporallobe epilepsy. Front Cell Neurosci,2013,7:130
17Henshall DC. Apoptosis signalling pathways in seizure-induced neuronaldeath and epilepsy. Biochem Soc Trans,2007,35(Pt2):421-3
18Ewen CL, Kane KP, Bleackley RC. Granzyme H induces cell deathprimarily via a Bcl-2-sensitive mitochondrial cell death pathway that doesnot require direct Bid activation. Mol Immunol,2013,54(3-4):309-18
19Chen Q, Lesnefsky EJ. Blockade of electron transport during ischemiapreserves bcl-2and inhibits opening of the mitochondrial permeabilitytransition pore. FEBS Lett,2011,585(6):921-6
20Lu HF, Chie YJ, Yang MS, et al. Apigenin induces caspase-dependentapoptosis in human lung cancer A549cells through Bax-andBcl-2-triggered mitochondrial pathway. Int J Oncol,2010,36(6):1477-84
21Tomiyama A, Tachibana K, Suzuki K, et al. MEK-ERK-dependentmultiple caspase activation by mitochondrial proapoptotic Bcl-2familyproteins is essential for heavy ion irradiation-induced glioma cell death.Cell Death Dis,2010,1: e60
22Donovan M, Cotter TG. Control of mitochondrial integrity by Bcl-2familymembers and caspase-independent cell death. Biochim Biophys Acta,2004,1644(2-3):133-47
23Chen Q, Gong B, Almasan A. Distinct stages of cytochrome c release frommitochondria: evidence for a feedback amplification loop linking caspaseactivation to mitochondrial dysfunction in genotoxic stress inducedapoptosis. Cell Death Differ,2000,7(2):227-33
24Schindler CK, Pearson EG, Bonner HP, et al. Caspase-3cleavage andnuclear localization of caspase-activated DNase in human temporal lobeepilepsy. Journal of cerebral blood flow and metabolism,2006,26(4):583-9
25Hu K, Li SY, Xiao B, et al. Protective effects of quercetin against statusepilepticus induced hippocampal neuronal injury in rats: involvement ofX-linked inhibitor of apoptosis protein. Acta neurologica Belgica,2011,111(3):205-12
26Yuzefovych LV, Ledoux SP, Wilson GL, et al. Mitochondrial DNADamage via Augmented Oxidative Stress Regulates EndoplasmicReticulum Stress and Autophagy: Crosstalk, Links and Signaling. PLoSOne,2013,8(12): e83349
27Shi K, Wang D, Cao X, et al. Endoplasmic reticulum stress signaling isinvolved in mitomycin C (MMC)-induced apoptosis in human fibroblastsvia PERK pathway. PLoS One,2013,8(3): e59330
28Liu CY, Yang JS, Huang SM, et al. Smh-3induces G(2)/M arrest andapoptosis through calciummediated endoplasmic reticulum stress andmitochondrial signaling in human hepatocellular carcinoma Hep3B cells.Oncol Rep,2013,29(2):751-62
29Qu K, Shen NY, Xu XS, et al. Emodin induces human T cell apoptosis invitro by ROS-mediated endoplasmic reticulum stress and mitochondrialdysfunction. Acta Pharmacol Sin,2013,34(9):1217-28
30Yamamoto A, Murphy N, Schindler CK, et al. Endoplasmic reticulumstress and apoptosis signaling in human temporal lobe epilepsy. JNeuropathol Exp Neurol,2006,65(3):217-25
31Muzio M, Stockwell BR, Stennicke HR, et al. An induced proximitymodel for caspase-8activation. J Biol Chem,1998,273(5):2926-30
32Schug ZT, Gonzalvez F, Houtkooper RH, et al. BID is cleaved bycaspase-8within a native complex on the mitochondrial membrane. CellDeath Differ,2011,18(3):538-48
33Kim YJ, Jung EB, Seo SJ, et al. Quercetin-3-O-(2"-galloyl)-alpha-l-rhamnopyranoside prevents TRAIL-induced apoptosis in humankeratinocytes by suppressing the caspase-8-and Bid-pathways and themitochondrial pathway. Chem Biol Interact,2013,204(3):144-52
34El-Hodhod MA, Tomoum HY, Abd AMM, et al. Serum Fas and Bcl-2inpatients with epilepsy. Acta Neurol Scand,2006,113(5):315-21
35Henshall DC, Bonislawski DP, Skradski SL, et al. Cleavage of bid mayamplify caspase-8-induced neuronal death following focally evokedlimbic seizures. Neurobiol Dis,2001,8(4):568-80
