SIRT1信号通路通过氧化应激参与大鼠慢性脑缺血致认知损伤的研究
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摘要
血管性痴呆是发展中国家痴呆首要原因，迄今为止，人类还未找到治疗血管性痴呆行之有效的方法，防治手段十分有限。慢性脑缺血是研究血管性痴呆发病机理的重要组成部分，被认为是血管性痴呆、阿尔茨海默病等神经系统变性疾病、Binswanger病发病中的一个共同病理过程，可导致持久性进展性认知损伤，但其导致认识损害的病理生理机制仍不完全清楚，是丞待解决的医学难题。
信号转导系统功能失调及氧化应激在脑缺血、阿尔茨海默病等变性病所致痴呆中的重要作用已得到公认，临床上一些抗氧化剂已在痴呆的治疗中得到获益。细胞信号转导系统控制着细胞的生长、分化和死亡，参与调节细胞的活性。目前已知众多疾病都是由信号通路的缺陷所致。病理状态下信号通路的重构将有助于人们更多的了解疾病的病因和发病过程，同时提供了发现治疗疾病新方法的机会。
SIRT1（沉默信息调节因子1）是NAD+依赖性蛋白脱乙酰酶，在细胞分化、衰老、凋亡、生理节律、代谢调控、转录调节、信号转导、氧化应激等多种重要的生物学过程中发挥重要作用。最近的氧糖剥夺体外实验、急性脑缺血和缺血预处理动物实验表明SIRT1通过抗氧化、抗炎、减少凋亡等机制发挥神经保护作用，并有证据表明SIRT1是控制出生后血管生长的内皮细胞基因表达的关键调节因子，提示它可能在慢性脑缺血状态仍发挥重要作用。
为明确SIRT1信号通路在慢性脑缺血中的作用，本研究通过双侧颈总动脉永久性结扎法（双血管阻断，即2-VO）建立了慢性脑缺血的大鼠痴呆模型，利用Morris水迷宫检测大鼠的学习记忆能力，通过免疫组化和Wstern blot法检测慢性缺血时SIRT1在不同时间点的表达变化，并利用激活剂白藜芦醇及抑制剂EX-527对模型进行干预，利用免疫组化、实时定量PCR及Wstern blot检测SIRT1信号通路下游底物磷酸化FOXO3α（Ser253）、PGC-1α表达水平变化，及SIRT1信号通路对氧化应激的影响，最终为SIRT1信号通路的抗血管性认知损伤作用提供更多的理论依据。1慢性脑缺血大鼠模型制备及认知功能评价选用健康雄性Wistar大鼠，鼠龄2-3个月，体重260-300克，随机分为假手术6周组和慢性脑缺血6周组。采用双侧颈总动脉永久结扎(2-VO)法建立大鼠空间学习记忆障碍模型，利用Morris水迷宫检测大鼠的学习和记忆能力。定位航行试验中检测大鼠逃避潜伏期，每天进行2次试验，2次试验中间间隔15分钟，连续进行试验5天。第5天在定位航行试验结束后开始进行空间探索试验，检测大鼠跨越原平台所在象限时间。于2-VO术后6周对大鼠断头取脑，留取额叶皮层及海马组织，通过HE染色法进行病理学评估。实验结果显示2-VO大鼠死亡率为22.7%，与文献报道相近。术后6周定位航行试验显示，假手术组大鼠逃避潜伏期迅速下降并进入平台期，对隐藏平台的空间定位主要花费在前2天，而慢性脑缺血组则花费了4天时间学会寻找隐藏的平台，而且其学习能力并不稳定，表现为第5天的时候花费了更多的时间寻找隐藏的平台。空间探索试验中慢性脑缺血组大鼠跨越平台时间明显小于假手术组。HE染色镜下可见慢性脑缺血组大鼠额叶皮层和海马CA1区内散在缺血性改变，正常神经元数目减少，可见神经细胞脱失，组织排列紊乱，细胞形态不规则排列紊乱，出现神经元变性和死亡，散在嗜伊红细胞出现，细胞核固缩，核仁显示不清，核膜境界不清。假手术组大鼠组织结构完好，细胞排列整齐，无神经元凋亡、变性及坏死表现，胞质和核仁显示正常。以上结果提示本实验成功建立大鼠慢性脑缺血致认知损伤模型，双侧颈总动脉永久性结扎法可以较好的显示慢性脑缺血的行为学和病理学变化，并可造成显著认知损伤，模型可靠。2慢性脑缺血大鼠脑内SIRT1表达及氧化应激变化
将健康雄性Wistar大鼠分组如下：（1）假手术6周组（2）假手术9周组（3）假手术12周组（4）慢性脑缺血6周组（5）慢性脑缺血9周组（6）慢性脑缺血12周组。利用2-VO法建立慢性脑缺血模型，对额叶皮层和海马组织利用免疫组化染色及Western blot检测大鼠SIRT1蛋白表达水平。将海马和额叶制成10％的匀浆，离心后取上清液按试剂盒说明书进行SOD、MDA水平测定。
Morris水迷宫试验显示，在2-VO术后的6周、9周和12周，慢性脑缺血大鼠认知损伤随着缺血时间的延长呈现动态变化。术后6周定位航行试验显示慢性脑缺血大鼠在试验第2天、第3天和第5天逃避潜伏期明显长于假手术组。术后9周，在试验第2天至5天，慢性脑缺血大鼠的逃避潜伏期均显著长于假手术组，并在试验第4天即出现了逃避潜伏期再次延长。术后12周，慢性脑缺血大鼠逃避潜伏期在整个试验周期均明显高于假手术组。空间探索试验中3个时间点慢性脑缺血大鼠跨越原平台所在象限时间均明显小于假手术组，并随着缺血时间的延长逐渐缩短。慢性脑缺血HE染色病理切片显示随着缺血时间的延长，额叶和海马内神经元脱失及变性坏死逐渐增加，星形胶质细胞及血管增生逐渐增加，组织结构紊乱，排列不规则。细胞严重变形，胞质内有不均匀空泡逐渐增加，核固缩现象增多，白质区出现小软化灶。免疫组化结果显示SIRT1蛋白在细胞内主要表达于细胞核。2-VO术后SIRT1阳性细胞比率明显减少，以缺血6周组最明显。Western blot的检测结果显示2-VO术后6周、9周、12周SIRT1的蛋白水平均低于相应对照组，6周时SIRT1蛋白降低最明显，9周和12周时略有增加，12周高于9周，慢性缺血组各时间点之间SIRT1蛋白水平比较差异显著。2-VO术后6周、9周及12周氧化应激检测结果显示，慢性脑缺血时抗氧化物质SOD降低而脂质氧化标志物MDA升高，提示慢性脑缺血时体内抗氧化能力降低、氧化应激反应增强。慢性脑缺血组与假手术组之间SOD与MDA的显著差异均仅发生在脑缺血6周。以上结果提示2-VO模型可造成大鼠进行性认知损害，有效模拟血管性痴呆的临床经过。SIRT1活性在慢性脑缺血受到抑制，参与慢性脑缺血所致认知损伤的发生发展过程。慢性脑缺血时氧化应激反应主要发生在缺血6周的早期阶段，这为本实验后续选择氧化应激干预时间点提供了依据。3慢性脑缺血脑内SIRT1信号通路对大鼠认知功能及氧化应激的影响
健康雄性Wistar大鼠实验分组如下：（1）假手术6周组（2）慢性脑缺血6周组（3）白藜芦醇+慢性脑缺血6周组（4）白藜芦醇+EX-527+慢性脑缺血6周组（5）EX-527+慢性脑缺血6周组。白藜芦醇通过腹腔注射的方式进行给药，给药剂量为每天50mg/Kg。EX-527每天向侧脑室内注射5μg。于2-VO术后6周对各组大鼠利用Morris水迷宫进行学习记忆能力检测，实时定量PCR及Western blot检测SIRT1、FOXO3α、PGC-1α表达水平。按试剂盒说明书对脑组织匀浆进行SOD、MDA水平测定。
Morris水迷宫行为学试验结果显示，定位航行试验中慢性脑缺血大鼠在接受白藜芦醇治疗后，试验第2天、第3天和第5天逃避潜伏期明显缩短，空间探索试验中跨越原平台所在象限时间明显延长；慢性脑缺血大鼠接受SIRT1抑制剂EX-527治疗后定位航行试验第2至5天逃避潜伏期均明显延长，空间探索试验中跨越原平台所在象限时间明显缩短；同时给予白藜芦醇及EX-527治疗的大鼠，与单纯慢性脑缺血大鼠对比，试验第1天、第2天和第5天组逃避潜伏期变化不明显，第3天及第4天逃避潜伏期明显延长，空间探索试验中跨越原平台所在象限时间则明显缩短。实时定量PCR检测结果显示FOXO3α的mRNA水平在慢性脑缺血时降低，慢性脑缺血组与假手术组比较FOXO3α的mRNA水平差异显著。白藜芦醇干预后FOXO3α的mRNA水平升高，白藜芦醇+慢性脑缺血组与单纯慢性脑缺血组比较FOXO3α的mRNA水平差异显著。EX-527+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组大鼠FOXO3α的mRNA水平较单纯慢性脑缺血组明显下降，并明显低于白藜芦醇+慢性脑缺血组。SIRT1与PGC-1α的mRNA在各组之间的表达水平无明显差异。额叶及海马CA1区的免疫组化结果显示，SIRT1蛋白主要在细胞核内表达。假手术组可见一定程度的SIRT1蛋白阳性表达。2-VO术后额叶皮层和海马CA1区细胞排列分散，胞体变形。慢性脑缺血组SIRT1蛋白表达与假手术组对比明显减低，而白藜芦醇+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组SIRT1蛋白表达明显增强，EX-527+慢性脑缺血组与单纯慢性脑缺血组对比SIRT1的蛋白阳性表达无明显差异。磷酸化的FOXO3α（Ser253）蛋白主要在细胞核内表达。假手术组内FOXO3α蛋白在神经元细胞核内表达丰富，细胞浆表达罕见，慢性脑缺血组大鼠FOXO3α蛋白神经元内表达显著减少，细胞核及细胞浆内均有FOXO3α蛋白表达，以细胞核为著，变性的神经元无明显表达。白藜芦醇+慢性脑缺血组大鼠额叶皮层和海马CA1区内变性神经元及正常神经元均有FOXO3α蛋白表达，主要见于细胞核，较2-VO组大鼠表达显著增加。额叶皮层内EX-527+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组与单纯2-VO组对比FOXO3α表达变化不明显，但显著低于白藜芦醇+慢性脑缺血组。海马CA1区EX-527+慢性脑缺血组FOXO3α表达水平明显低于单纯慢性脑缺血组，白藜芦醇+EX-527+慢性脑缺血组与单纯慢性脑缺血组对比FOXO3α表达变化不明显，但显著低于白藜芦醇+慢性脑缺血组。假手术组PGC-1α蛋白表达丰富表达，细胞核和细胞浆均表达，细胞浆可见较多表达。慢性脑缺血组神经元数量减少，细胞肿胀明显，PGC-1α表达明显减少，细胞核及细胞浆均见表达，胞浆表达相对明显，部分在胞膜下表达。白藜芦醇干预后PGC-1α表达增加，主要出现在细胞核。EX-527+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组PGC-1α总体表达减少，主要见于胞浆表达，与白藜芦醇组比较差异显著。Western blot结果显示慢性脑缺血组SIRT1蛋白水平表达明显低于假手术组，白藜芦醇+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组SIRT1蛋白水平明显高于单纯慢性脑缺血组，EX-527+慢性脑缺血组SIRT1蛋白水平与单纯慢性脑缺血组对比无明显差异。磷酸化FOXO3α（Ser253）蛋白在慢性脑缺血组表达与假手术比较明显降低，白藜芦醇+慢性脑缺血组磷酸化FOXO3α（Ser253）的蛋白水平升高，与单纯慢性脑缺血组比较差异显著。EX-527+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组磷酸化FOXO3α（Ser253）的蛋白水平与单纯慢性脑缺血组比较下降不明显，但明显低于白藜芦醇+慢性脑缺血组。慢性脑缺血组PGC-1α蛋白水平明显低于假手术组。白藜芦醇+慢性脑缺血组PGC-1α蛋白水平明显高于单纯慢性脑缺血组，EX-527+慢性脑缺血组PGC-1α蛋白水平明显低于单纯慢性脑缺血组。白藜芦醇+EX-527+慢性脑缺血组PGC-1α蛋白水平明显低于单纯慢性脑缺血组。2-VO术后6周各组间氧化应激检测结果显示，慢性脑缺血组SOD水平降低，而MDA水平升高，与假手术组比较差异显著。与单纯慢性脑缺血组比较，白藜芦醇+慢性脑缺血组SOD水平升高，MDA水平降低，组间比较差异显著。与单纯慢性脑缺血组比较，EX-527+慢性脑缺血组SOD表达水平降低，MDA表达水平升高，组间比较差异显著。白藜芦醇+EX-527+慢性脑缺血组大鼠脑内MDA水平明显高于单纯慢性脑缺血组，SOD水平两组之间比较差异不显著。
以上结果提示在慢性脑缺血状态下，SIRT1以及其下游底物PGC-1α、FOXO3α表达受到抑制，SIRT1可以对FOXO3α从转录水平进行调节，而对PGC-1α的表达调节主要发生在蛋白水平。SIRT1-PGC-1α/FOXO3α信号通路影响慢性脑缺血大鼠的氧化应激反应，活性提高可以增强大鼠的抗氧化应激的能力，有效改善慢性脑缺血大鼠的认知损伤。白藜芦醇对慢性脑缺血大鼠认知损伤的改善作用，与增强SIRT1信号通路介导的抗氧化应激的能力有关，本研究为其用于血管性认知损伤的防治提供了实验室证据，有望成为血管性认知损伤新的治疗药物之一。
Among all diseases of dementia, vascular dementia represents the first cause indeveloping countries. To date, mankind has yet found an effective treatment to preventvascular dementia, and good means of prevention and treatment for it is little. Chroniccerebral ischemia (CCI) is an important component in the study of the pathogenesis ofvascular dementia. And it was a common pathological process of vascular dementia,Alzheimer's disease and other neurodegenerative diseases, Binswanger disease, which couldlead to progressive cognitive impairment. The pathophysiological mechanisms for process ofchronic cerebral ischemia lead to cognitive impairment remain unclear, which need to beaddressed urgently.
Role of cell signaling pathway dysfunction and oxidative stress in brain ischemia,dementia caused by Alzheimer's disease and other degenerative diseases have beenrecognized. Treatments of some antioxidants have benefited patients suffered fromdementia. Cellular signal transduction systems control growth, differentiation and death ofcells, and take part in regulation of cell activity. It is well known that many diseases arecaused by the defects of the signaling pathways. Reconstruction of signaling pathwaysunder pathological state will help people learn more about the etiology and pathogenesis ofthe diseases, and provide opportunities to find new ways for disease treatment meanwhile.
As a NAD+-dependent deacetylase, SIRT1(silent information regulator1)impactspotentially in different important biological processes, such as cell differentiation,senescence, apoptosis, circadian rhythm, metabolic control, transcriptional regulation, signaltransduction, oxidative stress. Recently studies have revealed that SIRT1played aneuroprotective effect through anti-oxidation, anti-inflammatory, reducing apoptosis andother mechanisms in oxygen and glucose deprivation experiments in vitro and in acutecerebral ischemia and ischemic preconditioning animal models. Evidence also showed SIRT1was a critical regulator of the expression of genes involved in postnatal angiogenesisin endotheliocyte, which suggesting that SIRT1may play an important role under conditionsof chronic cerebral ischemia.
This study was to investigate the role of SIRT1signaling pathway on cognitiveimpairment caused by chronic cerebral hypoperfusion. For this, a rat model of chroniccerebral ischemic dementia induced by permanent bilateral common carotid arteryocclusions(2-VO) was established. Using the Morris water maze, learning and memoryabilities of the rats were evaluated. Serial changes of SIRT1expression and activity wasmeasured by immunohistochemistry and Western blot. After that, resveratrol and EX-527were used to regulate activity of SIRT1in animal model, and expression of SIRT1togetherwith its target genes including phospho-FOXO3α(Ser253) and PGC-1α were detected byimmunohistochemistry, real-time PCR and Western blot. Impact on Oxidative stress ofSIRT1signaling pathway was also observed in the present study. The study was to provide atheoretical basis for SIRT1signaling pathway on role of anti-vascular cognitive impairment.1Establishment rat model of chronic cerebral ischemia and assessment of cognitivefunction
Healthy Male Wistar rats(aged2-3months, weighing260-300g) were randomlydivided into the sham operated group and chronic cerebral ischemia group for6weeks. Ratmodel of spatial learning and memory impairment was induced by permanent bilateralcommon carotid artery ligation (2-VO). Morris water maze was used to evaluate learningand memory abilities of rats. Place navigation test was carried out twice with an interval of15minutes for5consecutive days, and the escape latency was measured to evaluateanimals’ ability of learning and memory. Spatial probe test was performed on day5afterplace navigation test. Total time for rats spent in crossing the original quadrant where thehidden platform located was determined. Six weeks after2-VO rats were decapitated, andthe frontal cortex and hippocampus were collected for pathological assessment byhematoxylin-eosin(HE) staining. Experimental results showed that mortality rate of2-VOrats was22.7%, similar to ones reported in the literature. In place navigation test the escapelatency of sham operated rats decreased rapidly and leveled off and spatial localization for hidden platform occurred mainly in the first two trial days. CCI rats spent four days inlearning to find the hidden platform and escape latency on day5was prolonged again. Inspatial probe test time spent in crossing the original quadrant of2-VO rats was significantlyless than the sham operated ones. HE staining of2-VO rats showed scattered ischemicchanges in the frontal cortex and hippocampus, such as decrease in the number of normalneurons, loss of neural cells, disorder of organization arrangement, irregular cellmorphology and disorganized cell arrangements, degeneration and necrosis of neurons,scattered eosinophils, uneven vacuoles in the cytoplasm, nuclear pyknosis, and unclearnucleoli. In sham operated group structure of organization was intact, cells arranged orderly,no apoptosis and degeneration and necrosis of neurons was found, and cytoplasm andnucleolus normal. The results above suggested that cognitive dysfunction of rat modelinduced by chronic cerebral ischemia was established successfully, and2-VO rat modelcould well display the behavioral and pathological process of chronic cerebral ischemia,which could cause significant cognitive impairment reliably.2Changes of SIRT1gene expression and level of oxidative stress in rat model ofchronic cerebral ischemia
Healthy male Wistar rats were grouped as follows:(1)sham operated for6weeks(2)sham operated for9weeks (3)sham operated for12weeks (4)chronic cerebral ischemiafor6weeks (5)chronic cerebral ischemia for9weeks (6)chronic cerebral ischemia for12weeks. Levels of SIRT1protein expression were examined by western blot andimmunohistochemical staining via SP method. SOD and MDA levels in hippocampus andfrontal lobe were examined according to the corresponding kit instructions.
In Morris water maze cognitive impairment of2-VO rats showed dynamic changes withthe ischemia time prolonged.6weeks after operation escape latency of2-VO rats lengthenedsignificantly on day2,3, and5compared to sham operated ones.9weeks after operationescape latency of2-VO rats extended significantly on day2to5. In the whole trial escapelatencies of2-VO rats were longer than sham operated ones significantly12weeks afteroperation. time spent in crossing the original quadrant in CCI group gradually reduced as theischemia time extended and which was less significantly than the sham group. HE staining from brains of the consecutive three months2-VO rats demonstrated that loss of neuron anddegeneration and necrosis gradually increased with the ischemia time extended, proliferationof astrocytes and vessels gradually increased, organizational structure was disordered andirregularly arranged. The cells were severely deformed, uneven vacuoles gradually increasedin cytoplasm, karyopyknosis increased, and small liquefaction lesion could be seen in whitematter areas. Results of immunohistochemistry showed that SIRT1protein was locatedmainly in neulei. After2-VO the ratio of SIRT1-positive cells was significantly reduced,especially six weeks after operation. Western blot showed that SIRT1protein expressionlevels decreased significantly, which was lowest6weeks after operation. Reduction of SODas an antioxaditive substance and increase of MDA as a markers of lipid oxidation wereobserved at the three time point after operation, but the significant alteration occurred only at6weeks after2-VO. These results suggested that2-VO could cause progressive cognitiveimpairment in rats, effectively demonstrated the clinical course of vascular dementia, anddownregulation of SIRT1was involved in the development and progression of cognitiveimpairment induced by chronic cerebral ischemia. Oxidative stress in chronic cerebralischemia occurred mainly in the early stages of ischemia six weeks, which provided a basisfor selection of time point in the follow-up experiment of oxidative stress intervention.3Impact of SIRT1signaling pathway on cognitive function and oxidative stress of ratssubjected to chronic cerebral ischemia
Healthy male Wistar rats were grouped as follows:(1)sham operated(SH) group(2)chronic cerebral ischemia(CCI) group (3)resveratrol+chronic cerebral ischemia(Res)group (4)resveratrol+EX-527+chronic cerebral ischemia(Res+EX-527) group (5)EX-527+chronic cerebral ischemia(EX-527) group. Resveratrol was administered by intraperitonealinjections at a dose of50mg/kg daily for6weeks. EX-527was was injected to the lateralventricle at a dose of5μg.6weeks after2-VO learning and memory ability of all rats weredetected via the Morris water maze. Expression levels of SIRT1, FOXO3α and PGC-1α wereexamined through real-time quantitative PCR and western blot analysis.10%homogenatesupernatant of hippocampus and frontal lobe were centrifuged, and obtained supernatantfluid was used to measure SOD and MDA levels according to the corresponding kit instructions.
Behavioral test of water maze showed that the rats' learning and memory abilities ofRes group were significantly higher than CCI group, expressed as shorter escape latency onday2,3,5, and more time in crossing the original quadrant. In EX-527group rats showedlonger escape latencies on day2to5and less time in crossing the original quadrant than CCIgroup. In Res+EX-527group rats demonstrated longer escape latency and less time incrossing the original platform too. Results of real-time quantitative PCR showed differencesof mRNA levels of SIRT1and PGC-1α among the five groups were not significant.FOXO3αmRNA level was lower in2-VO rats compared to sham operated ones, which couldbe elevated by resveratrol and reduced by EX-527significantly. Immunohistochemicalresults of frontal cortex and hippocampal CA1region showed SIRT1protein was locatedmainly in neulei. A certain mount of SIRT1protein was observed in sham operated group,which was lower in2-VO group. SIRT1protein level could be elevated by resveratrol butcould not be altered by EX-527in2-VO group. Phospho-FOXO3α（Ser253）protein wasobserved mainly in cytoblast. In sham operated group amount of phospho-FOXO3α wasabundant in in the nuclei of the neurons, and little in cytoplasm. Phospho-FOXO3α（Ser253）protein in neurons were reduced significantly in2-VO group, but could be seen in bothcytoplasm and nuclei, and markedly in nuclei. Level of phospho-FOXO3α（Ser253）proteinwas increased by resveratrol in2-VO group which mainly seen in nuclei. In frontal cortex,phospho-FOXO3α（Ser253）protein levels of EX-527and Res+EX-527group were notsignificant different to CCI group，but lower than Res group significantly. In hippocampalCA1region, difference of phospho-FOXO3α（Ser253）protein levels between EX-527andCCI group was significant, and phospho-FOXO3α（Ser253）protein level of Res+EX-527group were not significant different to CCI group，but lower than Res group significantly.Rich expression of PGC-1α protein was detected in sham operated group, which was more incytoplasm than that of nulei. Level of PGC-1α protein was reduced both in nucleus andcytoplasm in2-VO group accompanied by less number of neurons and PGC-1α protein wasseen near the cytomambrane. PGC-1α protein level was increased in Res group and locatedmainly in nuclei. Contrarily PGC-1α protein level was decreased in EX-527and Res+ EX-527group and located mainly in cytoplasm. Western blot results demonstratedresveratrol could strengthen expression of SIRT1protein in2-VO rat brain. Resveratrolcould elevate inhibited phospho-FOXO3α（Ser253）protein level in2-VO rat brain. Althoughphospho-FOXO3α（Ser253）protein levels of EX-527group and Res+EX-527group were notreduced than that of CCI group significantly but lower than that of Res group significantly.The reduced PGC-1α protein level in2-VO rat brain was increased by resveratrol and lowerafter EX-527treatment. Reduced level of SOD and elevated level of MDA in CCI groupwere significantly different to sham operated group6weeks after operation. These changescould be lessened by resveratrol treatment and enlarged by EX-527significantly. Levels ofSOD and MDA were different significantly between Res group and CCI group, EX-527group and CCI group.
The results above suggested that SIRT1-FOXO3α/PGC-1α signaling pathway wasinhibited in chronic cerebral ischemic brain. SIRT1could regulate transcription ofFOXO3α but its regulation of PGC-1α expression was mainly on protein level in chroniccerebral ischemic brain. Activity of SIRT1-FOXO3α/PGC-1α signaling pathway could alteroxidative stress reaction in chronic cerebral ischemic brain. Enhanced activity ofSIRT1-FOXO3α/PGC-1α signaling pathway could increase the ability of anti-oxidativestress for rat in chronic cerebral ischemic brain, and effectively improved cognitiveimpairment of CCI rats. Improvement of resveratrol on cognitive dysfunction caused bychronic cerebral ischemia in rats was associated with enhanced ability of anti-oxidativestress mediated by SIRT1signaling pathway. The present study provided laboratoryevidences for its application to the prevention and treatment of vascular cognitiveimpairment, and it was expected to become one of the new drugs in vascular cognitiveimpairment.
信号转导系统功能失调及氧化应激在脑缺血、阿尔茨海默病等变性病所致痴呆中的重要作用已得到公认，临床上一些抗氧化剂已在痴呆的治疗中得到获益。细胞信号转导系统控制着细胞的生长、分化和死亡，参与调节细胞的活性。目前已知众多疾病都是由信号通路的缺陷所致。病理状态下信号通路的重构将有助于人们更多的了解疾病的病因和发病过程，同时提供了发现治疗疾病新方法的机会。
SIRT1（沉默信息调节因子1）是NAD+依赖性蛋白脱乙酰酶，在细胞分化、衰老、凋亡、生理节律、代谢调控、转录调节、信号转导、氧化应激等多种重要的生物学过程中发挥重要作用。最近的氧糖剥夺体外实验、急性脑缺血和缺血预处理动物实验表明SIRT1通过抗氧化、抗炎、减少凋亡等机制发挥神经保护作用，并有证据表明SIRT1是控制出生后血管生长的内皮细胞基因表达的关键调节因子，提示它可能在慢性脑缺血状态仍发挥重要作用。
为明确SIRT1信号通路在慢性脑缺血中的作用，本研究通过双侧颈总动脉永久性结扎法（双血管阻断，即2-VO）建立了慢性脑缺血的大鼠痴呆模型，利用Morris水迷宫检测大鼠的学习记忆能力，通过免疫组化和Wstern blot法检测慢性缺血时SIRT1在不同时间点的表达变化，并利用激活剂白藜芦醇及抑制剂EX-527对模型进行干预，利用免疫组化、实时定量PCR及Wstern blot检测SIRT1信号通路下游底物磷酸化FOXO3α（Ser253）、PGC-1α表达水平变化，及SIRT1信号通路对氧化应激的影响，最终为SIRT1信号通路的抗血管性认知损伤作用提供更多的理论依据。1慢性脑缺血大鼠模型制备及认知功能评价选用健康雄性Wistar大鼠，鼠龄2-3个月，体重260-300克，随机分为假手术6周组和慢性脑缺血6周组。采用双侧颈总动脉永久结扎(2-VO)法建立大鼠空间学习记忆障碍模型，利用Morris水迷宫检测大鼠的学习和记忆能力。定位航行试验中检测大鼠逃避潜伏期，每天进行2次试验，2次试验中间间隔15分钟，连续进行试验5天。第5天在定位航行试验结束后开始进行空间探索试验，检测大鼠跨越原平台所在象限时间。于2-VO术后6周对大鼠断头取脑，留取额叶皮层及海马组织，通过HE染色法进行病理学评估。实验结果显示2-VO大鼠死亡率为22.7%，与文献报道相近。术后6周定位航行试验显示，假手术组大鼠逃避潜伏期迅速下降并进入平台期，对隐藏平台的空间定位主要花费在前2天，而慢性脑缺血组则花费了4天时间学会寻找隐藏的平台，而且其学习能力并不稳定，表现为第5天的时候花费了更多的时间寻找隐藏的平台。空间探索试验中慢性脑缺血组大鼠跨越平台时间明显小于假手术组。HE染色镜下可见慢性脑缺血组大鼠额叶皮层和海马CA1区内散在缺血性改变，正常神经元数目减少，可见神经细胞脱失，组织排列紊乱，细胞形态不规则排列紊乱，出现神经元变性和死亡，散在嗜伊红细胞出现，细胞核固缩，核仁显示不清，核膜境界不清。假手术组大鼠组织结构完好，细胞排列整齐，无神经元凋亡、变性及坏死表现，胞质和核仁显示正常。以上结果提示本实验成功建立大鼠慢性脑缺血致认知损伤模型，双侧颈总动脉永久性结扎法可以较好的显示慢性脑缺血的行为学和病理学变化，并可造成显著认知损伤，模型可靠。2慢性脑缺血大鼠脑内SIRT1表达及氧化应激变化
将健康雄性Wistar大鼠分组如下：（1）假手术6周组（2）假手术9周组（3）假手术12周组（4）慢性脑缺血6周组（5）慢性脑缺血9周组（6）慢性脑缺血12周组。利用2-VO法建立慢性脑缺血模型，对额叶皮层和海马组织利用免疫组化染色及Western blot检测大鼠SIRT1蛋白表达水平。将海马和额叶制成10％的匀浆，离心后取上清液按试剂盒说明书进行SOD、MDA水平测定。
Morris水迷宫试验显示，在2-VO术后的6周、9周和12周，慢性脑缺血大鼠认知损伤随着缺血时间的延长呈现动态变化。术后6周定位航行试验显示慢性脑缺血大鼠在试验第2天、第3天和第5天逃避潜伏期明显长于假手术组。术后9周，在试验第2天至5天，慢性脑缺血大鼠的逃避潜伏期均显著长于假手术组，并在试验第4天即出现了逃避潜伏期再次延长。术后12周，慢性脑缺血大鼠逃避潜伏期在整个试验周期均明显高于假手术组。空间探索试验中3个时间点慢性脑缺血大鼠跨越原平台所在象限时间均明显小于假手术组，并随着缺血时间的延长逐渐缩短。慢性脑缺血HE染色病理切片显示随着缺血时间的延长，额叶和海马内神经元脱失及变性坏死逐渐增加，星形胶质细胞及血管增生逐渐增加，组织结构紊乱，排列不规则。细胞严重变形，胞质内有不均匀空泡逐渐增加，核固缩现象增多，白质区出现小软化灶。免疫组化结果显示SIRT1蛋白在细胞内主要表达于细胞核。2-VO术后SIRT1阳性细胞比率明显减少，以缺血6周组最明显。Western blot的检测结果显示2-VO术后6周、9周、12周SIRT1的蛋白水平均低于相应对照组，6周时SIRT1蛋白降低最明显，9周和12周时略有增加，12周高于9周，慢性缺血组各时间点之间SIRT1蛋白水平比较差异显著。2-VO术后6周、9周及12周氧化应激检测结果显示，慢性脑缺血时抗氧化物质SOD降低而脂质氧化标志物MDA升高，提示慢性脑缺血时体内抗氧化能力降低、氧化应激反应增强。慢性脑缺血组与假手术组之间SOD与MDA的显著差异均仅发生在脑缺血6周。以上结果提示2-VO模型可造成大鼠进行性认知损害，有效模拟血管性痴呆的临床经过。SIRT1活性在慢性脑缺血受到抑制，参与慢性脑缺血所致认知损伤的发生发展过程。慢性脑缺血时氧化应激反应主要发生在缺血6周的早期阶段，这为本实验后续选择氧化应激干预时间点提供了依据。3慢性脑缺血脑内SIRT1信号通路对大鼠认知功能及氧化应激的影响
健康雄性Wistar大鼠实验分组如下：（1）假手术6周组（2）慢性脑缺血6周组（3）白藜芦醇+慢性脑缺血6周组（4）白藜芦醇+EX-527+慢性脑缺血6周组（5）EX-527+慢性脑缺血6周组。白藜芦醇通过腹腔注射的方式进行给药，给药剂量为每天50mg/Kg。EX-527每天向侧脑室内注射5μg。于2-VO术后6周对各组大鼠利用Morris水迷宫进行学习记忆能力检测，实时定量PCR及Western blot检测SIRT1、FOXO3α、PGC-1α表达水平。按试剂盒说明书对脑组织匀浆进行SOD、MDA水平测定。
Morris水迷宫行为学试验结果显示，定位航行试验中慢性脑缺血大鼠在接受白藜芦醇治疗后，试验第2天、第3天和第5天逃避潜伏期明显缩短，空间探索试验中跨越原平台所在象限时间明显延长；慢性脑缺血大鼠接受SIRT1抑制剂EX-527治疗后定位航行试验第2至5天逃避潜伏期均明显延长，空间探索试验中跨越原平台所在象限时间明显缩短；同时给予白藜芦醇及EX-527治疗的大鼠，与单纯慢性脑缺血大鼠对比，试验第1天、第2天和第5天组逃避潜伏期变化不明显，第3天及第4天逃避潜伏期明显延长，空间探索试验中跨越原平台所在象限时间则明显缩短。实时定量PCR检测结果显示FOXO3α的mRNA水平在慢性脑缺血时降低，慢性脑缺血组与假手术组比较FOXO3α的mRNA水平差异显著。白藜芦醇干预后FOXO3α的mRNA水平升高，白藜芦醇+慢性脑缺血组与单纯慢性脑缺血组比较FOXO3α的mRNA水平差异显著。EX-527+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组大鼠FOXO3α的mRNA水平较单纯慢性脑缺血组明显下降，并明显低于白藜芦醇+慢性脑缺血组。SIRT1与PGC-1α的mRNA在各组之间的表达水平无明显差异。额叶及海马CA1区的免疫组化结果显示，SIRT1蛋白主要在细胞核内表达。假手术组可见一定程度的SIRT1蛋白阳性表达。2-VO术后额叶皮层和海马CA1区细胞排列分散，胞体变形。慢性脑缺血组SIRT1蛋白表达与假手术组对比明显减低，而白藜芦醇+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组SIRT1蛋白表达明显增强，EX-527+慢性脑缺血组与单纯慢性脑缺血组对比SIRT1的蛋白阳性表达无明显差异。磷酸化的FOXO3α（Ser253）蛋白主要在细胞核内表达。假手术组内FOXO3α蛋白在神经元细胞核内表达丰富，细胞浆表达罕见，慢性脑缺血组大鼠FOXO3α蛋白神经元内表达显著减少，细胞核及细胞浆内均有FOXO3α蛋白表达，以细胞核为著，变性的神经元无明显表达。白藜芦醇+慢性脑缺血组大鼠额叶皮层和海马CA1区内变性神经元及正常神经元均有FOXO3α蛋白表达，主要见于细胞核，较2-VO组大鼠表达显著增加。额叶皮层内EX-527+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组与单纯2-VO组对比FOXO3α表达变化不明显，但显著低于白藜芦醇+慢性脑缺血组。海马CA1区EX-527+慢性脑缺血组FOXO3α表达水平明显低于单纯慢性脑缺血组，白藜芦醇+EX-527+慢性脑缺血组与单纯慢性脑缺血组对比FOXO3α表达变化不明显，但显著低于白藜芦醇+慢性脑缺血组。假手术组PGC-1α蛋白表达丰富表达，细胞核和细胞浆均表达，细胞浆可见较多表达。慢性脑缺血组神经元数量减少，细胞肿胀明显，PGC-1α表达明显减少，细胞核及细胞浆均见表达，胞浆表达相对明显，部分在胞膜下表达。白藜芦醇干预后PGC-1α表达增加，主要出现在细胞核。EX-527+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组PGC-1α总体表达减少，主要见于胞浆表达，与白藜芦醇组比较差异显著。Western blot结果显示慢性脑缺血组SIRT1蛋白水平表达明显低于假手术组，白藜芦醇+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组SIRT1蛋白水平明显高于单纯慢性脑缺血组，EX-527+慢性脑缺血组SIRT1蛋白水平与单纯慢性脑缺血组对比无明显差异。磷酸化FOXO3α（Ser253）蛋白在慢性脑缺血组表达与假手术比较明显降低，白藜芦醇+慢性脑缺血组磷酸化FOXO3α（Ser253）的蛋白水平升高，与单纯慢性脑缺血组比较差异显著。EX-527+慢性脑缺血组及白藜芦醇+EX-527+慢性脑缺血组磷酸化FOXO3α（Ser253）的蛋白水平与单纯慢性脑缺血组比较下降不明显，但明显低于白藜芦醇+慢性脑缺血组。慢性脑缺血组PGC-1α蛋白水平明显低于假手术组。白藜芦醇+慢性脑缺血组PGC-1α蛋白水平明显高于单纯慢性脑缺血组，EX-527+慢性脑缺血组PGC-1α蛋白水平明显低于单纯慢性脑缺血组。白藜芦醇+EX-527+慢性脑缺血组PGC-1α蛋白水平明显低于单纯慢性脑缺血组。2-VO术后6周各组间氧化应激检测结果显示，慢性脑缺血组SOD水平降低，而MDA水平升高，与假手术组比较差异显著。与单纯慢性脑缺血组比较，白藜芦醇+慢性脑缺血组SOD水平升高，MDA水平降低，组间比较差异显著。与单纯慢性脑缺血组比较，EX-527+慢性脑缺血组SOD表达水平降低，MDA表达水平升高，组间比较差异显著。白藜芦醇+EX-527+慢性脑缺血组大鼠脑内MDA水平明显高于单纯慢性脑缺血组，SOD水平两组之间比较差异不显著。
以上结果提示在慢性脑缺血状态下，SIRT1以及其下游底物PGC-1α、FOXO3α表达受到抑制，SIRT1可以对FOXO3α从转录水平进行调节，而对PGC-1α的表达调节主要发生在蛋白水平。SIRT1-PGC-1α/FOXO3α信号通路影响慢性脑缺血大鼠的氧化应激反应，活性提高可以增强大鼠的抗氧化应激的能力，有效改善慢性脑缺血大鼠的认知损伤。白藜芦醇对慢性脑缺血大鼠认知损伤的改善作用，与增强SIRT1信号通路介导的抗氧化应激的能力有关，本研究为其用于血管性认知损伤的防治提供了实验室证据，有望成为血管性认知损伤新的治疗药物之一。
Among all diseases of dementia, vascular dementia represents the first cause indeveloping countries. To date, mankind has yet found an effective treatment to preventvascular dementia, and good means of prevention and treatment for it is little. Chroniccerebral ischemia (CCI) is an important component in the study of the pathogenesis ofvascular dementia. And it was a common pathological process of vascular dementia,Alzheimer's disease and other neurodegenerative diseases, Binswanger disease, which couldlead to progressive cognitive impairment. The pathophysiological mechanisms for process ofchronic cerebral ischemia lead to cognitive impairment remain unclear, which need to beaddressed urgently.