36Larsen BD, Megeney LA. Parole terms for a killer: directingcaspase3/CAD induced DNA strand breaks to coordinate changes in geneexpression. Cell cycle (Georgetown, Tex.),2010,9(15):2940-5
37Chen N, Gao Y, Yan N, et al. High-frequency stimulation of thehippocampus protects against seizure activity and hippocampal neuronalapoptosis induced by kainic acid administration in macaques.Neuroscience,2014,256:370-8
38Henshall DC, Chen J, Simon RP. Involvement of caspase-3-like proteasein the mechanism of cell death following focally evoked limbic seizures. JNeurochem,2000,74(3):1215-23
39Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam,diazepam, and placebo for the treatment of out-of-hospital statusepilepticus. N Engl J Med Overseas Ed,2001,345(9):631-7
40Liefaard LC, Gunput RA, Danhof M, et al. Decreased Efficacy ofGABAA-receptor modulation by midazolam in the kainate model oftemporal lobe epilepsy. Epilepsia,2007,48(7):1378-87
41Holsti M, Dudley N, Schunk J, et al. Intranasal midazolam vs rectaldiazepam for the home treatment of acute seizures in pediatric patientswith epilepsy. Archives of pediatrics&adolescent medicine,2010,164(8):747-53
42Darrah SD, Chuang J, Mohler LM, et al. Dilantin therapy in anexperimental model of traumatic brain injury: effects of limited versusdaily treatment on neurological and behavioral recovery. J Neurotrauma,2011,28(1):43-55
43Inoue Y, Usui N, Hiroki T, et al. Bioavailability of intravenousfosphenytoin sodium in healthy Japanese volunteers. Eur J Drug MetabPharmacokinet,2013,38(2):139-48
44Karlovassitou-Koniari A, Alexiou D, Angelopoulos P, et al. Low dosesodium valproate in the treatment of juvenile myoclonic epilepsy. J Neurol,2002,249(4):396-9
45Wang W, Wu J, Li S, et al. Sodium valproate for epilepsy in rural China: anefficacy and safety assessment in primary care. Epilepsy Res,2012,102(3):201-5
46Cai YH, Wang H. Effects of valproate sodium on pituitary gonadotropin inadolescent girls with epilepsy. Chinese journal of contemporary pediatrics,2011,13(9):725-7
47Kanemura H, Sano F, Maeda Y, et al. Valproate sodium enhances bodyweight gain in patients with childhood epilepsy: a pathogenic mechanismsand open-label clinical trial of behavior therapy. Seizure,2012,21(7):496-500
48Monot R. Technique for venous general anesthesia using sodium pentothal.Annales francaises d'anesthesie et de reanimation,2008,27Suppl2: S310-22
49Schneider F, Herzer W, Schroeder HW, et al. Effects of propofol onelectrocorticography in patients with intractable partial epilepsy. JNeurosurg Anesthesiol,2011,23(2):150-5
50Agrawal N, Rao S, Nair R. A death associated with possible propofolinfusion syndrome. Indian J Surg,2013,75(Suppl1):407-8
51Power KN, Flaatten H, Gilhus NE, et al. Propofol treatment in adultrefractory status epilepticus. Mortality risk and outcome. Epilepsy Res,2011,94(1-2):53-60
52Kholin AA, Zavadenko NN, Il'ina ES, et al. Efficacy and safety oftopiramate depending on patient's age and forms of epilepsy.Vserossiiskoe obshchestvo psikhiatrov,2013,113(4Pt2):45-51
53Demir CF, Ozdemir HH, Mungen B. Efficacy of topiramate as add-ontherapy in two different types of progressive myoclonic epilepsy. Actamedica (Hradec Kralove)/Universitas Carolina, Facultas Medica HradecKralove,2013,56(1):36-8
54Kiviranta AM, Laitinen-Vapaavuori O, Hielm-Bjorkman A, et al.Topiramate as an add-on antiepileptic drug in treating refractory canineidiopathic epilepsy. J Small Anim Pract,2013,54(10):512-20
55Kremenchugskaia MR, Globa OV, Kuzenkova LM. The use of topiramatein the treatment of focal epilepsy in children. Vserossiiskoe obshchestvopsikhiatrov,2013,113(12):33-38