Role of cell signaling pathway dysfunction and oxidative stress in brain ischemia,dementia caused by Alzheimer's disease and other degenerative diseases have beenrecognized. Treatments of some antioxidants have benefited patients suffered fromdementia. Cellular signal transduction systems control growth, differentiation and death ofcells, and take part in regulation of cell activity. It is well known that many diseases arecaused by the defects of the signaling pathways. Reconstruction of signaling pathwaysunder pathological state will help people learn more about the etiology and pathogenesis ofthe diseases, and provide opportunities to find new ways for disease treatment meanwhile.
As a NAD+-dependent deacetylase, SIRT1(silent information regulator1)impactspotentially in different important biological processes, such as cell differentiation,senescence, apoptosis, circadian rhythm, metabolic control, transcriptional regulation, signaltransduction, oxidative stress. Recently studies have revealed that SIRT1played aneuroprotective effect through anti-oxidation, anti-inflammatory, reducing apoptosis andother mechanisms in oxygen and glucose deprivation experiments in vitro and in acutecerebral ischemia and ischemic preconditioning animal models. Evidence also showed SIRT1was a critical regulator of the expression of genes involved in postnatal angiogenesisin endotheliocyte, which suggesting that SIRT1may play an important role under conditionsof chronic cerebral ischemia.
This study was to investigate the role of SIRT1signaling pathway on cognitiveimpairment caused by chronic cerebral hypoperfusion. For this, a rat model of chroniccerebral ischemic dementia induced by permanent bilateral common carotid arteryocclusions(2-VO) was established. Using the Morris water maze, learning and memoryabilities of the rats were evaluated. Serial changes of SIRT1expression and activity wasmeasured by immunohistochemistry and Western blot. After that, resveratrol and EX-527were used to regulate activity of SIRT1in animal model, and expression of SIRT1togetherwith its target genes including phospho-FOXO3α(Ser253) and PGC-1α were detected byimmunohistochemistry, real-time PCR and Western blot. Impact on Oxidative stress ofSIRT1signaling pathway was also observed in the present study. The study was to provide atheoretical basis for SIRT1signaling pathway on role of anti-vascular cognitive impairment.1Establishment rat model of chronic cerebral ischemia and assessment of cognitivefunction
Healthy Male Wistar rats(aged2-3months, weighing260-300g) were randomlydivided into the sham operated group and chronic cerebral ischemia group for6weeks. Ratmodel of spatial learning and memory impairment was induced by permanent bilateralcommon carotid artery ligation (2-VO). Morris water maze was used to evaluate learningand memory abilities of rats. Place navigation test was carried out twice with an interval of15minutes for5consecutive days, and the escape latency was measured to evaluateanimals’ ability of learning and memory. Spatial probe test was performed on day5afterplace navigation test. Total time for rats spent in crossing the original quadrant where thehidden platform located was determined. Six weeks after2-VO rats were decapitated, andthe frontal cortex and hippocampus were collected for pathological assessment byhematoxylin-eosin(HE) staining. Experimental results showed that mortality rate of2-VOrats was22.7%, similar to ones reported in the literature. In place navigation test the escapelatency of sham operated rats decreased rapidly and leveled off and spatial localization for hidden platform occurred mainly in the first two trial days. CCI rats spent four days inlearning to find the hidden platform and escape latency on day5was prolonged again. Inspatial probe test time spent in crossing the original quadrant of2-VO rats was significantlyless than the sham operated ones. HE staining of2-VO rats showed scattered ischemicchanges in the frontal cortex and hippocampus, such as decrease in the number of normalneurons, loss of neural cells, disorder of organization arrangement, irregular cellmorphology and disorganized cell arrangements, degeneration and necrosis of neurons,scattered eosinophils, uneven vacuoles in the cytoplasm, nuclear pyknosis, and unclearnucleoli. In sham operated group structure of organization was intact, cells arranged orderly,no apoptosis and degeneration and necrosis of neurons was found, and cytoplasm andnucleolus normal. The results above suggested that cognitive dysfunction of rat modelinduced by chronic cerebral ischemia was established successfully, and2-VO rat modelcould well display the behavioral and pathological process of chronic cerebral ischemia,which could cause significant cognitive impairment reliably.2Changes of SIRT1gene expression and level of oxidative stress in rat model ofchronic cerebral ischemia
Healthy male Wistar rats were grouped as follows:(1)sham operated for6weeks(2)sham operated for9weeks (3)sham operated for12weeks (4)chronic cerebral ischemiafor6weeks (5)chronic cerebral ischemia for9weeks (6)chronic cerebral ischemia for12weeks. Levels of SIRT1protein expression were examined by western blot andimmunohistochemical staining via SP method. SOD and MDA levels in hippocampus andfrontal lobe were examined according to the corresponding kit instructions.
In Morris water maze cognitive impairment of2-VO rats showed dynamic changes withthe ischemia time prolonged.6weeks after operation escape latency of2-VO rats lengthenedsignificantly on day2,3, and5compared to sham operated ones.9weeks after operationescape latency of2-VO rats extended significantly on day2to5. In the whole trial escapelatencies of2-VO rats were longer than sham operated ones significantly12weeks afteroperation. time spent in crossing the original quadrant in CCI group gradually reduced as theischemia time extended and which was less significantly than the sham group. HE staining from brains of the consecutive three months2-VO rats demonstrated that loss of neuron anddegeneration and necrosis gradually increased with the ischemia time extended, proliferationof astrocytes and vessels gradually increased, organizational structure was disordered andirregularly arranged. The cells were severely deformed, uneven vacuoles gradually increasedin cytoplasm, karyopyknosis increased, and small liquefaction lesion could be seen in whitematter areas. Results of immunohistochemistry showed that SIRT1protein was locatedmainly in neulei. After2-VO the ratio of SIRT1-positive cells was significantly reduced,especially six weeks after operation. Western blot showed that SIRT1protein expressionlevels decreased significantly, which was lowest6weeks after operation. Reduction of SODas an antioxaditive substance and increase of MDA as a markers of lipid oxidation wereobserved at the three time point after operation, but the significant alteration occurred only at6weeks after2-VO. These results suggested that2-VO could cause progressive cognitiveimpairment in rats, effectively demonstrated the clinical course of vascular dementia, anddownregulation of SIRT1was involved in the development and progression of cognitiveimpairment induced by chronic cerebral ischemia. Oxidative stress in chronic cerebralischemia occurred mainly in the early stages of ischemia six weeks, which provided a basisfor selection of time point in the follow-up experiment of oxidative stress intervention.3Impact of SIRT1signaling pathway on cognitive function and oxidative stress of ratssubjected to chronic cerebral ischemia
Healthy male Wistar rats were grouped as follows:(1)sham operated(SH) group(2)chronic cerebral ischemia(CCI) group (3)resveratrol+chronic cerebral ischemia(Res)group (4)resveratrol+EX-527+chronic cerebral ischemia(Res+EX-527) group (5)EX-527+chronic cerebral ischemia(EX-527) group. Resveratrol was administered by intraperitonealinjections at a dose of50mg/kg daily for6weeks. EX-527was was injected to the lateralventricle at a dose of5μg.6weeks after2-VO learning and memory ability of all rats weredetected via the Morris water maze. Expression levels of SIRT1, FOXO3α and PGC-1α wereexamined through real-time quantitative PCR and western blot analysis.10%homogenatesupernatant of hippocampus and frontal lobe were centrifuged, and obtained supernatantfluid was used to measure SOD and MDA levels according to the corresponding kit instructions.
Behavioral test of water maze showed that the rats' learning and memory abilities ofRes group were significantly higher than CCI group, expressed as shorter escape latency onday2,3,5, and more time in crossing the original quadrant. In EX-527group rats showedlonger escape latencies on day2to5and less time in crossing the original quadrant than CCIgroup. In Res+EX-527group rats demonstrated longer escape latency and less time incrossing the original platform too. Results of real-time quantitative PCR showed differencesof mRNA levels of SIRT1and PGC-1α among the five groups were not significant.FOXO3αmRNA level was lower in2-VO rats compared to sham operated ones, which couldbe elevated by resveratrol and reduced by EX-527significantly. Immunohistochemicalresults of frontal cortex and hippocampal CA1region showed SIRT1protein was locatedmainly in neulei. A certain mount of SIRT1protein was observed in sham operated group,which was lower in2-VO group. SIRT1protein level could be elevated by resveratrol butcould not be altered by EX-527in2-VO group. Phospho-FOXO3α（Ser253）protein wasobserved mainly in cytoblast. In sham operated group amount of phospho-FOXO3α wasabundant in in the nuclei of the neurons, and little in cytoplasm. Phospho-FOXO3α（Ser253）protein in neurons were reduced significantly in2-VO group, but could be seen in bothcytoplasm and nuclei, and markedly in nuclei. Level of phospho-FOXO3α（Ser253）proteinwas increased by resveratrol in2-VO group which mainly seen in nuclei. In frontal cortex,phospho-FOXO3α（Ser253）protein levels of EX-527and Res+EX-527group were notsignificant different to CCI group，but lower than Res group significantly. In hippocampalCA1region, difference of phospho-FOXO3α（Ser253）protein levels between EX-527andCCI group was significant, and phospho-FOXO3α（Ser253）protein level of Res+EX-527group were not significant different to CCI group，but lower than Res group significantly.Rich expression of PGC-1α protein was detected in sham operated group, which was more incytoplasm than that of nulei. Level of PGC-1α protein was reduced both in nucleus andcytoplasm in2-VO group accompanied by less number of neurons and PGC-1α protein wasseen near the cytomambrane. PGC-1α protein level was increased in Res group and locatedmainly in nuclei. Contrarily PGC-1α protein level was decreased in EX-527and Res+ EX-527group and located mainly in cytoplasm. Western blot results demonstratedresveratrol could strengthen expression of SIRT1protein in2-VO rat brain. Resveratrolcould elevate inhibited phospho-FOXO3α（Ser253）protein level in2-VO rat brain. Althoughphospho-FOXO3α（Ser253）protein levels of EX-527group and Res+EX-527group were notreduced than that of CCI group significantly but lower than that of Res group significantly.The reduced PGC-1α protein level in2-VO rat brain was increased by resveratrol and lowerafter EX-527treatment. Reduced level of SOD and elevated level of MDA in CCI groupwere significantly different to sham operated group6weeks after operation. These changescould be lessened by resveratrol treatment and enlarged by EX-527significantly. Levels ofSOD and MDA were different significantly between Res group and CCI group, EX-527group and CCI group.
The results above suggested that SIRT1-FOXO3α/PGC-1α signaling pathway wasinhibited in chronic cerebral ischemic brain. SIRT1could regulate transcription ofFOXO3α but its regulation of PGC-1α expression was mainly on protein level in chroniccerebral ischemic brain. Activity of SIRT1-FOXO3α/PGC-1α signaling pathway could alteroxidative stress reaction in chronic cerebral ischemic brain. Enhanced activity ofSIRT1-FOXO3α/PGC-1α signaling pathway could increase the ability of anti-oxidativestress for rat in chronic cerebral ischemic brain, and effectively improved cognitiveimpairment of CCI rats. Improvement of resveratrol on cognitive dysfunction caused bychronic cerebral ischemia in rats was associated with enhanced ability of anti-oxidativestress mediated by SIRT1signaling pathway. The present study provided laboratoryevidences for its application to the prevention and treatment of vascular cognitiveimpairment, and it was expected to become one of the new drugs in vascular cognitiveimpairment.
引文
[1] Imai S, Armstrong C M, Kaeberlein M, et al. Transcriptional silencing and longevityprotein Sir2is an NAD+-dependent histone deacetylase. Nature,2000,403:795–800.
[2] Huhtiniemi T, Wittekindt C, Laitinen T, et al. Comparative and pharmacophore modelfor deacetylase SIRT1. J Comput Aided Mol Des,2006,20:589–599.
[3] Sinclair D A, Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast.Cell,1997,91(7):1033–1042.
[4] Kaeberlein M, McVey M, Guarente L. The SIR2/3/4complex and SIR2alonepromote longevity in Saccharomyces cerevisiae by two different mechanisms. GenesDev,1999,13:2570–2580.
[5] Yamamoto H, Schoonjans K, Auwerx J. Sirtuin functions in health and disease. MolEndocrinol,2007,21:1745–1755.
[6] McCay C M, Crowell M F, Maynard L A. The effect of retarded growth upon lengthof life span and upon the ultimate body size[J]. Nutrition,1989,5(3):155-171.
[7] Csiszar A, Labinskyy N, Jimenez R, et al. Anti-oxidative and anti-inflammatoryvasoprotective effects of caloric restriction in aging: role of circulating factors andSIRT1. Mech Ageing Dev.2009,130(8):518–527.
[8] Morris K C, Lin H W, Thompson J W, et al. Pathways for ischemic cytoprotection:Role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning. JCereb Blood Flow Metab.2011,31(4):1003–1019.
[9] Kim E J, Kho J H, Kang M R, et al. Active regulator of SIRT1cooperates with SIRT1and facilitates suppression of p53activity. Mol Cell,2007,28:277–290.
[10] Zakhary S M, Ayubcha D, Dileo J N, et al. Distribution Analysis of DeacetylaseSIRT1in Rodent and Human Nervous Systems. Anat Rec (Hoboken),2010,293(6):1024–1032.
[11] Ramadori G, Lee C E, Bookout A L, et al. Brain SIRT1: Anatomical Distribution andRegulation by Energy Availability. J. Neurosci,2008,28(40):9989–9996.
[12] Gan L, Mucke L. Paths of Convergence: Sirtuins in aging and neurodegeneration.Neuron,2008,58:10–14.
[13] Michán S, Li Y, Chou MM, et al. SIRT1is essential for normal cognitive function andsynapticplasticity. J Neurosci,2010,30(29):9695–9707.
[14] Tanno M, Sakamoto J, Miura T, et al. Nucleo-cytoplasmic shuttling of NAD+-dependent histone deacetylase SIRT1. J Biol Chem,2007,282(9):6823-32.
[15] Li Y, Xu W, McBurney M W, et al. SirT1inhibition reduces IGF-I/IRS-2/Ras/ERK1/2signaling and protects neurons. Cell Metab,2008,8:38–48.
[16] Tanny J C, Moazed D. Coupling of histone deacetylation to NAD breakdown by theyeast silencing protein Sir2: Evidence for acetyl transfer from substrate to an NADbreakdown product. Proc Natl Acad Sci U S A,2001,98:415–420.
[17] Tanner K G, et al. Silent information regulator2family of NAD-dependenthistone/protein deacetylases generates a unique product-1-O-acetyl-ADP-ribose.Proceedings of the National Academy of Sciences of the United States of America,2000,97(26):14178–14182.
[18] Chen D, Bruno J, Easlon E, et al.(2008) Tissue-specifc regulation of SIRT1bycalorie restriction. Genes Dev.2008,22:1753–1757.
[19] Luo J, Nikolaev A Y, Imai S, et al. Negative control of p53by Sir2alpha promotes cellsurvival under stress. Cell,2001,107:137–148.
[20] Sauve A A, Celic I, Avalos J, et al. Chemistry of gene silencing: the mechanism ofNAD+-dependent deacetylation reactions. Biochemistry,2001,40:15456–15463.
[21] Sauve A A, Schramm V L. Sir2regulation by nicotinamide results from switchingbetween base exchange and deacetylation chemistry. Biochemistry,2003,42:9249–9256.
[22] Jackson M D, Schmidt M T, Oppenheimer N J, et al. Mechanism of NicotinamideInhibition and Transglycosidation by Sir2Histone/Protein Deacetylases. Journal ofBiological Chemistry,2003,278:50985–50998.
[23] Zhao K, Harshaw R, Chai X, et al. Structural basis for nicotinamide cleavage andADP-ribose transfer by NAD(+)-dependent Sir2histone/protein deacetylases.Proceedings of the National Academy of Sciences of the United States of America,2004,101:8563–8568.
[24] Zhao W, et al. Negative regulation of the deacetylase SIRT1by DBC1. Nature,2008,451(7178):587–590.
[25] Bedalov A, et al. NAD-dependent deacetylase Hst1p controls biosynthesis andcellular NAD levels in Saccharomyces cerevisiae. Mol Cell Biol,2003,23(19):7044-7054.
[26] Anderson R M, et al. Manipulation of a nuclear NAD+salvage pathway delays agingwithout altering steady-state NAD+levels. Journal of Biological Chemistry,2002,277(21):18881–18890.
[27] Anderson R M, et al. Nicotinamide and PNC1govern lifespan extension by calorierestriction in Saccharomyces cerevisiae. Nature,2003,423(6936):181–185.
[28] Revollo J R, Grimm A A, Imai S. The NAD biosynthesis pathway mediated bynicotinamide phosphoribosyltransferase regulates Sir2activity in mammalian cells. JBiol Chem,2004,279(49):50754–50763.
[29] Ramsey K M, Yoshino J, Brace C S, et al. Circadian clock feedback cycle throughNAMPT-mediated NAD+biosynthesis. Science,2009,324(5927):651–654.
[30] Nakahata Y, Sahar S, Astarita G, et al. Circadian control of the NAD+salvagepathway by CLOCK-SIRT1. Science,2009,324(5927):654–657.
[31] Lin S J, Ford E, Haigis M, et al. Calorie restriction extends yeast life span bylowering the level of NADH. Genes Dev,2004,18(1):12–16.
[32] Fulco M, Schiltz RL, Iezzi S, et al. Sir2regulates skeletal muscle differentiation as apotential sensor of the redox state. Mol Cell,2003,12(1):51-62.
[33] Prozorovski T, Schulze-Topphoff U, Glumm R, et al. Sirt1contributes critically to theredox-dependent fate of neural progenitors. Nat Cell Biol,2008,10(4):385–394.
[34] Schmidt M T, Smith B C, Jackson M D, et al. Coenzyme specificity of Sir2proteindeacetylases: implications for physiological regulation. J Biol Chem,2004,279(38):40122–40129.
[35] Rodgers J T, Lerin C, Haas W et al. Nutrient control of glucose homeostasis through acomplex of PGC-1alpha and SIRT1. Nature,2005,434(7029):113–118.
[36] Nemoto S, Fergusson M M, Finkel T. Nutrient availability regulates SIRT1through aforkhead-dependent pathway. Science,2004,306:2105–2108.
[37] Xiong S, Salazar G, Patrushev N, et al. FoxO1Mediates an Autofeedback Loop RegulatingSIRT1Expression. Journal of Biological Chemistry,2011,286:5289–5299.
[38] Zschoernig B, Mahlknecht U. SIRTUIN1: regulating the regulator. Biochem BiophysRes Commun,2008,376:251–255.
[39] Wang C L，Chen X，Hou Z, et al. Interactions between E2F1and SirT1regulateapoptotic response to DNA damage, Nat. Cell Biol.2006,8:1025–1031.
[40] Chen W Y, Wang D H, Yen R C, et al. Tumor suppressor HIC1directly regulates IRT1to modulate p53-dependent DNA-damage responses. Cell,2005,123:437–448.
[41] Iwahara N, Hisahara S, Hayashi T, et al. Transcriptional activation ofNAD+-dependent protein eacetylase SIRT1by nuclear receptor TLX. Biochemicaland Biophysical Research ommunications,2009,386:671–675.
[42] Han L, Zhou R, Niu J, et al. SIRT1is regulated by a PPAR{gamma}-SIRT1egativefeedback loop associated with senescence. Nucleic Acids Res,2010,38:7458–7471.
[43] Mattagajasingh I,Kim C S, Naqvi A, et al. SIRT1promotes endothelium-dependentvascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl. Acad.Sci. U. S. A,2007,104:14855–14860
[44] Nisoli E, Tonello C, Cardile a,et al. Calorie restriction promotes mitochondrialbiogenesis by inducing the expression of eNOS. Science,2005,310:314–317.
[45] Noriega L G, Feige J N, Canto C, et al. CREB and ChREBP oppositely regulate SIRT1expression in response to energy availability.EMBO Rep,2011,12(10):1069-76.
[46] Cheadle C, Fan J, Cho-Chung Y S, et al. Stability regulation of mRNA and the controlof gene expression. Ann N Y Acad Sci,2005,1058:196–204.
[47] Lee J, Kemper J K. Controlling SIRT1expression by microRNAs in health andmetabolic disease.Aging (Albany NY),2010,2:527–534.
[48] Yamakuchi M. MicroRNA regulation of SIRT1. Front Physiol,2012,3:68.
[49] Abdelmohsen K, Pullmann R Jr. Lal A, et al. Phosphorylation of HuR by Chk2regulates SIRT1expression. Mol Cell,2007,25:543–557.
[50] Yang Y, Fu W, Chen J, et al. SIRT1sumoylation regulates its deacetylase activity andcellular response to genotoxic stress. Nat Cell Biol2007,9:1253–62.
[51] Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W Negative regulation of thedeacetylase SIRT1by DBC1. Nature.2008,451:587–90.
[52] Kim J E, Chen J, Lou Z. DBC1is a negative regulator of SIRT1. Nature,2008,451:583–586.
[53] Yuan J, Luo K, Liu T, et al. Regulation of SIRT1activity by genotoxic stress. GENES&DEVELOPMENT,2012,26:791–796.
[54] Sasaki T, Maier B, Koclega K D, et al. Phosphorylation regulates SIRT1function.PLoS One,2008,3(12):e4020.
[55] Nasrin N, Kaushik V K, Fortier E, et al. JNK1phosphorylates SIRT1and promotes itsenzymatic activity. PLoS One,2009,4(12):e8414.
[56] Guo X, Williams J G, Schug T T, et al. DYRK1A and DYRK3promote cell survivalthrough phosphorylation and activation of SIRT1. J Biol Chem,2010,285:13223–13232.
[57] Kang H, Jung J W, Kim M K, et al. CK2is the regulator of SIRT1substrate-bindingaffinity, deacetylase activity and cellular response to DNA-damage. PLoS One,2009,4(8):e6611.
[58] Yuan F, Xie Q, Wu J, et al. MST1promotes apoptosis through regulatingSirt1-dependent p53deacetylation.J Biol Chem.2011,286(9):6940-6945.
[59] Liu X, Wang D, Zhao Y，et al.Methyltransferase Set7/9regulates p53activity byinteracting with Sirtuin1(SIRT1).Proc Natl Acad Sci U S A,2011,108(5):1925-30.
[60] Franziska Flick and Bernhard Lüscher. Regulation of Sirtuin Function byPosttranslational Modifications. Front Pharmacol,2012,3:29.
[61] Chung S, Yao H, Caito S, et al. Regulation of SIRT1in cellular functions: role ofpolyphenols. Arch Biochem Biophys,2010,501:79–90.
[62] Davis J M, Murphy E A, Carmichael M D, et al. Quercetin increases brain andmuscle mitochondrial biogenesis and exercise tolerance. Am J Physiol Regul IntegrComp Physiol,2009,296:R1071–1077.
[63] Bordet R, Ouk T, Petrault O, et al. PPAR: a new pharmacological target forneuroprotection in stroke and neurodegenerative diseases. Biochem Soc Trans,2006,34:1341–1346.
[64] Howitz K T, Bitterman K J, Cohen H Y, et al. Small molecule activators of sirtuinsextend Saccharomyces cerevisiae lifespan. Nature,2003,425:191–196.
[65] Borriello A, Cucciolla V, Ragione F D. Dietary polyphenols: Focus on resveratrol：apromising agent in the prevention of cardiovascular diseases and control of glucosehomeostasis[J]. Nutr Metab Cardiovasc Dis,2010,20(5):618.
[66] Das S, Alagappan V K, Bagchi D, et al. Coordinated induction of iNOS-VEGF-KDR-eNOS after resveratrol consumption: a potential mechanism for resveratrolpreconditioning of the heart. Vascul Pharmacol,2005,42:281–289.
[67] Frankel E N, Waterhouse A L, Kinsella J E. Inhibition of human LDL oxidation byresveratrol. Lancet,1993,341:1103–1104.
[68] Fremont L, Belguendouz L, and Delpal S. Antioxidant activity of resveratrol andalcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fattyacids. Life Sci,1999,64:2511–2521.
[69] Mizutani K, Ikeda K, Kawai Y, et al. Protective effect of resveratrol on oxidativedamage in male and female stroke-prone spontaneously hypertensive rats. Clin. Exp.Pharmacol Physiol,2001,28:55–59.
[70] Jang J H, Surh Y J. Protective effect of resveratrol on beta-amyloid-induced oxidativePC12cell death. Free Radic. Biol Med,2003,34:1100–1110.
[71] Wood J G, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction anddelay ageing in metazoans. Nature,2004,430(7000):686–689.
[72] Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrialfunction and protects against metabolic disease by activating SIRT1and PGC-1alpha.Cell,2006,127(6):1109–1122.
[73] Baur J A, Pearson K J, Price N L, et al. Resveratrol improves health and survival ofmice on a high-calorie diet. Nature,2006,444(7117):337–342.
[74] Delmas D, Jannin B, Latruffe N. Resveratrol: Preventing properties against vascularalterations and ageing[J]. Mol Nutr Food Res,2005,49(1):377.
[75] Kim D, Nguyen M D, Dobbin M M, et al. SIRT1deacetylase protects againstneurodegeneration in models for Alzheimer’s disease and amyotrophic lateralsclerosis. EMBO J,2007,26:3169–3179.
[76] Sun A Y, Wang Q, Simonyi A, et al. Resveratrol as a therapeutic agent forneurodegenerative diseases. Mol Neurobiol,2010,41:375–383.
[77] Milne J C, Lambert P D, Schenk S, et al. Small molecule activators of SIRT1astherapeutics for the treatment of type2diabetes. Nature,2007,450(7170):712–716.
[78] Sauve A A, Moir R D, Schramm V L, et al. Chemical activation of Sir2-dependentsilencing by relief of nicotinamide inhibition. Mol Cell,2005,17(4):595–601.
[79] Cao C, Lu S, Kivlin R, et al. SIRT1confers protection against UVB-andH2O2-induced cell death via modulation of p53and JNK in cultured skinkeratinocytes.J Cell Mol Med,2009,13(9B):3632-43.
[80] Grozinger C M, Chao E D, Blackwell HE,et al.Identification of a class of smallmolecule inhibitors of the sirtuin family of NAD-dependent deacetylases byphenotypic screening.J Biol Chem.2001,276(42):38837-43.
[81] Heltweg B, Gatbonton T, Schuler A D, et al. Antitumor activity of a small moleculeinhibitor of human Sir2enzymes. Cancer Res,2006,66(8):4368–4377.
[82] Neugebauer R C, Uchiechowska U, Meier R, et al. Structure-activity studies onsplitomicin derivatives as sirtuin inhibitors and computational prediction of bindingmode. J Med Chem,2008,51(5):1203–1213.
[83] Napper A D, Hixon J, McDonagh T, et al. Discovery of indoles as potent and selectiveinhibitors of the deacetylase SIRT1.J Med Chem,2005,48(25):8045–8054.
[84] Peck B, Chen CY, Ho KK, et al. SIRT inhibitors induce cell death and p53acetylationthrough targeting both SIRT1and SIRT2.Mol Cancer Ther,2010,9(4):844-55.
[85] Solomon J M, Pasupuleti R, Xu L, et al. Inhibition of SIRT1catalytic activityincreases p53acetylation but does not alter cell survival following DNA damage. MolCell Biol,2006,26:28–38.
[86] Kabra N, Li Z, Chen L, et al.SirT1is an inhibitor of proliferation and tumor formationin colon cancer. J Biol Chem,2009,284(27):18210-18217.
[87] Vetterli L, Brun T, Giovannoni L, et al.Resveratrol potentiates glucose-stimulatedinsulin secretion in INS-1E beta-cells and human islets through a SIRT1-dependentmechanism.J Biol Chem,2011,286(8):6049-60.
[88] Trapp J, Meier R, Hongwiset D, et al. Structure-activity studies on suramin analoguesas inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem,2007,2(10):1419–1431.
[89] Voogd T E, Vansterkenburg E L, Wilting J, et al. Recent research on the biologicalactivity of suramin. Pharmacol Rev,1993,45(2):177–203.
[90] Schuetz A, Min J, Antoshenko T, et al. Structural basis of inhibition of the humanNAD+-dependent deacetylase SIRT5by suramin. Structure,2007,15(3):377–389.
[91] Lain S, Hollick J J, Campbell J, et al.Discovery, in vivo activity, and mechanism ofaction of a small-molecule p53activator.Cancer Cell,2008,13(5):454-63
[92] Saunders L R, Verdin E. Sirtuins: critical regulators at the crossroads between cancerand aging. Oncogene,2007,26:5489–5504.
[93] Dali-Youcef N, Lagouge M, Froelich S, et al. Sirtuins: the ‘magnificent seven’,function, metabolism and longevity. Ann Med,2007,39:335–345.
[94] Haigis M C, Guarente L P. Mammalian sirtuins–emerging roles in physiology, aging,and calorie restriction. Genes Dev,2006,20:2913–2921.
[95] Bouras T, Fu M, Sauve A A, et al. SIRT1Deacetylation and Repression of p300Involves Lysine Residues1020/1024within the Cell Cycle Regulatory Domain1.Journal of Biological Chemistry,2005,280:10264–10276.
[96] Iyer N G, Ozdag H, Caldas C. p300//CBP and cancer. Oncogene,2004,23:4225–4231.
[97] Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrialfunction and protects against metabolic disease by activating SIRT1andPGC-1alpha.Cell,2006,127(6):1109-22.
[98] Ramon Amat, Anna Planavila, Shen Liang Chen, et al.SIRT1Controls theTranscription of the Peroxisome Proliferator-activated Receptor-Co-activator-1α(PGC-1α) Gene in Skeletal Muscle through the PGC-1Autoregulatory Loop andInteraction with MyoD. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL,2009,284:21872–21880.
[99] Fernandez-Marcos P J, Auwerx J. Regulation of PGC-1a, a nodal regulator ofmitochondrial biogenesis. Am J Clin Nutr,2011,93:884S–890S.
[100]Puigserver P, Wu Z, Park C W, et al. A Cold-Inducible Coactivator of NuclearReceptors Linked to Adaptive Thermogenesis. Cell,1998,92:829–839.
[101]Lin J D. Minireview: the PGC-1coactivator networks: chromatin-remodeling andmitochondrial energy metabolism. Mol Endocrinol,2009,23:2–10.
[102]Vega R B, Huss J M, Kelly D P. The coactivator PGC-1cooperates with peroxisomeproliferator-activated receptor alpha in transcriptional control of nuclear genesencoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol,2000,20:1868–1876.
[103]Yoon J C, Puigserver P, Chen G, et al. Control of hepatic gluconeogenesis through thetranscriptional coactivator PGC-1. Nature,2001,413:131–138.
[104]Puigserver P, Rhee J, Donovan J, et al. Insulin-regulated hepatic gluconeogenesisthrough FOXO1-PGC-1alpha interaction. Nature,2003,423:550–555.
[105]Hong L Z, Zhao X Y, Zhang H L. p53-mediated neuronal cell death in ischemic braininjury. Neurosci Bull,2010,26:232–240.
[106]van Leeuwen I, Lain S. Sirtuins and p53. Adv Cancer Res,2009,102:171–195.
[107]Langley E, Pearson M, Faretta M，et a1．Human SIR2deacetylates p53andantagonizes PML/p53-induced cellular senescence[J]． EMBO J,2002,21(10):2383-2396.
[108]Yang Y, Hou H, Haller EM, Nicosia SV, Bai W. Suppression of FOXO1activity byFHL2through SIRT1-mediated deacetylation. EMBO J.2005,24:1021–1032.
[109]Motta M C, Divecha N, Lemieux M, et al. Mammalian SIRT1represses forkheadtranscription factors. Cell,2004,116:551–563.
[110]Purushotham, A. et al. Hepatocyte-specifc deletion of SIRT1alters fatty acidmetabolism and results in hepatic steatosis and infammation. Cell Metab,2009,9:327–338
[111]Hasegawa K, Wakino S, Yoshioka K, et al. Sirt1protects against oxidativestress-induced renal tubular cell apoptosis by the bidirectional regulation of catalaseexpression. Biochem Biophys Res Commun,2008,372(1):51–56.
[112]Wang F, Nguyen M, Qin FX-F, et al. SIRT2deacetylates FOXO3a in response tooxidative stress and caloric restriction. Aging Cell,2007,6:505–514.
[113]Mojsilovic-Petrovic J, Nedelsky N, Boccitto M, et al. FOXO3a is broadlyneuroprotective in vitro and in vivo against insults implicated in motor neurondiseases. J Neurosci,2009,29:8236–8247.
[114]Gilley J, Coffer P J, Ham J. FOXO transcription factors directly activate bim geneexpression and promote apoptosis in sympathetic neurons. J Cell Biol,2003,162:613–622.
[115]Kobayashi Y, Furukawa-Hibi Y, Chen C, et al. SIRT1is critical regulator ofFOXO-mediated transcription in response to oxidative stress. Int J Mol Med,2005,16:237–243.
[116]Kwon H S, Ott M. The ups and downs of SIRT1.Trends Biochem Sci,2008,33(11):517–525.
[117]Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependenttranscription and cell survival by the SIRT1deacetylase. EMBO J,2004,23:2369–2380.
[118]Chen J, Zhou Y, Mueller-Steiner S, et al. SIRT1protects against microglia-dependentamyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem,2005,280:40364–40374.
[119]Teng F Y, Tang B L. NF-kappaB signaling in neurite growth and neuronal survival.Rev Neurosci,2010,21:299–313.
[120]Gao J, Wang WY, Mao YW, Graff J, Guan JS, Pan L, Mak G, Kim D, Su SC, Tsai LH.A novel pathway regulates memory and plasticity via SIRT1and miR-134. Nature,2010,466:1105–1109.
[121]Li J, Calkins MJ, Johnson DA, et al. Role of Nrf2-dependent ARE-driven antioxidantpathway in neuroprotection. Methods Mol Biol,2007,399:67–78.
[122]Kensler TW, Wakabayashi N. Nrf2: friend or foe for chemoprevention?Carcinogenesis,2010,31:90–99.
[123]Kawai Y, Garduno L, Theodore M, et al. Acetylation-Deacetylation of theTranscription Factor Nrf2(nuclear factor erythroid2-related factor2) Regulates itsTranscriptional Activity and Nucleo-cytoplasmic Localization. Journal of BiologicalChemistry,2011,286:7629–7640.
[124]Zhang F, Xing J, Liou AK, et al. Enhanced Delivery of Erythropoietin Across theBlood-Brain Barrier for Neuroprotection against Ischemic Neuronal Injury. TranslStroke Res,2010,1:113–121.
[125]Wang YQ, Guo X, Qiu MH, et al. VEGF overexpression enhances striatalneurogenesis in brain of adult rat after a transient middle cerebral artery occlusion.Journal of Neuroscience Research,2007,85:73–82.
[126]Correia SC, Moreira PI. Hypoxia-inducible factor1: a new hope to counteractneurodegeneration?. J Neurochem,2010,112:1–12.
[127]Balaiya S, Khetpal V, Chalam KV. Hypoxia initiates sirtuin1-mediated vascularendothelial growth factor activation in choroidal endothelial cells through hypoxiainducible factor–2α. Molecular Vision,2012,18:114-120.
[128]Dioum EM, Chen R, Alexander MS, et al. Regulation of hypoxia-inducible factor2alpha signaling by the stress-responsive deacetylase sirtuin1. Science,2009,324:1289–1293.
[129]Lim JH, Lee YM, Chun YS, et al. Sirtuin1Modulates Cellular Responses toHypoxia by Deacetylating Hypoxia-Inducible Factor1[alpha]. Molecular Cell,2010,38:864–878.
[130]Zocchi L, Sassone-Corsi P.SIRT1-mediated deacetylation of MeCP2contributes toBDNF expression. Epigenetics,2012,7:695-700.
[131]Donmez G, Wang D, Cohen D E, et al. SIRT1suppresses beta-amyloid production byactivating the alpha-secretase gene ADAM10. Cell,2010,142:320–332.
[132]Cheng O, Ostrowski RP, Liu W, et al. Activation of liver X receptor reduces globalischemic brain injury by reduction of nuclear factor-[kappa]B. Neuroscience,2010,166:1101–1109.
[133]Fitz NF, Cronican A, Pham T, et al. Liver X Receptor Agonist Treatment AmelioratesAmyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23Mice. J.Neurosci,2010,30:6862–6872.
[134]Li J, Zeng Z, Viollet B, et al. Neuroprotective effects of adenosinemonophosphate-activated protein kinase inhibition and gene deletion in stroke. Stroke,2007,38:2992–2999.
[135]Purushotham A, Schug TT, Xu Q, et al. Hepatocyte-Specific Deletion of SIRT1AltersFatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation. CellMetabolism,2009,9:327–338.
[136]Deplanque D, Gele P, Petrault O, et al. Peroxisome proliferator-activatedreceptor-alpha activation as a mechanism of preventive neuroprotection induced bychronic fenofibrate treatment.J Neurosci,2003,23:6264–6271.
[137]Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory andneuroprotective actions of PPAR-gamma agonists. Front Biosci,2008,13:1813–1826.
[138]Luo Y, Yin W, Signore AP, et al. Neuroprotection against focal ischemic brain injuryby the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. JNeurochem,2006,97:435–448.
[139]Shie FS, Nivison M, Hsu PC, et al. Modulation of microglial innate immunity inAlzheimer’s disease by activation of peroxisome proliferator-activated receptorgamma. Curr Med Chem,2009,16:643–651.
[140]Yamamori T, DeRicco J, Naqvi A, et al. SIRT1deacetylates APE1and regulatescellular base excision repair. Nucleic Acids Research,2010,38:832–845.
[141]Woodhouse BC, Dianova II, Parsons JL, et al. Poly(ADP-ribose) polymerase-1modulates DNA repair capacity and prevents formation of DNA double strand breaks.DNA Repair (Amst),2008,7:932–940.
[142]Moroni F. Poly(ADP-ribose)polymerase1(PARP-1) and postischemic brain damage.Current Opinion in Pharmacology,2008,8:96–103.
[143]Rajamohan SB, Pillai VB, Gupta M, et al. SIRT1Promotes Cell Survival under Stressby Deacetylation-Dependent Deactivation of Poly(ADP-Ribose) Polymerase1. MolCell Biol,2009,29:4116–4129.
[144]Eliasson MJ, Sampei K, Mandir AS, et al. Poly(ADP-ribose) polymerase genedisruption renders mice resistant to cerebral ischemia. Nat Med,1997,3:1089–1095.
[145]Endres M, Wang ZQ, Namura S, et al. Ischemic brain injury is mediated by theactivation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab,1997,17:1143–1151.
[146]Sawada M, Hayes P, Matsuyama S. Cytoprotective membrane-permeable peptidesdesigned from the Bax-binding domain of Ku70. Nat Cell Biol,2003,5:352–357.
[147]Kim GW, Noshita N, Sugawara T, et al. Early Decrease in DNA Repair Proteins,Ku70and Ku86, and Subsequent DNA Fragmentation After Transient Focal CerebralIschemia in Mice. Stroke,2001,32:1401–1407.