56Park KM, Kim SH, Nho SK, et al. A randomized open-label observationalstudy to compare the efficacy and tolerability between topiramate andvalproate in juvenile myoclonic epilepsy. Journal of clinical neuroscience,2013,20(8):1079-82
57Koo DL, Hwang KJ, Kim D, et al. Effects of levetiracetam monotherapyon the cognitive function of epilepsy patients. Eur Neurol,2013,70(1-2):88-94
58Kang BS, Moon HJ, Kim YS, et al. The long-term efficacy and safety oflevetiracetam in a tertiary epilepsy centre. Epileptic Disord,2013,15(3):302-10
59Goldberg-Stern H, Feldman L, Eidlitz-Markus T, et al. Levetiracetam inchildren, adolescents and young adults with intractable epilepsy: efficacy,tolerability and effect on electroencephalogram--a pilot study. EuropeanPaediatric Neurology Society,2013,17(3):248-53
60Kanemura H, Sano F, Sugita K, et al. Effects of levetiracetam on seizurefrequency and neuropsychological impairments in children with refractoryepilepsy with secondary bilateral synchrony. Seizure,2013,22(1):43-7
61Biton V, Berkovic SF, Abou-Khalil B, et al. Brivaracetam as adjunctivetreatment for uncontrolled partial epilepsy in adults: A phase IIIrandomized, double-blind, placebo-controlled trial. Epilepsia,2014,55(1):57-66
62Nicita F, Spalice A, Papetti L, et al. Efficacy of verapamil as an adjunctivetreatment in children with drug-resistant epilepsy: A pilot study. Seizure,2014,23(1):36-40
63Yamada J, Zhu G, Okada M, et al. A novel prophylactic effect offurosemide treatment on autosomal dominant nocturnal frontal lobeepilepsy (ADNFLE). Epilepsy Res,2013,107(1-2):127-37
64Petkova Z, Tchekalarova J, Pechlivanova D, et al. Treatment withmelatonin after status epilepticus attenuates seizure activity and neuronaldamage but does not prevent the disturbance in diurnal rhythms andbehavioral alterations in spontaneously hypertensive rats in kainate modelof temporal lobe epilepsy. Epilepsy Behav,2014,31C:198-208
65Maschio M, Dinapoli L, Sperati F, et al. Effect of pregabalin add-ontreatment on seizure control, quality of life, and anxiety in patients withbrain tumour-related epilepsy: a pilot study. Epileptic Disord,2012,14(4):388-97
66Ben-Menachem E. Medical management of refractory epilepsy-Practicaltreatment with novel antiepileptic drugs. Epilepsia,2014,55Suppl1:3-8
67Kissin MY, Bondarenko II. The experience treatment of adjunctivelacosamide for patients with drug-resistance partial epilepsy. Vserossiis-koe obshchestvo psikhiatrov,2013,113(9):23-8.
68Zaccara G, Giovannelli F, Cincotta M, et al. AMPA receptor inhibitors forthe treatment of epilepsy: the role of perampanel. Expert Rev Neurother,2013,13(6):647-55
69Craig D, Rice S, Paton F, et al. Retigabine for the adjunctive treatment ofadults with partial-onset seizures in epilepsy with and without secondarygeneralization: a NICE single technology appraisal. Pharmacoeconomics,2013,31(2):101-10
70Dhanushkodi A, Shetty AK. Is exposure to enriched environmentbeneficial for functional post-lesional recovery in temporal lobe epilepsy.Neurosci Biobehav Rev,2008,32(4):657-74
71Hu K, Xie YY, Zhang C, et al. MicroRNA expression profile of thehippocampus in a rat model of temporal lobe epilepsy andmiR-34a-targeted neuroprotection against hippocampal neurone cellapoptosis post-status epilepticus. BMC Neurosci,2012,13:115
72Perry MS, Duchowny M. Surgical versus medical treatment for refractoryepilepsy: outcomes beyond seizure control. Epilepsia,2013,54(12):2060-70
73Luan G, Zhao Y, Zhai F, et al. Ketogenic diet reduces Smac/Diablo andcytochrome c release and attenuates neuronal death in a mouse model oflimbic epilepsy. Brain Res Bull,2012,89(3-4):79-85