[148]Sugawara T, Noshita N, Lewen A, et al. Neuronal Expression of the DNA RepairProtein Ku70After Ischemic Preconditioning Corresponds to Tolerance to GlobalCerebral Ischemia. Stroke,2001,32:2388–2393.
[149]Cohen HY, Lavu S, Bitterman KJ, et al. Acetylation of the C terminus of Ku70byCBP and PCAF controls Bax-mediated apoptosis. Mol Cell,2004,13:627–638.
[150]Jeong J, Juhn K, Lee H, et al. SIRT1promotes DNA repair activity and deacetylationof Ku70. Exp Mol Med,2007,39:8–13.
[151]Yuan Z, Zhang X, Sengupta N, et al. SIRT1Regulates the Function of the NijmegenBreakage Syndrome Protein. Molecular Cell,2007,27:149–162.
[152]Zu Y, Liu L, Lee MYK, et al. SIRT1Promotes Proliferation and Prevents SenescenceThrough Targeting LKB1in Primary Porcine Aortic Endothelial Cells. CirculationResearch,2010,106:1384–1393.
[153]Wang P, Xu TY, Guan YF, et al. Nicotinamide phosphoribosyltransferase protectsagainst ischemic stroke through SIRT1-dependent adenosine monophosphate–activated kinase pathway. Annals of Neurology,2011,69:360–374.
[154]Ikenoue T, Inoki K, Zhao B, et al. PTEN acetylation modulates its interaction withPDZ domain.Cancer Res,2008,68:6908–6912.
[155]Mattagajasingh I, Kim CS, Naqvi A, et al. SIRT1promotes endothelium-dependentvascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad SciU S A,2007,104:14855–14860.
[156]Ittner LM, G tz J. Amyloid-β and tau--a toxic pas de deux in Alzheimer’s disease.Nat Rev Neurosci,2011,12:67–72.
[157]Min SW, Cho SH, Zhou Y, et al. Acetylation of tau inhibits its degradation andcontributes to tauopathy. Neuron,2010,67:953–966.
[158]Hollander P. Anti-Diabetes and Anti-Obesity Medications: Effects on Weight inPeople With Diabetes. Diabetes Spectrum,2007,20(3):159-165.
[159]Bernier M, Paul RK, Martin-Montalvo A, et al. Negative Regulation of STAT3Protein-mediated Cellular Respiration by SIRT1. J Biol Chem,2011,286(22):19270–19279.
[160]Esteves TC, Brand MD. The reactions catalysed by the mitochondrial uncouplingproteins UCP2and UCP3. Biochim Biophys Acta,2005,1709:35–44.
[161]Lee FY, Li Y, Zhu H, et al. Tumor necrosis factor increases mitochondrial oxidantproduction and induces expression of uncoupling protein-2in the regenerating mice
[correction of rat] liver. Hepatology,1999,29:677–687.
[162]Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2gene in mice reveals a role in immunity and reactive oxygen species production. NatGenet,2000,26:435–439.
[163]Trenker M, Malli R, Fertschai I, et al. Uncoupling proteins2and3are fundamentalfor mitochondrial Ca2+uniport. Nat Cell Biol,2007,9:445–452.
[164]Brand MD, Esteves TC. Physiological functions of the mitochondrial uncouplingproteins UCP2and UCP3. Cell Metab,2005,2:85–93.
[165]Bordone L, Motta M C, Picard F, et al. Sirt1regulates insulin secretion by repressingUCP2in pancreatic beta cells. PLoS Biol,2006,4(2):e31.
[166]Moynihan KA, Grimm AA, Plueger MM, et al. Increased dosage of mammalian Sir2in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. CellMetab,2005,2:105–117.
[167]Della-Morte D, Dave KR, DeFazio RA, et al. Resveratrol pretreatment protects ratbrain from cerebral ischemic damage via a sirtuin1-uncoupling protein2pathway.Neuroscience,2009,159(3):993–1002.
[168]Aquilano K, Vigilanza P, Baldelli S, et al. Peroxisome Proliferator-activated Receptorγ Co-activator1α (PGC-1α) and Sirtuin1(SIRT1) Reside in Mitochondria. J BiolChem,2010,285(28):21590–21599.
[169]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol Improves MitochondrialFunction and Protects against Metabolic Disease by Activating SIRT1and PGC-1a.Cell.2006,127(6):1109-1122.
[170]Erion DM, Yonemitsu S, Nie Y, et al. SirT1knockdown in liver decreases basalhepatic glucose production and increases hepatic insulin responsiveness in diabeticrats. Proc Natl Acad Sci,2009,106:11288–11293.
[171]Gerhart-Hines Z, Rodgers JT, Bare O, et al. Metabolic control of musclemitochondrial function and fatty acid oxidation through SIRT1/PGC-1a. EMBO J,2007,26:1913–1923.
[172]St-Pierre J, Drori S, Uldry M, et al. Suppression of reactive oxygen species andneurodegeneration by the PGC-1transcriptional coactivators. Cell,2006,127,397–408.
[173]Hisahara S, Chiba S, Matsumoto H, et al. Histone deacetylase SIRT1modulatesneuronal differentiation by its nuclear translocation. P Natl Acad Sci USA,2008,105(40):15599–15604.
[174]Codocedo J F, Allard C, Godoy J A, et al. SIRT1Regulates Dendritic Development inHippocampal Neurons. PLoS One,2012,7(10): e47073.
[175]Fischer A, Sananbenesi F, Wang X, et al. Recovery of learning and memory isassociated with chromatin remodelling. Nature,2007,447:178–182.
[176] Levenson JM, O'Riordan KJ, Brown KD, et al. Regulation of histone acetylation duringmemory formation in the hippocampus. J Biol Chem,2004,279(39):40545-40559.
[177]Weiss EP, Fontana L. Caloric restriction: powerful protection for the aging heart andvasculature. AmJPhysiol. Heart Circ. Physiol,2011,301:H1205–H1219.
[178]Wu P, Shen Q, Dong S, et al. Calorie restriction ameliorates neurodegenerativephenotypes in forebrain-specific presenilin-1and presenilin-2double knockout mice.Neurobiol.Aging,2008,29:1502–1511.
[179]Jiang JC, Jaruga E, Repnevskaya MV, et al. An intervention resembling caloricrestriction prolongs life span and retards aging in yeast. FASEB J,2000,14(14):2135–2137.
[180]Masoro EJ. Caloric restriction and aging: an update. Exp Gerontol,2000,35(3):299–305.
[181]Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cellsurvival by inducing the SIRT1deacetylase. Science,2004,305:390–392.
[182]Guarente L. Sirtuins, aging, and metabolism. Cold Spring Harb. Symp. Quant. Biol,2011,76:81–90.
[183]Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, et al. Sirt1promotes fatmobilization in white adipocytes by repressing PPAR-γ. Nature,2004,429:771–776.
[184]Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, et al. Calorie restriction promotesmitochondrial biogenesis by inducing the expression of eNOS. Science,2005,310:314–317.
[185]Roth GS, Ingram DK, Lane MA. Slowing aging by calorie restriction. Nature Med,1995,1:414–415.
[186]Fontan-Lozano A, Saez-Cassanelli JL, Inda MC, et al. Caloric restriction increaseslearning consolidation and facilitates synaptic plasticity through mechanismsdependent on NR2B Subunits of the NMDA receptor. J Neurosci,2007,27:10185–10195.
[187]Pearson KJ, Lewis KN, Price NL, et al. Nrf2mediates cancer protection but notprolongevity induced by caloric restriction. P Natl Acad Sci USA,2008,105:2325–2330.
[188]Guarente L. Calorie restriction and SIR2genes-Towards a mechanism. Mech AgeingDev,2005,126:923–928.
[189]Guan, J, Skinner, SJ, Beilharz EJ, et al. The movement of IGF-I into the brainparenchyma after hypoxic–ischaemic injury. Neuroreport,1996,7:632–636.
[190]Liu XF, Fawcett JR, Thorne RG, et al. Non-invasive intranasal insulin-like growthfactor-I reduces infarct volume and improves neurologic function in rats followingmiddle cerebral artery occlusion. Neurosci Lett,2001,308:91–94.
[191]Scheepens A, Sirimanne ES, Breier BH, et al. Growth hormone as a neuronal rescuefactor during recovery from CNS injury. Neuroscience,2001,104:677–687.
[192]Nyberg F. Aging effects on growth hormone receptor binding in the brain. ExpGerontol,1997,32:521–528.
[193]O’Donnell SL, Frederick TJ, Krady JK, et al. IGF-I and microglia/macrophageproliferation in the ischemic mouse brain. Glia,2002,39:85–97.
[194]Sonntag WE, Lynch CD, Bennett SA, et al. Alterations in insulin-like growth factor-1gene and protein expression and type1insulin-like growth factor receptors in thebrains of ageing rats. Neuroscience,1999,88:269–279.
[195]Rollero A, Murialdo G, Fonzi S, et al. Relationship between cognitive function,growth hormone and insulin-like growth factor I plasma levels in aged subjects.Neuropsychobiology,1998,38:73–79.
[196]Dik MG, Pluijm SM, Jonker C, et al. Insulin-like growth factor I (IGF-I)and cognitivedecline in older persons. Neurobiol Aging,2003,24(4):573–581.
[197]Lemieux ME, Yang X, Jardine K, et al. The Sirt1deacetylase modulates theinsulin-like growth factor signaling pathway in mammals., Mech Ageing Dev,2005,126(10):1097-1105.
[198]Li Y, Xu W, McBurney MW, et al. SirT1inhibition reduces IGF-I/IRS-2/Ras/ERK1/2signaling and protects neurons. Cell Metab,2008,8(1):38-48.
[199]Cohen DE, Supinski AM, Bonkowski MS, et al. Neuronal SIRT1regulates endocrineand behavioral responses to calorie restriction Gene Dev,2009,23:2812–2817.
[200]Chong ZZ, Lin SH, Kang JQ, et al. Erythropoietin prevents early and late neuronaldemise through modulation of Akt1and induction of caspase1,3, and8. J NeurosciRes,2003,71(5):659–669.
[201]Hou J, Wang S, Shang YC, et al. Erythropoietin employs cell longevity pathways ofSIRT1to foster endothelial vascular integrity during oxidant stress. Curr NeurovascRes,2011,8(3):220–235.
[202]Donmez G, Wang D, Cohen DE, et al. SIRT1suppresses beta-amyloid production byactivating the alpha-secretase gene ADAM10. Cell,2010,142(2):320–332.
[203]Guarente L. Mitochondria--a nexus for aging, calorie restriction, and sirtuins?. Cell,2008,132(2):171–176.
[204]Tupe RS, Tupe SG, Agte VV. Dietary nicotinic acid supplementation improves hepaticzinc uptake and offers hepatoprotection against oxidative damage. Br J Nutr,2011,25:1–9.
[205]Bonda DJ, Wang X, Perry G, et al. Oxidative stress in Alzheimer disease: a possibilityfor prevention. Neuropharmacology,2010,59(4–5):290–294.
[206]Hüttemann M, Pecina P, Rainbolt M, et al. The multiple functions of cytochrome cand their regulation in life and death decisions of the mammalian cell: fromrespiration to apoptosis. Mitochondrion,2011,11(3):369–381.
[207]Wang X. The expanding role of mitochondria in apoptosis. Genes Dev,2001,15(22):2922-2933.
[208]Caito S, Rajendrasozhan S, Cook S, et al. SIRT1is a redox-sensitive deacetylase thatis post-translationally modified by oxidants and carbonyl stress. FASEB J,2010,24:3145–3159.
[209]Maiese K, Chong ZZ, Hou J, et al. New strategies for Alzheimer’s disease andcognitive impairment. Oxid Med Cell Longev,2009,2(5):279–289.
[210]Zhang G, Zhao Z, Gao L, et al. Gypenoside attenuates white matter lesions induced bychronic cerebral hypoperfusion in rats. Pharmacol Biochem Behav,2011,99(1):42–51.
[211]Chong ZZ, Shang YC, Hou J, et al. Wnt1neuroprotection translates into improvedneurological function during oxidant stress and cerebral ischemia through AKT1andmitochondrial apoptotic pathways. Oxid Med Cell Longev,2010,3(2):153–165.
[212]Khan MM, Ahmad A, Ishrat T, et al. Resveratrol attenuates6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson’sdisease. Brain Res,2010,1328:139–151.
[213]Cardaci S, Filomeni G, Ciriolo, MR. Redox implications of AMPK-mediated signaltransduction beyond energetic clues. J. Cell Sci,2012,125:2115–2125.
[214]Canto C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure bymodulating NAD+metabolism and SIRT1activity. Nature,2009,458:1056–1060.
[215]Furukawa A, Tada-Oikawa S, Kawanishi S, et al. H2O2accelerates cellular senescenceby accumulation of acetylated p53via decrease in the function of SIRT1by NAD+depletion. Cell. Physiol. Biochem,2007,20:45–54.
[216]Rajendrasozhan S, Yang SR, Kinnula, et al. SIRT1, an antiinflammatory and antiagingprotein, is decreased in lungs of patients with chronic obstructive pulmonary disease.Am. J. Respir. Crit. Care Med.2008,177:861–870.
[217]Hou J, Chong ZZ, Shang YC, et al. Early apoptotic vascular signaling is determinedby Sirt1through nuclear shuttling, forkhead trafficking, bad, and mitochondrialcaspase activation. Curr Neurovasc Res,2010;7(2):95–112.
[218]Ota H, Akishita M, Akiyoshi T, et al. Testosterone Deficiency Accelerates Neuronaland Vascular Aging of SAMP8Mice: Protective Role of eNOS and SIRT1. PLoS One,2012,7(1): e29598.
[219]Chen SD, Wu HY, Yang DI, et al. Effects of rosiglitazone on global ischemia-inducedhippocampal injury and expression of mitochondrial uncoupling protein2. Biochem.Biophys. Res. Commun,2006,351,198–203.
[220]Chan PH. Mitochondria and neuronal death/survival signaling pathways in cerebralischemia. Neurochem. Res,2004,29,1943–1949.
[221]Castellani RJ, Rolston RK, Smith MA. Alzheimer disease. Dis Mon,2010,56(9):484–546.
[222]Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science,1992,256(5054):184–185.
[223]Kehoe P, Wavrant-De Vrieze F, Crook R, et al. A full genome scan for late onsetAlzheimer's disease. Hum Mol Genet,1999,8:237-245.
[224]Bertram L, Blacker D, Mullin K, et al. Evidence for genetic linkage of Alzheimer'sdisease to chromosome10q. Science,2000,290:2302-2303.
[225]Kojro E, Fahrenholz F. The non-amyloidogenic pathway: structure and function ofalpha-secretases. Subcell Biochem,2005,38:105–127.
[226]Qin W, Yang T, Ho L, et al. Neuronal SIRT1activation as a novel mechanismunderlying the prevention of Alzheimer disease amyloid neuropathology by calorierestriction. J Biol Chem,2006,281:21745–21754.
[227]Kim D, Nguyen MD, Dobbin MM, Fischer A, et al. SIRT1deacetylase protectsagainstneurodegeneration in models for Alzheimer’s disease and amyotrophic lateralsclerosis. Embo J,2007,26:3169–3179.
[228]Helisalmi S, Vepsalainen S, Hiltunen M, et al. Genetic study between SIRT1, PPARD,PGC-1alpha genes and Alzheimer's disease. J Neurol,2008,255:668-673.
[229]Julien C, Tremblay C, Emond V, et al. SIRT1Decrease Parallels the Accumulation oftau in Alzheimer Disease. J Neuropathol Exp Neurol,2009,68(1):48-58.
[230]Spilman P, Podlutskaya N, Hart M J, et al. Inhibition of mTOR by rapamycinabolishes cognitive deficits and reduces amyloid beta levels in a mouse model ofAlzheimer’s disease. Plos ONE,2010,5(4):e9979.
[231]Potente M, Ghaeni L, Baldessari D, et al. SIRT1controls endothelial angiogenicfunctions during vascular growth. GENES&DEVELOPMENT,2007,21:2644–2658.
[232]Csiszar A, Labinskyy N, Podlutsky A, et al. Vasoprotective effects of resveratrol andSIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatoryphenotypic alterations. Am J Physiol Heart Circ Physiol,2008,294(6):H2721–H2735.
[233]Oomen CA, Farkas E, Roman V, et al. Resveratrol preserves cerebrovascular densityand cognitive function in aging mice. Front Aging Neurosci,2009,1:1-8.
[234]Raval AP, Dave KR, Perez-Pinzon MA. Resveratrol mimics ischemic preconditioningin the brain. J Cereb Blood Flow Metab,2006,26:1141–1147.
[235]Raval AP, Lin HW, Dave KR, et al. Resveratrol and ischemic preconditioning in thebrain. Curr Med Chem,2008;15:1545–1551.
[236]Chong ZZ, Maiese K. Enhanced tolerance against early and late apoptotic oxidativestress in mammalian neurons through nicotinamidase and sirtuin mediated pathways.Curr Neurovasc Res,2008,5:159–170.
[237]Wang S, Xing Z, Vosler PS, et al. Cellular NAD replenishment confers markedneuroprotection against ischemic cell death: role of enhanced DNA repair. Stroke,2008,39:2587–2595.
[238]Wang S, Vosler PS, Gan Y, et al. NAD protects neurons from NMDA-induced toxicityin vitro by a SIRT1-dependent mechanism.39th annual meeting of SFN; Chicago, IL.2009. p. Online.2009, Neuroscience Meeting.
[239]Ying W, Wei G, Wang D, et al. Intranasal administration with NAD+profoundlydecreases brain injury in a rat model of transient focal ischemia. Front Biosci,2007,12:2728–2734.
[240]Tsai SK, Hung LM, Fu YT, et al. Resveratrol neuroprotective effects during focalcerebral ischemia injury via nitric oxide mechanism in rats. Journal of VascularSurgery,2007,46:346–353.
[241]Alano CC, Ying W, Swanson RA. Poly(ADP-ribose) polymerase-1-mediated celldeath in astrocytes requires NAD+depletion and mitochondrial permeabilitytransition. J Biol Chem,2004,279:18895–18902.
[242]Liu D, Gharavi R, Pitta M, et al. Nicotinamide Prevents NAD+Depletion andProtects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+Consumptionby SIRT1may Endanger Energetically Compromised Neurons. Neuromolecular Med.2009,11(1):28–42.
[243]Liu D, Smith CL, Barone FC, et al. Astrocytic demise precedes delayed neuronaldeath in focal ischemic rat brain. Molecular Brain Research,1999,68:29–41.
[244] Sim o F, Matté A, Matté C, et al. Resveratrol prevents oxidative stress and inhibitionof Na(+)K(+)-ATPase activity induced by transient global cerebral ischemia in rats. JNutr Biochem,2011,22(10):921–928.
[245]Wang T, Gu J, Wu PF, et al. Protection by tetrahydroxystilbene glucoside againstcerebral ischemia: involvement of JNK, SIRT1, and NF-[kappa]B pathways andinhibition of intracellular ROS/RNS generation. Free Radical Biology and Medicine,2009,47:229–240.
[246]Avraham Y, Davidi N, Porat M, et al. Leptin reduces infarct size in association withenhanced expression of CB2, TRPV1, SIRT-1and leptin receptor. Curr NeurovascRes,2010,7:136–143.
[247]Zhu HR, Wang ZY, Zhu XL, et al. Icariin protects against brain injury by enhancingSIRT1-dependent PGC-1alpha expression in experimental stroke. Neuropharmacology,2010,59:70–76.
[248]Valerio A, Dossena M, Bertolotti P, et al. Leptin is induced in the ischemic cerebralcortex and exerts neuroprotection through NF-kappaB/c-Rel-dependent transcription.Stroke,2009,40:610–617.
[249]Zhang F, Chen J. Leptin protects hippocampal CA1neurons against ischemic injury. JNeurochem,2008,107:578–587.
[250]Zhang F, Wang S, Signore AP, et al. Neuroprotective effects of leptin against ischemicinjury induced by oxygen-glucose deprivation and transient cerebral ischemia. Stroke,2007,38:2329–2336.
[251]Kakefuda K, Fujita Y, Oyagi A, et al. Sirtuin1overexpression mice show a referencememory deficit, but not neuroprotection. Biochemical and Biophysical ResearchCommunications,2009,387:784–788.
[252]Chong ZZ, Lin SH, Li F, et al. The sirtuin inhibitor nicotinamide enhances neuronalcell survival during acute anoxic injury through AKT, BAD, PARP, and mitochondrialassociated “anti-apoptotic” pathways. Curr Neurovasc Res,2005,2:271–285.
[253]Dubois MF, Hebert R. The incidence of vascular dementia in Canada: a comparisonwith Europe and East Asia. Neuroepidemiology,2001,20:179-187.
[254]De Deyn PP, D’Hooge R, van Zutphen LFM. Animal models of human disorders—General aspects, Neurosci. Res. Commun.2000,26:141–148.
[255]Tsuchiya M, Sako K, Yura S, et al. Local cerebral glucose utilization following acuteand chronic bilateral carotid artery ligation in Wistar rat: relation to change in localcerebral blood flow. Exp Brain Res,1993,95:17.
[256]Sarti C, Pantoni L, Bartolini L, et al. Cognitive impairment and chronic cerebralhypoperfusion: what can be learned from experimental models. J Neurol Sci,2002,203204:263266.
[257]Wakita H, Tomimoto H, Akiguchi I, et al. Glial activation and white matter changes inthe rat brain induced by chronic cerebral hypoperfusion: an immunohistochemicalstudy. Acta Neuropathol,1994,87:484492,
[258]Tomimoto H, Akiguchi I, Suenaga T, et al.Alterations of the blood brain barrier andglial cells in white-matter lesions in cerebro-vascular and Alzheimer’s disease patients.Stroke,1996,27:2069-2074.
[259]Otori T, Katsumata T, Muramatsu H, et al. Long-term measurement of cerebral bloodflow and metabolism in a rat chronic hypoperfusion model. Clin Exp PharmacolPhysiol,2003,30:266-272.
[260]Farkas E, Luiten PG and Bari F. Permanent, bilateral common carotid artery occlusionin the rat: a model for chronic cerebral hypoperfusion-related neurodegenerativediseases. Brain Res Rev,2007,54:162-180.
[261]De la Torre JC, Fortin T, Park GA, et al.Chronic cerebrovascular insuffciency inducesdementia-like defcits in aged rats, Brain Res,1992,582:186–195.
[262]Block F. Global ischemia and behavioural defcits, Prog. Neurobiol,1999,58:279–295.
[263]Pappas BA, de la Torre JC, Davidson CM, et al. Chronic reduction of cerebral bloodfow in the adult rat: late emerging CA1cell loss and memory dysfunction. Brain Res,1996,708:50–58.
[264]Silva AJ, Giese KP, Fedorov NB, et al. Molecular, cellular, and neuroanatomicalsubstrates of place learning, Neurobiol. Learn. Mem,1998,70:44–61.
[265]Brandeis R, Brandys Y, Yehuda S. The use of the Morris water maze in the study ofmemory and learning, Int. J. Neurosci,1989,48:29–69.
[266]Poucet b, Save e, Lenck-Santini P.-P. Sensory and memory properties of hippocampalplace cells, Rev. Neurosci,2000,11:95–111.
[267]Schmidt-Kastner R. and Freund T. Selective vulnerability of the hippocampus in brainischemia. Neuroscience,1991,40599–636.
[268]Olsen G.M, Scheel-Kruger J, Moller A, et al. Relation of spatial learning of rats in theMorris water maze task to the number of viable CA1neurons following four-vesselocclusion, Behav. Neurosci,1994,108:681–690.
[269]Nunn J A, LePeillet E, Netto C A, et al. Global ischaemia: hippocampal pathology andspatial defcits in the water maze, Behav. Brain Res,1994,62:41–54.
[270]Mogensen J, Pedersen TK, Holm S, et al. Prefrontal cortical mediation of rats’ placelearning in a modifed water maze, Brain Res. Bull,1995,38:425–434.
[271]Ohtaki H, Fujimoto T, Sato T, et al. Progressive expression of vascular endothelialgrowth factor (VEGF) and angiogenesis after chronic ischemic hypoperfusion in rat.Acta Neurochir,2006, Suppl.96:283–287.
[272]De Jong G, Farkas E, Stienstra CM, et al. Cerebral hypoperfusion yields capillarydamage in the hippocampal CA1area that correlates with spatial memory impairment[J].Neuroscience,1999,91(1):203-210.
[273]Liu HX, Zhang JJ, Zheng P, et al. Altered expression of MAP-2, GAP-43, andsynaptophysin in the hippocampus of rats with chronic cerebral hypoperfusioncorrelates with cognitive impairment. Brain Res. Mol. Brain Res,2005,139:169–177.
[274]Wahlund LET, Gauthier S. Vascular Cognitive Impairment in Clinical Practice.Cambridge, UK: Cambridge University Press,2009.
[275]Farkasa E, Luiten PG, Bari F.Permanent, bilateral common carotid artery occlusion inthe rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases.BRAIN RESEARCH REVIEWS,2007,54:162–180
[276]Ni J, Ohm H,‘Matsumoto K, et al. Progressive cognitive impairment followingchronic cerebral hypoperfusion induced by permament occlusion of bilateral carotidarteries in rats. Brain Res,1994,653:231-236.
[277]Driscoll I, Hamilton D A, Petropoulos H, et al. The aging hippocampus: cognitive,biochemical and structural findings. Cerebral cortex,2003,13:1344-351.
[278]Burke SN, Barnes CA. Neural plasticity in the aging brain. Nature Rev Neurosci,2006,7:30-40.
[279]Sarangi S, San Pedro EC, Mountz J M. Antrior choroidal artery infarction presentingas Proressive cognitive deficit. Clin Nucl Med,2000,25（3）：187-190.
[280]Lojkowska W, Ryglewicz D, Jedrzejczak T, et a. SPECT as a diagnosticestint in theinvestigation of dementia. Neurol Sci,2002,15:215-219.
[281]Yang DW, Kim BS, Park JK, et al.Analysis of cerebral blood flow of subcorticalvascular dementia with single photon emission computered tomography: adaptationof statistical parametric mapping.Neurol Sci,2002,15:199-205.
[282]Bennett SA, Tenniswood M, Chen JH, et al. Chronic cerebral hypoperfusion elicitsneuronal apoptosis and behavioral impairment. Neuroreport,1998,9:161-166.
[283]Bennett SA, Tenniswood M, Chen JH, et al. Chronic cerebral hypoperfusion elicitsneuronal apoptosis and behavioral impairment. NeuroReport,1998,9:161–166.
[284]Ni JW, MatsumotoK, Li HB, et al.Neuronal damage and decrease of centralAcetylcholine level following permanent occlusion of bilateral common carotidarteries in rat.Brain Res,1995,673(2):290-296.
[285]Nanti M, Watanabe H. Availability of2VO rats as a model for chroniccerebrovascular disease [J].Nippon Yakurigaku Zasshi,1999,113(2):85-95.
[286]Ramadori G, Lee CE, Bookout AL, et al. Brain SIRT1: Anatomical distribution andregulation by energy availability. J Neurosci,2008,28(40):9989–9996.
[287]Samuel SM, Thirunavukkarasu M, Penumathsa SV, et al. Akt/FOXO3a/SIRT1Mediated Cardioprotection by n-Tyrosol against Ischemic Stress in Rat In vivo modelof Myocardial Infarction: Switching Gears towards Survival and Longevity. J AgricFood Chem,2008,56(20):9692–9698.
[288]Yan W, Fang ZP, Yang QZ, et al. SirT1mediates hyperbaric oxygen preconditioning-induced ischemic tolerance in rat brain. J Cereb Blood Flow Metab,2013,33(3):396–406.
[289]Harman D.Aging: A theory based on free radical and radiation chemistry. J Gerontol,1956,11:298–300.
[290]Barbara Shukitt-Hale.The effects of aging and oxidative stress on psychomotor andbehavior. Age,1999,22:9-17.
[291]Kim JS, Yun I, Choi YB, et a1．Ramipril protects from free radical induced whitematter damage in chronic hypoporfusion in the rat[J]．J Clin Neurosci,2008,15(2):174-178.
[292]Smith MA, Nunomura A, Lee HG, et al. Chronological primacy of oxidative stress inAlzheimer disease. Neurobiology of aging,2005,26:579–580.
[293]W rtwein G, Stackman RW, Walsh TJ. Vitamin E prevents the place learning defcitand the cholinergic hypofunction induced by AF64A. Exp. Neurol,125(1994)15–21.
[294]Chan PH. Role of oxidants in ischemic brain damage. Stroke,1996,27:1124–1129.
[295]Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. JCereb Blood Flow Metab,2001,21:2–14.
[296]Tanaka K, Wada-Tanaka N, Miyazaki I, Nomura M, Ogawa N.Chronic cerebralhypoperfusion induces striatal alterations due to the transient increase of NOproduction and the depression of glutathione content.Neurochem Res,2002,27(4):331-336.
[297]Aytac E, Seymen HO, Uzun H, et al. Effects of iloprost on visual evoked potentialsand brain tissue oxidative stress after bilateral common carotid artery occlusion.Prostaglandins, Leukotrienes and Essential Fatty Acids.2006,74:373–378.
[298]Farkas E, Luiten PG, Bari F.Permanent, bilateral common carotid artery occlusion inthe rat: A model for chronic cerebral hypoperfusion-related neurodegenerativediseases. BRAIN RESEARCH REVIEWS,2007,54:162–180.
[299]Liu C, Wu J, Gu J, et a1．Baicalein improves cognitive deficits induced by chroniccerebral hypoperfusion in rats[J]. Pharmacol Biochem Behav,2007,86(3);423-430．
[300]Ozacmak VH, Sayan H, Cetin A, et al．ATl receptor blocker eandesartan-inducedaRenuation of brain injury of rats subjected to chronic cerebral hypoperfusion[J].Neurochem Res,2007,32(8);1314-1321．
[301]Chong ZZ, Shang YC, Wang S, et al. SIRT1: new avenues of discovery for disordersof oxidative stress. Expert Opin Ther Targets,2012,16(2):167–178.
[302] Wilcock G, M bius HJ, St ffler A, et al.A double-blind，placebo-controlled multicenterstudy of memantine in mild to moderate vascular dementia（MMM500）Int ClinPsychophamnacol,2002,17:297-305.
[303]Blander G, Guarente L. The Sir2family of protein deacetylases. Annual Review ofBiochemistry,2004,73:417-435.
[304]Hsu CP, Zhai P, Yamamoto T, et al. Sirt1Protects the Heart from Ischemia/Reperfusion. Circulation,2010,122(21):2170–2182.
[305]de Kreutzenberg SV, Ceolotto G, Papparella I, et al.Downregulation of theLongevity-Associated Protein Sirtuin1in Insulin Resistance and MetabolicSyndrome:Potential Biochemical Mechanisms. Diabetes,2010,59:1006–1015.
[306]Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I.SIRT1, an antiinflammatory andantiaging protein, is decreased in lungs of patients with chronic obstructivepulmonary disease. Am J Respir Crit Care Med,2008,177(8):861-70.
[307]Clark D, Tuor UI, Thompson R, et al. Protection against Recurrent Stroke withResveratrol:Endothelial Protection. PLoS One,2012,7(10):e47792.
[308]Heyward FD, Walton RG, Carle MS, et al. Adult mice maintained on a high-fat dietexhibit object location memory deficits and reduced hippocampal SIRT1geneexpression. Neurobiol Learn Mem,2012,98(1):25-32.
[309]Yan WJ, Fang ZP, Yang QZ, et al. SirT1mediates hyperbaric oxygenpreconditioning-induced ischemic tolerance in rat brain. J Cereb Blood Flow Metab,2013,33(3):396–406.
[310]Zhu HR, Wang ZY, Zhu XL, et al. Icariin protects against brain injury by enhancingSIRT1-dependent PGC-1α Expression in experimental stroke. Neuropharmacology,2010,59(1-2):70-6.
[311]Dal-Pan A, Pifferi F, Marchal J, et al. Cognitive Performances Are SelectivelyEnhanced during Chronic Caloric Restriction or Resveratrol Supplementation in aPrimate. PLoS One,2011,6(1): e16581.
[312]Abraham J, Johnson RW.Consuming a Diet Supplemented with Resveratrol ReducedInfection-Related Neuroinflammation and Deficits in Working Memory in Aged Mice.Rejuvenation Res,2009,12(6):445–453.
[313]Schirmer H, Pereira TC, Rico EP, et al. Modulatory effect of resveratrol on SIRT1,SIRT3, SIRT4, PGC1α and NAMPT gene expression profiles in wild-type adultzebrafish liver.Mol Biol Rep,2012,39(3):3281-3289.
[314]Anne Brunet, Lora B, Sweeney J, et al. Stress-Dependent Regulation of FOXOTranscription Factors by the SIRT1Deacetylase. SCIENCE,2004,303(26).
[315]Kenyon C, Murphy CT. Enrichment of regulatory motifs upstream of predictedDAF-16targets. Nat Genet,2006,38:397–398.
[316]Jacobs FM, van der Heide LP, Wijchers PJ, et al. FoxO6, a novel member of the FoxOclass of transcription factors with distinct shuttling dynamics. J Biol Chem,2003,278:35959–67.
[317]Anderson MJ, Viars CS, Czekay S, et al. Cloning and characterization of three humanforkhead genes that comprise an FKHR-like gene subfamily. Genomics,1998,47:187–99.
[318]Hoekman M F, Jacobs F M, Smidt M P, Burbach J P. Spatial and temporal expressionof FoxO transcription factors in the developing and adult murine brain. Gene ExprPatterns2006,6:134–140.
[319]Lehtinen MK, Yuan Z, Boag PR, et al. A Conserved MST-FOXO Signaling PathwayMediates Oxidative-Stress Responses and Extends Life Span. Cell,2006,125:987–1001.
[320]Bradley J. Willcox, Timothy A. Donlon, Qimei He, et al. FOXO3A genotype isstrongly associated with human longevity. PNAS,2008,105(37):13987–13992.
[321]Lam EW, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cellfate. Biochem Soc Trans,2006,34(Pt5):722–6.
[322]Fukunaga K, Ishigami T, Kawano T. Transcriptional regulation of neuronal genes andits effect on neural functions: expression and function of forkhead transcriptionfactors in neurons. J Pharmacol Sci,2005,98:205–11.
[323]Hillion JA, Li Y, Maric D, et al. Involvement of Akt in preconditioning-inducedtolerance to ischemia in PC12cells.J Cereb Blood Flow Metab,2006,26:1323–31.
[324]Won CK, Ji HH, Koh PO. Estradiol prevents the focal cerebral ischemicinjury-induced decrease of forkhead transcription factors phosphorylation. NeurosciLett,2006,398:39–43.
[325]Sherry M. Zakhary1, Diana Ayubcha1, Jeffery N. Dileo, et al.Distribution Analysis ofDeacetylase SIRT1in Rodent and Human Nervous Systems. Anat Rec (Hoboken),2010,293(6):1024–1032.
[326]Brunet A, Sweeney LB, Sturgill JF, et al.Greenberg ME.Stress-dependent regulationof FOXO transcription factors by the SIRT1deacetylase. Science,2004,303(5666):2011–5.
[327]Brunet A, Bonni A, Zigmond M J, et al.Akt promotes cell survival by phosphorylatingand inhibiting a Forkhead transcription factor.Cell,1999,96(6):857-68.
[328]Biggs WH3rd, Meisenhelder J, Hunter T, et al.Protein kinase B/Akt-mediatedphosphorylation promotes nuclear exclusion of the winged helix transcription factorFKHR1.Proc Natl Acad Sci U S A,1999,96(13):7421-6.
[329]Lam EW, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cellfate. Biochem Soc Trans,2006,34(Pt5):722–6.
[330]Fu Z, Tindall DJ. FOXOs, cancer and regulation of apoptosis. Oncogene,2008,27:2312–2319.
[331]Michishita E, Park JY, Burneskis JM, et al. Evolutionarily conserved andnonconserved cellular localizations and functions of human SIRT proteins. Mol BiolCell,2005,16(10):4623–35.
[332]Sugden MC, Caton PW, Holness MJ. PPAR control: it's SIRTainly as easy as PGC. JEndocrinol,2010,204:93–104.
[333]Nemoto S, Fergusson MM, Finkel T. SIRT1functionally interacts with the metabolicregulator and transcriptional coactivator PGC-1a. J Biol Chem,2005,280:16456–16460.
[334]Finck BN, Kelly DP. PGC-1coactivators: Inducible regulators of energy metabolismin health and disease. J. Clin. Invest,2006,116:615–622.
[335]Lin J, Wu PH, Tarr PT, et al. Defects in adaptive energy metabolism with CNS-linkedhyperactivity in PGC-1alpha null mice. Cell,2004,119:121–135.
[336]Qin WP, Vahram H, Pavel K, et al. PGC-1α Expression Decreases in the AlzheimerDisease Brain as a Function of Dementia.Arch Neurol,2009,66(3):352-361.
[337]Liu L, Zhang P, Li Y, et al.Curcumin protects brain from oxidative stress throughinducing expression of UCP2in chronic cerebral hypoperfusion aging-rats.MolNeurodegener,2012,7(Suppl1): S10.
[338]Zhang GL, Deng JP, Wang BH, et al.Gypenosides improve cognitive impairmentinduced by chronic cerebral hypoperfusion in rats by suppressing oxidative stress andastrocytic activation. Behav Pharmacol,2011,22(7):633-44.
[339]Xu Y, Zhang JJ, Xiong L, et al.Green tea polyphenols inhibit cognitive impairmentinduced by chronic cerebral hypoperfusion via modulating oxidative stress. J NutrBiochem,2010,21(8):741-8.
[340]Wareski P, Vaarmann A, Choubey V, et al. PGC-1{alpha} and PGC-1{beta} regulatemitochondrial density in neurons. J. Biol. Chem,2009,284:21379–21385.
[341]Chinetti G., Fruchart JC, Staels B. Peroxisome proliferator-activated receptors(PPARs): Nuclear receptors at the crossroads between lipid metabolism andinflammation. Inflamm. Res,2000,49;497–505.
[342]Yin KJ, Deng Z, Hamblin M, et al. Peroxisome proliferator-activated receptor deltaregulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. J.Neurosci,2010,30:6398–6408.
[343]Yin KJ, Deng Z, Hamblin M, et al. Vascular PPARdelta protects againststroke-induced brain injury. Arterioscler. Thromb. Vasc. Biol,2011,31:574–581.
[344]Li PF, Dietz R, and von Harsdorf R. Superoxide induces apoptosis in cardiomyocytes,but proliferation and expression of transforming growth factor-beta1in cardiacfbroblasts. FEBS Lett,1999,448:206–210.
[345]Lam EW, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cellfate. Biochem Soc Trans,2006,34(Pt5):722–6.
[346]Giannakou ME, Partridge L. The interaction between FOXO and SIRT1: tipping thebalance towards survival. Trends Cell Biol,2004,14(8):408–12.
[347]Huang H, Tindall DJ. Dynamic FoxO transcription factors. J Cell Sci,2007,120:2479–2487.
[348]Essers, MA,Weijzen S, de Vries-Smits AM, et al. FOXO transcription factoractivation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J,2004,23:4802–4812.
[349]Kops GJ, Dansen TB, Polderman PE, et al. Forkhead transcription factor FOXO3aprotects quiescent cells from oxidative stress.Nature,2002,419(6904):316-21.