74Pablos-Sanchez T, Oliveros-Leal L, Nunez-Enamorado N, et al. The use ofthe ketogenic diet as treatment for refractory epilepsy in the paediatric age.Revista de neurologia,2014,58(2):55-62
75Cervenka MC, Kossoff EH. Dietary treatment of intractable epilepsy.Continuum (Minneapolis, Minn.),2013,19(3Epilepsy):756-66
76Sharma S, Sankhyan N, Gulati S, et al. Use of the modified Atkins diet fortreatment of refractory childhood epilepsy: a randomized controlled trial.Epilepsia,2013,54(3):481-6
77Morris GL3rd, Gloss D, Buchhalter J, et al. Evidence-based guidelineupdate: vagus nerve stimulation for the treatment of epilepsy: report of theguideline development subcommittee of the american academy ofneurology. Epilepsy currents/American Epilepsy Society,2013,13(6):297-303
78Roldan P, Brell M, Perla YPC, et al. Vagal nerve stimulation treatment inpatients with drug resistant epilepsy: Son Espases University Hospitalexperience. Neurocirugia (Asturias, Spain),2013,24(5):204-9
79Patel KS, Labar DR, Gordon CM, et al. Efficacy of vagus nervestimulation as a treatment for medically intractable epilepsy in brain tumorpatients. A case-controlled study using the VNS therapy Patient OutcomeRegistry. Seizure,2013,22(8):627-33
80Sun W, Mao W, Meng X, et al. Low-frequency repetitive transcranialmagnetic stimulation for the treatment of refractory partial epilepsy: acontrolled clinical study. Epilepsia,2012,53(10):1782-9
81Zhong K, Wu DC, Jin MM, et al. Wide therapeutic time-window oflow-frequency stimulation at the subiculum for temporal lobe epilepsytreatment in rats. Neurobiol Dis,2012,48(1):20-6
82Shen FZ, Wang F, Yang GM, et al. The effects of low-frequency electricstimulus on hippocampal of Effects of low-frequency electric stimulus onhippocampal of alpha5subunit of extra synapse GABAA receptor inkainic acid-induced epilepsy rats. Zhonghua yi xue za zhi,2013,93(7):550-3
83Ghotbedin Z, Janahmadi M, Mirnajafi-Zadeh J, et al. Electrical lowfrequency stimulation of the kindling site preserves the electrophysio-logical properties of the rat hippocampal CA1pyramidal neurons from thedestructive effects of amygdala kindling: the basis for a possible promisingepilepsy therapy. Brain Stimul,2013,6(4):515-23
84Li LY, Li JL, Zhang HM, et al. TGFbeta1treatment reduces hippocampaldamage, spontaneous recurrent seizures, and learning memory deficits inpilocarpine-treated rats. J Mol Neurosci,2013,50(1):109-23
1Hou ZH, Yu X. Activity-regulated somatostatin expression reducesdendritic spine density and lowers excitatory synaptic transmission viapostsynaptic somatostatin receptor4. J Biol Chem,2013,288(4):2501-9
2Sala C, Futai K, Yamamoto K, et al. Inhibition of dendritic spinemorphogenesis and synaptic transmission by activity-inducible proteinHomer1a. The Journal of neuroscience: the official journal of the Societyfor Neuroscience,2003,23(15):6327-37
3Hasan A, Nitsche MA, Rein B, et al. Dysfunctional long-termpotentiation-like plasticity in schizophrenia revealed by transcranial directcurrent stimulation. Behav Brain Res,2011,224(1):15-22
4Shi Y, Pontrello CG, DeFea KA, et al. Focal adhesion kinase actsdownstream of EphB receptors to maintain mature dendritic spines byregulating cofilin activity. The Journal of neuroscience: the official journalof the Society for Neuroscience,2009,29(25):8129-42
5Tetzlaff C, Kolodziejski C, Timme M, et al. Synaptic scaling enablesdynamically distinct short-and long-term memory formation. PLoSComput Biol,2013,9(10): e1003307
6Sharrad DF, Gai WP, Brookes SJ. Selective coexpression of synapticproteins, alpha-synuclein, cysteine string protein-alpha, synaptophysin,synaptotagmin-1, and synaptobrevin-2in vesicular acetylcholinetransporter-immunoreactive axons in the guinea pig ileum. J Comp Neurol,2013,521(11):2523-37
7Trovo L, Ahmed T, Callaerts-Vegh Z, et al. Low hippocampal PI(4,5)P(2)contributes to reduced cognition in old mice as a result of loss ofMARCKS. Nat Neurosci,2013,16(4):449-55
8Kiraly DD, Lemtiri-Chlieh F, Levine ES, et al. Kalirin binds the NR2Bsubunit of the NMDA receptor, altering its synaptic localization andfunction. The Journal of neuroscience: the official journal of the Societyfor Neuroscience,2011,31(35):12554-65
9Youn H, Jeoung M, Koo Y, et al. Kalirin is under-expressed in Alzheimer'sdisease hippocampus. J Alzheimers Dis,2007,11(3):385-97
10Kushima I, Nakamura Y, Aleksic B, et al. Resequencing and associationanalysis of the KALRN and EPHB1genes and their contribution toschizophrenia susceptibility. Schizophr Bull,2012,38(3):552-60
11Spires TL, Grote HE, Garry S, et al. Dendritic spine pathology and deficitsin experience-dependent dendritic plasticity in R6/1Huntington's diseasetransgenic mice. Eur J Neurosci,2004,19(10):2799-807
12Murray PS, Kirkwood CM, Gray MC, et al. beta-Amyloid42/40ratio andkalirin expression in Alzheimer disease with psychosis. Neurobiol Aging,2012,33(12):2807-16
13May V, Schiller MR, Eipper BA, et al. Kalirin Dbl-homology guaninenucleotide exchange factor1domain initiates new axon outgrowths viaRhoG-mediated mechanisms. The Journal of neuroscience: the officialjournal of the Society for Neuroscience,2002,22(16):6980-90
14Alam MR, Johnson RC, Darlington DN, et al. Kalirin, a cytosolic proteinwith spectrin-like and GDP/GTP exchange factor-like domains thatinteracts with peptidylglycine alpha-amidating monooxygenase, anintegral membrane peptide-processing enzyme. J Biol Chem,1997,272(19):12667-75
15Mandela P, Ma XM. Kalirin, a key player in synapse formation, isimplicated in human diseases. Neural Plast,2012,2012:728161
16Ma XM, Johnson RC, Mains RE, et al. Expression of kalirin, a neuronalGDP/GTP exchange factor of the trio family, in the central nervous systemof the adult rat. J Comp Neurol,2001,429(3):388-402
17Johnson RC, Penzes P, Eipper BA, et al. Isoforms of kalirin, a neuronalDbl family member, generated through use of different5'-and3'-endsalong with an internal translational initiation site. J Biol Chem,2000,275(25):19324-33
18Sommer JE, Budreck EC. Kalirin-7: linking spine plasticity and behavior.The Journal of neuroscience: the official journal of the Society forNeuroscience,2009,29(17):5367-9
19Mains RE, Alam MR, Johnson RC, et al. Kalirin, a multifunctional PAMCOOH-terminal domain interactor protein, affects cytoskeletalorganization and ACTH secretion from AtT-20cells. J Biol Chem,1999,274(5):2929-37
20Penzes P, Johnson RC, Alam MR, et al. An isoform of kalirin, abrain-specific GDP/GTP exchange factor, is enriched in the postsynapticdensity fraction. J Biol Chem,2000,275(9):6395-403
21Cahill ME, Xie Z, Day M, et al. Kalirin regulates cortical spinemorphogenesis and disease-related behavioral phenotypes. Proc Natl AcadSci U S A,2009,106(31):13058-63
22Cahill ME, Jones KA, Rafalovich I, et al. Control of interneuron dendriticgrowth through NRG1/erbB4-mediated kalirin-7disinhibition. MolPsychiatry,2012,17(1):1,99-107
23Penzes P, Beeser A, Chernoff J, et al. Rapid induction of dendritic spinemorphogenesis by trans-synaptic ephrinB-EphB receptor activation of theRho-GEF kalirin. Neuron,2003,37(2):263-74
24Xie Z, Cahill ME, Penzes P. Kalirin loss results in cortical morphologicalalterations. Mol Cell Neurosci,2010,43(1):81-9
25Ma XM, Huang J, Wang Y, et al. Kalirin, a multifunctional Rho guaninenucleotide exchange factor, is necessary for maintenance of hippocampalpyramidal neuron dendrites and dendritic spines. The Journal ofneuroscience: the official journal of the Society for Neuroscience,2003,23(33):10593-603