[350]Curtis C, Landis GN, Folk D, et al. Transcriptional profling of MnSOD-mediatedlifespan extension in Drosophila reveals a spe-cies-general network of aging andmetabolic genes. Genome Biol,2007,8:R262.
[351]Burgering BM, Medema RH. Decisions on life and death: FOXO Forkheadtranscription factors are in command when PKB/Akt is off duty. J Leukoc Biol,2003，73:689–701.
[352]Olmos Y, Sánchez-Gómez FJ, Wild B, et al. SirT1regulation of antioxidant genes isdependent on the formation of a FoxO3a/PGC-1α complex.Antioxid Redox Signal.2013Mar5.[Epub ahead of print]. online.liebertpub.com.
[2] Huhtiniemi T, Wittekindt C, Laitinen T, et al. Comparative and pharmacophore modelfor deacetylase SIRT1. J Comput Aided Mol Des,2006,20:589–599.
[3] Sinclair D A, Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast.Cell,1997,91(7):1033–1042.
[4] Kaeberlein M, McVey M, Guarente L. The SIR2/3/4complex and SIR2alonepromote longevity in Saccharomyces cerevisiae by two different mechanisms. GenesDev,1999,13:2570–2580.
[5] Yamamoto H, Schoonjans K, Auwerx J. Sirtuin functions in health and disease. MolEndocrinol,2007,21:1745–1755.
[6] McCay C M, Crowell M F, Maynard L A. The effect of retarded growth upon lengthof life span and upon the ultimate body size[J]. Nutrition,1989,5(3):155-171.
[7] Csiszar A, Labinskyy N, Jimenez R, et al. Anti-oxidative and anti-inflammatoryvasoprotective effects of caloric restriction in aging: role of circulating factors andSIRT1. Mech Ageing Dev.2009,130(8):518–527.
[8] Morris K C, Lin H W, Thompson J W, et al. Pathways for ischemic cytoprotection:Role of sirtuins in caloric restriction, resveratrol, and ischemic preconditioning. JCereb Blood Flow Metab.2011,31(4):1003–1019.
[9] Kim E J, Kho J H, Kang M R, et al. Active regulator of SIRT1cooperates with SIRT1and facilitates suppression of p53activity. Mol Cell,2007,28:277–290.
[10] Zakhary S M, Ayubcha D, Dileo J N, et al. Distribution Analysis of DeacetylaseSIRT1in Rodent and Human Nervous Systems. Anat Rec (Hoboken),2010,293(6):1024–1032.
[11] Ramadori G, Lee C E, Bookout A L, et al. Brain SIRT1: Anatomical Distribution andRegulation by Energy Availability. J. Neurosci,2008,28(40):9989–9996.
[12] Gan L, Mucke L. Paths of Convergence: Sirtuins in aging and neurodegeneration.Neuron,2008,58:10–14.
[13] Michán S, Li Y, Chou MM, et al. SIRT1is essential for normal cognitive function andsynapticplasticity. J Neurosci,2010,30(29):9695–9707.
[14] Tanno M, Sakamoto J, Miura T, et al. Nucleo-cytoplasmic shuttling of NAD+-dependent histone deacetylase SIRT1. J Biol Chem,2007,282(9):6823-32.
[15] Li Y, Xu W, McBurney M W, et al. SirT1inhibition reduces IGF-I/IRS-2/Ras/ERK1/2signaling and protects neurons. Cell Metab,2008,8:38–48.
[16] Tanny J C, Moazed D. Coupling of histone deacetylation to NAD breakdown by theyeast silencing protein Sir2: Evidence for acetyl transfer from substrate to an NADbreakdown product. Proc Natl Acad Sci U S A,2001,98:415–420.
[17] Tanner K G, et al. Silent information regulator2family of NAD-dependenthistone/protein deacetylases generates a unique product-1-O-acetyl-ADP-ribose.Proceedings of the National Academy of Sciences of the United States of America,2000,97(26):14178–14182.
[18] Chen D, Bruno J, Easlon E, et al.(2008) Tissue-specifc regulation of SIRT1bycalorie restriction. Genes Dev.2008,22:1753–1757.
[19] Luo J, Nikolaev A Y, Imai S, et al. Negative control of p53by Sir2alpha promotes cellsurvival under stress. Cell,2001,107:137–148.
[20] Sauve A A, Celic I, Avalos J, et al. Chemistry of gene silencing: the mechanism ofNAD+-dependent deacetylation reactions. Biochemistry,2001,40:15456–15463.
[21] Sauve A A, Schramm V L. Sir2regulation by nicotinamide results from switchingbetween base exchange and deacetylation chemistry. Biochemistry,2003,42:9249–9256.
[22] Jackson M D, Schmidt M T, Oppenheimer N J, et al. Mechanism of NicotinamideInhibition and Transglycosidation by Sir2Histone/Protein Deacetylases. Journal ofBiological Chemistry,2003,278:50985–50998.
[23] Zhao K, Harshaw R, Chai X, et al. Structural basis for nicotinamide cleavage andADP-ribose transfer by NAD(+)-dependent Sir2histone/protein deacetylases.Proceedings of the National Academy of Sciences of the United States of America,2004,101:8563–8568.
[24] Zhao W, et al. Negative regulation of the deacetylase SIRT1by DBC1. Nature,2008,451(7178):587–590.
[25] Bedalov A, et al. NAD-dependent deacetylase Hst1p controls biosynthesis andcellular NAD levels in Saccharomyces cerevisiae. Mol Cell Biol,2003,23(19):7044-7054.
[26] Anderson R M, et al. Manipulation of a nuclear NAD+salvage pathway delays agingwithout altering steady-state NAD+levels. Journal of Biological Chemistry,2002,277(21):18881–18890.
[27] Anderson R M, et al. Nicotinamide and PNC1govern lifespan extension by calorierestriction in Saccharomyces cerevisiae. Nature,2003,423(6936):181–185.
[28] Revollo J R, Grimm A A, Imai S. The NAD biosynthesis pathway mediated bynicotinamide phosphoribosyltransferase regulates Sir2activity in mammalian cells. JBiol Chem,2004,279(49):50754–50763.
[29] Ramsey K M, Yoshino J, Brace C S, et al. Circadian clock feedback cycle throughNAMPT-mediated NAD+biosynthesis. Science,2009,324(5927):651–654.
[30] Nakahata Y, Sahar S, Astarita G, et al. Circadian control of the NAD+salvagepathway by CLOCK-SIRT1. Science,2009,324(5927):654–657.
[31] Lin S J, Ford E, Haigis M, et al. Calorie restriction extends yeast life span bylowering the level of NADH. Genes Dev,2004,18(1):12–16.
[32] Fulco M, Schiltz RL, Iezzi S, et al. Sir2regulates skeletal muscle differentiation as apotential sensor of the redox state. Mol Cell,2003,12(1):51-62.
[33] Prozorovski T, Schulze-Topphoff U, Glumm R, et al. Sirt1contributes critically to theredox-dependent fate of neural progenitors. Nat Cell Biol,2008,10(4):385–394.
[34] Schmidt M T, Smith B C, Jackson M D, et al. Coenzyme specificity of Sir2proteindeacetylases: implications for physiological regulation. J Biol Chem,2004,279(38):40122–40129.
[35] Rodgers J T, Lerin C, Haas W et al. Nutrient control of glucose homeostasis through acomplex of PGC-1alpha and SIRT1. Nature,2005,434(7029):113–118.
[36] Nemoto S, Fergusson M M, Finkel T. Nutrient availability regulates SIRT1through aforkhead-dependent pathway. Science,2004,306:2105–2108.
[37] Xiong S, Salazar G, Patrushev N, et al. FoxO1Mediates an Autofeedback Loop RegulatingSIRT1Expression. Journal of Biological Chemistry,2011,286:5289–5299.
[38] Zschoernig B, Mahlknecht U. SIRTUIN1: regulating the regulator. Biochem BiophysRes Commun,2008,376:251–255.
[39] Wang C L，Chen X，Hou Z, et al. Interactions between E2F1and SirT1regulateapoptotic response to DNA damage, Nat. Cell Biol.2006,8:1025–1031.
[40] Chen W Y, Wang D H, Yen R C, et al. Tumor suppressor HIC1directly regulates IRT1to modulate p53-dependent DNA-damage responses. Cell,2005,123:437–448.
[41] Iwahara N, Hisahara S, Hayashi T, et al. Transcriptional activation ofNAD+-dependent protein eacetylase SIRT1by nuclear receptor TLX. Biochemicaland Biophysical Research ommunications,2009,386:671–675.
[42] Han L, Zhou R, Niu J, et al. SIRT1is regulated by a PPAR{gamma}-SIRT1egativefeedback loop associated with senescence. Nucleic Acids Res,2010,38:7458–7471.
[43] Mattagajasingh I,Kim C S, Naqvi A, et al. SIRT1promotes endothelium-dependentvascular relaxation by activating endothelial nitric oxide synthase. Proc. Natl. Acad.Sci. U. S. A,2007,104:14855–14860
[44] Nisoli E, Tonello C, Cardile a,et al. Calorie restriction promotes mitochondrialbiogenesis by inducing the expression of eNOS. Science,2005,310:314–317.
[45] Noriega L G, Feige J N, Canto C, et al. CREB and ChREBP oppositely regulate SIRT1expression in response to energy availability.EMBO Rep,2011,12(10):1069-76.
[46] Cheadle C, Fan J, Cho-Chung Y S, et al. Stability regulation of mRNA and the controlof gene expression. Ann N Y Acad Sci,2005,1058:196–204.
[47] Lee J, Kemper J K. Controlling SIRT1expression by microRNAs in health andmetabolic disease.Aging (Albany NY),2010,2:527–534.
[48] Yamakuchi M. MicroRNA regulation of SIRT1. Front Physiol,2012,3:68.
[49] Abdelmohsen K, Pullmann R Jr. Lal A, et al. Phosphorylation of HuR by Chk2regulates SIRT1expression. Mol Cell,2007,25:543–557.
[50] Yang Y, Fu W, Chen J, et al. SIRT1sumoylation regulates its deacetylase activity andcellular response to genotoxic stress. Nat Cell Biol2007,9:1253–62.
[51] Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W Negative regulation of thedeacetylase SIRT1by DBC1. Nature.2008,451:587–90.
[52] Kim J E, Chen J, Lou Z. DBC1is a negative regulator of SIRT1. Nature,2008,451:583–586.
[53] Yuan J, Luo K, Liu T, et al. Regulation of SIRT1activity by genotoxic stress. GENES&DEVELOPMENT,2012,26:791–796.
[54] Sasaki T, Maier B, Koclega K D, et al. Phosphorylation regulates SIRT1function.PLoS One,2008,3(12):e4020.
[55] Nasrin N, Kaushik V K, Fortier E, et al. JNK1phosphorylates SIRT1and promotes itsenzymatic activity. PLoS One,2009,4(12):e8414.
[56] Guo X, Williams J G, Schug T T, et al. DYRK1A and DYRK3promote cell survivalthrough phosphorylation and activation of SIRT1. J Biol Chem,2010,285:13223–13232.
[57] Kang H, Jung J W, Kim M K, et al. CK2is the regulator of SIRT1substrate-bindingaffinity, deacetylase activity and cellular response to DNA-damage. PLoS One,2009,4(8):e6611.
[58] Yuan F, Xie Q, Wu J, et al. MST1promotes apoptosis through regulatingSirt1-dependent p53deacetylation.J Biol Chem.2011,286(9):6940-6945.
[59] Liu X, Wang D, Zhao Y，et al.Methyltransferase Set7/9regulates p53activity byinteracting with Sirtuin1(SIRT1).Proc Natl Acad Sci U S A,2011,108(5):1925-30.
[60] Franziska Flick and Bernhard Lüscher. Regulation of Sirtuin Function byPosttranslational Modifications. Front Pharmacol,2012,3:29.
[61] Chung S, Yao H, Caito S, et al. Regulation of SIRT1in cellular functions: role ofpolyphenols. Arch Biochem Biophys,2010,501:79–90.
[62] Davis J M, Murphy E A, Carmichael M D, et al. Quercetin increases brain andmuscle mitochondrial biogenesis and exercise tolerance. Am J Physiol Regul IntegrComp Physiol,2009,296:R1071–1077.
[63] Bordet R, Ouk T, Petrault O, et al. PPAR: a new pharmacological target forneuroprotection in stroke and neurodegenerative diseases. Biochem Soc Trans,2006,34:1341–1346.
[64] Howitz K T, Bitterman K J, Cohen H Y, et al. Small molecule activators of sirtuinsextend Saccharomyces cerevisiae lifespan. Nature,2003,425:191–196.
[65] Borriello A, Cucciolla V, Ragione F D. Dietary polyphenols: Focus on resveratrol：apromising agent in the prevention of cardiovascular diseases and control of glucosehomeostasis[J]. Nutr Metab Cardiovasc Dis,2010,20(5):618.
[66] Das S, Alagappan V K, Bagchi D, et al. Coordinated induction of iNOS-VEGF-KDR-eNOS after resveratrol consumption: a potential mechanism for resveratrolpreconditioning of the heart. Vascul Pharmacol,2005,42:281–289.
[67] Frankel E N, Waterhouse A L, Kinsella J E. Inhibition of human LDL oxidation byresveratrol. Lancet,1993,341:1103–1104.
[68] Fremont L, Belguendouz L, and Delpal S. Antioxidant activity of resveratrol andalcohol-free wine polyphenols related to LDL oxidation and polyunsaturated fattyacids. Life Sci,1999,64:2511–2521.
[69] Mizutani K, Ikeda K, Kawai Y, et al. Protective effect of resveratrol on oxidativedamage in male and female stroke-prone spontaneously hypertensive rats. Clin. Exp.Pharmacol Physiol,2001,28:55–59.
[70] Jang J H, Surh Y J. Protective effect of resveratrol on beta-amyloid-induced oxidativePC12cell death. Free Radic. Biol Med,2003,34:1100–1110.
[71] Wood J G, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction anddelay ageing in metazoans. Nature,2004,430(7000):686–689.
[72] Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrialfunction and protects against metabolic disease by activating SIRT1and PGC-1alpha.Cell,2006,127(6):1109–1122.
[73] Baur J A, Pearson K J, Price N L, et al. Resveratrol improves health and survival ofmice on a high-calorie diet. Nature,2006,444(7117):337–342.
[74] Delmas D, Jannin B, Latruffe N. Resveratrol: Preventing properties against vascularalterations and ageing[J]. Mol Nutr Food Res,2005,49(1):377.
[75] Kim D, Nguyen M D, Dobbin M M, et al. SIRT1deacetylase protects againstneurodegeneration in models for Alzheimer’s disease and amyotrophic lateralsclerosis. EMBO J,2007,26:3169–3179.
[76] Sun A Y, Wang Q, Simonyi A, et al. Resveratrol as a therapeutic agent forneurodegenerative diseases. Mol Neurobiol,2010,41:375–383.
[77] Milne J C, Lambert P D, Schenk S, et al. Small molecule activators of SIRT1astherapeutics for the treatment of type2diabetes. Nature,2007,450(7170):712–716.
[78] Sauve A A, Moir R D, Schramm V L, et al. Chemical activation of Sir2-dependentsilencing by relief of nicotinamide inhibition. Mol Cell,2005,17(4):595–601.
[79] Cao C, Lu S, Kivlin R, et al. SIRT1confers protection against UVB-andH2O2-induced cell death via modulation of p53and JNK in cultured skinkeratinocytes.J Cell Mol Med,2009,13(9B):3632-43.
[80] Grozinger C M, Chao E D, Blackwell HE,et al.Identification of a class of smallmolecule inhibitors of the sirtuin family of NAD-dependent deacetylases byphenotypic screening.J Biol Chem.2001,276(42):38837-43.
[81] Heltweg B, Gatbonton T, Schuler A D, et al. Antitumor activity of a small moleculeinhibitor of human Sir2enzymes. Cancer Res,2006,66(8):4368–4377.
[82] Neugebauer R C, Uchiechowska U, Meier R, et al. Structure-activity studies onsplitomicin derivatives as sirtuin inhibitors and computational prediction of bindingmode. J Med Chem,2008,51(5):1203–1213.
[83] Napper A D, Hixon J, McDonagh T, et al. Discovery of indoles as potent and selectiveinhibitors of the deacetylase SIRT1.J Med Chem,2005,48(25):8045–8054.
[84] Peck B, Chen CY, Ho KK, et al. SIRT inhibitors induce cell death and p53acetylationthrough targeting both SIRT1and SIRT2.Mol Cancer Ther,2010,9(4):844-55.
[85] Solomon J M, Pasupuleti R, Xu L, et al. Inhibition of SIRT1catalytic activityincreases p53acetylation but does not alter cell survival following DNA damage. MolCell Biol,2006,26:28–38.
[86] Kabra N, Li Z, Chen L, et al.SirT1is an inhibitor of proliferation and tumor formationin colon cancer. J Biol Chem,2009,284(27):18210-18217.
[87] Vetterli L, Brun T, Giovannoni L, et al.Resveratrol potentiates glucose-stimulatedinsulin secretion in INS-1E beta-cells and human islets through a SIRT1-dependentmechanism.J Biol Chem,2011,286(8):6049-60.
[88] Trapp J, Meier R, Hongwiset D, et al. Structure-activity studies on suramin analoguesas inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem,2007,2(10):1419–1431.
[89] Voogd T E, Vansterkenburg E L, Wilting J, et al. Recent research on the biologicalactivity of suramin. Pharmacol Rev,1993,45(2):177–203.
[90] Schuetz A, Min J, Antoshenko T, et al. Structural basis of inhibition of the humanNAD+-dependent deacetylase SIRT5by suramin. Structure,2007,15(3):377–389.
[91] Lain S, Hollick J J, Campbell J, et al.Discovery, in vivo activity, and mechanism ofaction of a small-molecule p53activator.Cancer Cell,2008,13(5):454-63
[92] Saunders L R, Verdin E. Sirtuins: critical regulators at the crossroads between cancerand aging. Oncogene,2007,26:5489–5504.
[93] Dali-Youcef N, Lagouge M, Froelich S, et al. Sirtuins: the ‘magnificent seven’,function, metabolism and longevity. Ann Med,2007,39:335–345.
[94] Haigis M C, Guarente L P. Mammalian sirtuins–emerging roles in physiology, aging,and calorie restriction. Genes Dev,2006,20:2913–2921.
[95] Bouras T, Fu M, Sauve A A, et al. SIRT1Deacetylation and Repression of p300Involves Lysine Residues1020/1024within the Cell Cycle Regulatory Domain1.Journal of Biological Chemistry,2005,280:10264–10276.
[96] Iyer N G, Ozdag H, Caldas C. p300//CBP and cancer. Oncogene,2004,23:4225–4231.
[97] Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol improves mitochondrialfunction and protects against metabolic disease by activating SIRT1andPGC-1alpha.Cell,2006,127(6):1109-22.
[98] Ramon Amat, Anna Planavila, Shen Liang Chen, et al.SIRT1Controls theTranscription of the Peroxisome Proliferator-activated Receptor-Co-activator-1α(PGC-1α) Gene in Skeletal Muscle through the PGC-1Autoregulatory Loop andInteraction with MyoD. THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL,2009,284:21872–21880.
[99] Fernandez-Marcos P J, Auwerx J. Regulation of PGC-1a, a nodal regulator ofmitochondrial biogenesis. Am J Clin Nutr,2011,93:884S–890S.
[100]Puigserver P, Wu Z, Park C W, et al. A Cold-Inducible Coactivator of NuclearReceptors Linked to Adaptive Thermogenesis. Cell,1998,92:829–839.