26Mazzone CM, Larese TP, Kiraly DD, et al. Analysis of kalirin-7knockoutmice reveals different effects in female mice. Mol Pharmacol,2012,82(6):1241-9
27Cahill ME, Remmers C, Jones KA, et al. Neuregulin1signaling promotesdendritic spine growth through kalirin. J Neurochem,2013,126(5):625-35
28Jones KA, Srivastava DP, Allen JA, et al. Rapid modulation of spinemorphology by the5-HT2A serotonin receptor through kalirin-7signaling.Proc Natl Acad Sci U S A,2009,106(46):19575-80
29Kiraly DD, Nemirovsky NE, LaRese TP, et al. Constitutive knockout ofKalirin-7leads to increased rates of cocaine self-administration. MolPharmacol,2013,84(4):582-90
30Wang X, Cahill ME, Werner CT, et al. Kalirin-7mediates cocaine-inducedAMPA receptor and spine plasticity, enabling incentive sensitization. TheJournal of neuroscience: the official journal of the Society forNeuroscience,2013,33(27):11012-22
31Schiller MR, Blangy A, Huang J, et al. Induction of lamellipodia byKalirin does not require its guanine nucleotide exchange factor activity.Exp Cell Res,2005,307(2):402-17
32Sousa N, Lukoyanov NV, Madeira MD, et al. Reorganization of themorphology of hippocampal neurites and synapses after stress-induceddamage correlates with behavioral improvement. Neuroscience,2000,97(2):253-66
33Inestrosa NC, Carvajal FJ, Zolezzi JM, et al. Peroxisome proliferatorsreduce spatial memory impairment, synaptic failure, andneurodegeneration in brains of a double transgenic mice model ofAlzheimer's disease. J Alzheimers Dis,2013,33(4):941-59
34Selkoe DJ. Alzheimer's disease is a synaptic failure. Science (New York,N.Y.),2002,298(5594):789-91
35Reddy PH, Tripathi R, Troung Q, et al. Abnormal mitochondrial dynamicsand synaptic degeneration as early events in Alzheimer's disease:implications to mitochondria-targeted antioxidant therapeutics. BiochimBiophys Acta,2012,1822(5):639-49
36Arendt T. Synaptic degeneration in Alzheimer's disease. Acta Neuropathol,2009,118(1):167-79
37Penzes P, Vanleeuwen JE. Impaired regulation of synaptic actincytoskeleton in Alzheimer's disease. Brain research reviews,2011,67(1-2):184-92
38Penzes P, Beeser A, Chernoff J, et al. Rapid induction of dendritic spinemorphogenesis by trans-synaptic ephrinB-EphB receptor activation of theRho-GEF kalirin. Neuron,2003,37(2):263-74
39Lacor PN, Buniel MC, Furlow PW, et al. Abeta oligomer-inducedaberrations in synapse composition, shape, and density provide amolecular basis for loss of connectivity in Alzheimer's disease. TheJournal of neuroscience: the official journal of the Society forNeuroscience,2007,27(4):796-807
40Zhao L, Ma QL, Calon F, et al. Role of p21-activated kinase pathwaydefects in the cognitive deficits of Alzheimer disease. Nat Neurosci,2006,9(2):234-42
41Youn H, Ji I, Ji HP, et al. Under-expression of Kalirin-7Increases iNOSactivity in cultured cells and correlates to elevated iNOS activity inAlzheimer's disease hippocampus. J Alzheimers Dis,2007,12(3):271-81
42Li W, Li QJ, An SC. Preventive effect of estrogen on depression-likebehavior induced by chronic restraint stress. Neurosci Bull,2010,26(2):140-6
43A novel gene containing a trinucleotide repeat that is expanded andunstable on Huntington's disease chromosomes. The Huntington's DiseaseCollaborative Research Group. Cell,1993,72(6):971-83
44Beresewicz M, Kowalczyk JE, Zablocka B. Kalirin-7, a protein enrichedin postsynaptic density, is involved in ischemic signal transduction.Neurochem Res,2008,33(9):1789-94
45Penzes P, Jones KA. Dendritic spine dynamics--a key role for kalirin-7.Trends Neurosci,2008,31(8):419-2
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