[101]Lin J D. Minireview: the PGC-1coactivator networks: chromatin-remodeling andmitochondrial energy metabolism. Mol Endocrinol,2009,23:2–10.
[102]Vega R B, Huss J M, Kelly D P. The coactivator PGC-1cooperates with peroxisomeproliferator-activated receptor alpha in transcriptional control of nuclear genesencoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol,2000,20:1868–1876.
[103]Yoon J C, Puigserver P, Chen G, et al. Control of hepatic gluconeogenesis through thetranscriptional coactivator PGC-1. Nature,2001,413:131–138.
[104]Puigserver P, Rhee J, Donovan J, et al. Insulin-regulated hepatic gluconeogenesisthrough FOXO1-PGC-1alpha interaction. Nature,2003,423:550–555.
[105]Hong L Z, Zhao X Y, Zhang H L. p53-mediated neuronal cell death in ischemic braininjury. Neurosci Bull,2010,26:232–240.
[106]van Leeuwen I, Lain S. Sirtuins and p53. Adv Cancer Res,2009,102:171–195.
[107]Langley E, Pearson M, Faretta M，et a1．Human SIR2deacetylates p53andantagonizes PML/p53-induced cellular senescence[J]． EMBO J,2002,21(10):2383-2396.
[108]Yang Y, Hou H, Haller EM, Nicosia SV, Bai W. Suppression of FOXO1activity byFHL2through SIRT1-mediated deacetylation. EMBO J.2005,24:1021–1032.
[109]Motta M C, Divecha N, Lemieux M, et al. Mammalian SIRT1represses forkheadtranscription factors. Cell,2004,116:551–563.
[110]Purushotham, A. et al. Hepatocyte-specifc deletion of SIRT1alters fatty acidmetabolism and results in hepatic steatosis and infammation. Cell Metab,2009,9:327–338
[111]Hasegawa K, Wakino S, Yoshioka K, et al. Sirt1protects against oxidativestress-induced renal tubular cell apoptosis by the bidirectional regulation of catalaseexpression. Biochem Biophys Res Commun,2008,372(1):51–56.
[112]Wang F, Nguyen M, Qin FX-F, et al. SIRT2deacetylates FOXO3a in response tooxidative stress and caloric restriction. Aging Cell,2007,6:505–514.
[113]Mojsilovic-Petrovic J, Nedelsky N, Boccitto M, et al. FOXO3a is broadlyneuroprotective in vitro and in vivo against insults implicated in motor neurondiseases. J Neurosci,2009,29:8236–8247.
[114]Gilley J, Coffer P J, Ham J. FOXO transcription factors directly activate bim geneexpression and promote apoptosis in sympathetic neurons. J Cell Biol,2003,162:613–622.
[115]Kobayashi Y, Furukawa-Hibi Y, Chen C, et al. SIRT1is critical regulator ofFOXO-mediated transcription in response to oxidative stress. Int J Mol Med,2005,16:237–243.
[116]Kwon H S, Ott M. The ups and downs of SIRT1.Trends Biochem Sci,2008,33(11):517–525.
[117]Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF-kappaB-dependenttranscription and cell survival by the SIRT1deacetylase. EMBO J,2004,23:2369–2380.
[118]Chen J, Zhou Y, Mueller-Steiner S, et al. SIRT1protects against microglia-dependentamyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem,2005,280:40364–40374.
[119]Teng F Y, Tang B L. NF-kappaB signaling in neurite growth and neuronal survival.Rev Neurosci,2010,21:299–313.
[120]Gao J, Wang WY, Mao YW, Graff J, Guan JS, Pan L, Mak G, Kim D, Su SC, Tsai LH.A novel pathway regulates memory and plasticity via SIRT1and miR-134. Nature,2010,466:1105–1109.
[121]Li J, Calkins MJ, Johnson DA, et al. Role of Nrf2-dependent ARE-driven antioxidantpathway in neuroprotection. Methods Mol Biol,2007,399:67–78.
[122]Kensler TW, Wakabayashi N. Nrf2: friend or foe for chemoprevention?Carcinogenesis,2010,31:90–99.
[123]Kawai Y, Garduno L, Theodore M, et al. Acetylation-Deacetylation of theTranscription Factor Nrf2(nuclear factor erythroid2-related factor2) Regulates itsTranscriptional Activity and Nucleo-cytoplasmic Localization. Journal of BiologicalChemistry,2011,286:7629–7640.
[124]Zhang F, Xing J, Liou AK, et al. Enhanced Delivery of Erythropoietin Across theBlood-Brain Barrier for Neuroprotection against Ischemic Neuronal Injury. TranslStroke Res,2010,1:113–121.
[125]Wang YQ, Guo X, Qiu MH, et al. VEGF overexpression enhances striatalneurogenesis in brain of adult rat after a transient middle cerebral artery occlusion.Journal of Neuroscience Research,2007,85:73–82.
[126]Correia SC, Moreira PI. Hypoxia-inducible factor1: a new hope to counteractneurodegeneration?. J Neurochem,2010,112:1–12.
[127]Balaiya S, Khetpal V, Chalam KV. Hypoxia initiates sirtuin1-mediated vascularendothelial growth factor activation in choroidal endothelial cells through hypoxiainducible factor–2α. Molecular Vision,2012,18:114-120.
[128]Dioum EM, Chen R, Alexander MS, et al. Regulation of hypoxia-inducible factor2alpha signaling by the stress-responsive deacetylase sirtuin1. Science,2009,324:1289–1293.
[129]Lim JH, Lee YM, Chun YS, et al. Sirtuin1Modulates Cellular Responses toHypoxia by Deacetylating Hypoxia-Inducible Factor1[alpha]. Molecular Cell,2010,38:864–878.
[130]Zocchi L, Sassone-Corsi P.SIRT1-mediated deacetylation of MeCP2contributes toBDNF expression. Epigenetics,2012,7:695-700.
[131]Donmez G, Wang D, Cohen D E, et al. SIRT1suppresses beta-amyloid production byactivating the alpha-secretase gene ADAM10. Cell,2010,142:320–332.
[132]Cheng O, Ostrowski RP, Liu W, et al. Activation of liver X receptor reduces globalischemic brain injury by reduction of nuclear factor-[kappa]B. Neuroscience,2010,166:1101–1109.
[133]Fitz NF, Cronican A, Pham T, et al. Liver X Receptor Agonist Treatment AmelioratesAmyloid Pathology and Memory Deficits Caused by High-Fat Diet in APP23Mice. J.Neurosci,2010,30:6862–6872.
[134]Li J, Zeng Z, Viollet B, et al. Neuroprotective effects of adenosinemonophosphate-activated protein kinase inhibition and gene deletion in stroke. Stroke,2007,38:2992–2999.
[135]Purushotham A, Schug TT, Xu Q, et al. Hepatocyte-Specific Deletion of SIRT1AltersFatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation. CellMetabolism,2009,9:327–338.
[136]Deplanque D, Gele P, Petrault O, et al. Peroxisome proliferator-activatedreceptor-alpha activation as a mechanism of preventive neuroprotection induced bychronic fenofibrate treatment.J Neurosci,2003,23:6264–6271.
[137]Kapadia R, Yi JH, Vemuganti R. Mechanisms of anti-inflammatory andneuroprotective actions of PPAR-gamma agonists. Front Biosci,2008,13:1813–1826.
[138]Luo Y, Yin W, Signore AP, et al. Neuroprotection against focal ischemic brain injuryby the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. JNeurochem,2006,97:435–448.
[139]Shie FS, Nivison M, Hsu PC, et al. Modulation of microglial innate immunity inAlzheimer’s disease by activation of peroxisome proliferator-activated receptorgamma. Curr Med Chem,2009,16:643–651.
[140]Yamamori T, DeRicco J, Naqvi A, et al. SIRT1deacetylates APE1and regulatescellular base excision repair. Nucleic Acids Research,2010,38:832–845.
[141]Woodhouse BC, Dianova II, Parsons JL, et al. Poly(ADP-ribose) polymerase-1modulates DNA repair capacity and prevents formation of DNA double strand breaks.DNA Repair (Amst),2008,7:932–940.
[142]Moroni F. Poly(ADP-ribose)polymerase1(PARP-1) and postischemic brain damage.Current Opinion in Pharmacology,2008,8:96–103.
[143]Rajamohan SB, Pillai VB, Gupta M, et al. SIRT1Promotes Cell Survival under Stressby Deacetylation-Dependent Deactivation of Poly(ADP-Ribose) Polymerase1. MolCell Biol,2009,29:4116–4129.
[144]Eliasson MJ, Sampei K, Mandir AS, et al. Poly(ADP-ribose) polymerase genedisruption renders mice resistant to cerebral ischemia. Nat Med,1997,3:1089–1095.
[145]Endres M, Wang ZQ, Namura S, et al. Ischemic brain injury is mediated by theactivation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab,1997,17:1143–1151.
[146]Sawada M, Hayes P, Matsuyama S. Cytoprotective membrane-permeable peptidesdesigned from the Bax-binding domain of Ku70. Nat Cell Biol,2003,5:352–357.
[147]Kim GW, Noshita N, Sugawara T, et al. Early Decrease in DNA Repair Proteins,Ku70and Ku86, and Subsequent DNA Fragmentation After Transient Focal CerebralIschemia in Mice. Stroke,2001,32:1401–1407.
[148]Sugawara T, Noshita N, Lewen A, et al. Neuronal Expression of the DNA RepairProtein Ku70After Ischemic Preconditioning Corresponds to Tolerance to GlobalCerebral Ischemia. Stroke,2001,32:2388–2393.
[149]Cohen HY, Lavu S, Bitterman KJ, et al. Acetylation of the C terminus of Ku70byCBP and PCAF controls Bax-mediated apoptosis. Mol Cell,2004,13:627–638.
[150]Jeong J, Juhn K, Lee H, et al. SIRT1promotes DNA repair activity and deacetylationof Ku70. Exp Mol Med,2007,39:8–13.
[151]Yuan Z, Zhang X, Sengupta N, et al. SIRT1Regulates the Function of the NijmegenBreakage Syndrome Protein. Molecular Cell,2007,27:149–162.
[152]Zu Y, Liu L, Lee MYK, et al. SIRT1Promotes Proliferation and Prevents SenescenceThrough Targeting LKB1in Primary Porcine Aortic Endothelial Cells. CirculationResearch,2010,106:1384–1393.
[153]Wang P, Xu TY, Guan YF, et al. Nicotinamide phosphoribosyltransferase protectsagainst ischemic stroke through SIRT1-dependent adenosine monophosphate–activated kinase pathway. Annals of Neurology,2011,69:360–374.
[154]Ikenoue T, Inoki K, Zhao B, et al. PTEN acetylation modulates its interaction withPDZ domain.Cancer Res,2008,68:6908–6912.
[155]Mattagajasingh I, Kim CS, Naqvi A, et al. SIRT1promotes endothelium-dependentvascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad SciU S A,2007,104:14855–14860.
[156]Ittner LM, G tz J. Amyloid-β and tau--a toxic pas de deux in Alzheimer’s disease.Nat Rev Neurosci,2011,12:67–72.
[157]Min SW, Cho SH, Zhou Y, et al. Acetylation of tau inhibits its degradation andcontributes to tauopathy. Neuron,2010,67:953–966.
[158]Hollander P. Anti-Diabetes and Anti-Obesity Medications: Effects on Weight inPeople With Diabetes. Diabetes Spectrum,2007,20(3):159-165.
[159]Bernier M, Paul RK, Martin-Montalvo A, et al. Negative Regulation of STAT3Protein-mediated Cellular Respiration by SIRT1. J Biol Chem,2011,286(22):19270–19279.
[160]Esteves TC, Brand MD. The reactions catalysed by the mitochondrial uncouplingproteins UCP2and UCP3. Biochim Biophys Acta,2005,1709:35–44.
[161]Lee FY, Li Y, Zhu H, et al. Tumor necrosis factor increases mitochondrial oxidantproduction and induces expression of uncoupling protein-2in the regenerating mice
[correction of rat] liver. Hepatology,1999,29:677–687.
[162]Arsenijevic D, Onuma H, Pecqueur C, et al. Disruption of the uncoupling protein-2gene in mice reveals a role in immunity and reactive oxygen species production. NatGenet,2000,26:435–439.
[163]Trenker M, Malli R, Fertschai I, et al. Uncoupling proteins2and3are fundamentalfor mitochondrial Ca2+uniport. Nat Cell Biol,2007,9:445–452.
[164]Brand MD, Esteves TC. Physiological functions of the mitochondrial uncouplingproteins UCP2and UCP3. Cell Metab,2005,2:85–93.
[165]Bordone L, Motta M C, Picard F, et al. Sirt1regulates insulin secretion by repressingUCP2in pancreatic beta cells. PLoS Biol,2006,4(2):e31.
[166]Moynihan KA, Grimm AA, Plueger MM, et al. Increased dosage of mammalian Sir2in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. CellMetab,2005,2:105–117.
[167]Della-Morte D, Dave KR, DeFazio RA, et al. Resveratrol pretreatment protects ratbrain from cerebral ischemic damage via a sirtuin1-uncoupling protein2pathway.Neuroscience,2009,159(3):993–1002.
[168]Aquilano K, Vigilanza P, Baldelli S, et al. Peroxisome Proliferator-activated Receptorγ Co-activator1α (PGC-1α) and Sirtuin1(SIRT1) Reside in Mitochondria. J BiolChem,2010,285(28):21590–21599.
[169]Lagouge M, Argmann C, Gerhart-Hines Z, et al. Resveratrol Improves MitochondrialFunction and Protects against Metabolic Disease by Activating SIRT1and PGC-1a.Cell.2006,127(6):1109-1122.
[170]Erion DM, Yonemitsu S, Nie Y, et al. SirT1knockdown in liver decreases basalhepatic glucose production and increases hepatic insulin responsiveness in diabeticrats. Proc Natl Acad Sci,2009,106:11288–11293.
[171]Gerhart-Hines Z, Rodgers JT, Bare O, et al. Metabolic control of musclemitochondrial function and fatty acid oxidation through SIRT1/PGC-1a. EMBO J,2007,26:1913–1923.
[172]St-Pierre J, Drori S, Uldry M, et al. Suppression of reactive oxygen species andneurodegeneration by the PGC-1transcriptional coactivators. Cell,2006,127,397–408.
[173]Hisahara S, Chiba S, Matsumoto H, et al. Histone deacetylase SIRT1modulatesneuronal differentiation by its nuclear translocation. P Natl Acad Sci USA,2008,105(40):15599–15604.
[174]Codocedo J F, Allard C, Godoy J A, et al. SIRT1Regulates Dendritic Development inHippocampal Neurons. PLoS One,2012,7(10): e47073.
[175]Fischer A, Sananbenesi F, Wang X, et al. Recovery of learning and memory isassociated with chromatin remodelling. Nature,2007,447:178–182.
[176] Levenson JM, O'Riordan KJ, Brown KD, et al. Regulation of histone acetylation duringmemory formation in the hippocampus. J Biol Chem,2004,279(39):40545-40559.
[177]Weiss EP, Fontana L. Caloric restriction: powerful protection for the aging heart andvasculature. AmJPhysiol. Heart Circ. Physiol,2011,301:H1205–H1219.
[178]Wu P, Shen Q, Dong S, et al. Calorie restriction ameliorates neurodegenerativephenotypes in forebrain-specific presenilin-1and presenilin-2double knockout mice.Neurobiol.Aging,2008,29:1502–1511.
[179]Jiang JC, Jaruga E, Repnevskaya MV, et al. An intervention resembling caloricrestriction prolongs life span and retards aging in yeast. FASEB J,2000,14(14):2135–2137.
[180]Masoro EJ. Caloric restriction and aging: an update. Exp Gerontol,2000,35(3):299–305.
[181]Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cellsurvival by inducing the SIRT1deacetylase. Science,2004,305:390–392.
[182]Guarente L. Sirtuins, aging, and metabolism. Cold Spring Harb. Symp. Quant. Biol,2011,76:81–90.
[183]Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, et al. Sirt1promotes fatmobilization in white adipocytes by repressing PPAR-γ. Nature,2004,429:771–776.
[184]Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, et al. Calorie restriction promotesmitochondrial biogenesis by inducing the expression of eNOS. Science,2005,310:314–317.
[185]Roth GS, Ingram DK, Lane MA. Slowing aging by calorie restriction. Nature Med,1995,1:414–415.
[186]Fontan-Lozano A, Saez-Cassanelli JL, Inda MC, et al. Caloric restriction increaseslearning consolidation and facilitates synaptic plasticity through mechanismsdependent on NR2B Subunits of the NMDA receptor. J Neurosci,2007,27:10185–10195.
[187]Pearson KJ, Lewis KN, Price NL, et al. Nrf2mediates cancer protection but notprolongevity induced by caloric restriction. P Natl Acad Sci USA,2008,105:2325–2330.
[188]Guarente L. Calorie restriction and SIR2genes-Towards a mechanism. Mech AgeingDev,2005,126:923–928.
[189]Guan, J, Skinner, SJ, Beilharz EJ, et al. The movement of IGF-I into the brainparenchyma after hypoxic–ischaemic injury. Neuroreport,1996,7:632–636.
[190]Liu XF, Fawcett JR, Thorne RG, et al. Non-invasive intranasal insulin-like growthfactor-I reduces infarct volume and improves neurologic function in rats followingmiddle cerebral artery occlusion. Neurosci Lett,2001,308:91–94.
[191]Scheepens A, Sirimanne ES, Breier BH, et al. Growth hormone as a neuronal rescuefactor during recovery from CNS injury. Neuroscience,2001,104:677–687.
[192]Nyberg F. Aging effects on growth hormone receptor binding in the brain. ExpGerontol,1997,32:521–528.
[193]O’Donnell SL, Frederick TJ, Krady JK, et al. IGF-I and microglia/macrophageproliferation in the ischemic mouse brain. Glia,2002,39:85–97.
[194]Sonntag WE, Lynch CD, Bennett SA, et al. Alterations in insulin-like growth factor-1gene and protein expression and type1insulin-like growth factor receptors in thebrains of ageing rats. Neuroscience,1999,88:269–279.
[195]Rollero A, Murialdo G, Fonzi S, et al. Relationship between cognitive function,growth hormone and insulin-like growth factor I plasma levels in aged subjects.Neuropsychobiology,1998,38:73–79.
[196]Dik MG, Pluijm SM, Jonker C, et al. Insulin-like growth factor I (IGF-I)and cognitivedecline in older persons. Neurobiol Aging,2003,24(4):573–581.
[197]Lemieux ME, Yang X, Jardine K, et al. The Sirt1deacetylase modulates theinsulin-like growth factor signaling pathway in mammals., Mech Ageing Dev,2005,126(10):1097-1105.
[198]Li Y, Xu W, McBurney MW, et al. SirT1inhibition reduces IGF-I/IRS-2/Ras/ERK1/2signaling and protects neurons. Cell Metab,2008,8(1):38-48.
[199]Cohen DE, Supinski AM, Bonkowski MS, et al. Neuronal SIRT1regulates endocrineand behavioral responses to calorie restriction Gene Dev,2009,23:2812–2817.
[200]Chong ZZ, Lin SH, Kang JQ, et al. Erythropoietin prevents early and late neuronaldemise through modulation of Akt1and induction of caspase1,3, and8. J NeurosciRes,2003,71(5):659–669.
[201]Hou J, Wang S, Shang YC, et al. Erythropoietin employs cell longevity pathways ofSIRT1to foster endothelial vascular integrity during oxidant stress. Curr NeurovascRes,2011,8(3):220–235.
[202]Donmez G, Wang D, Cohen DE, et al. SIRT1suppresses beta-amyloid production byactivating the alpha-secretase gene ADAM10. Cell,2010,142(2):320–332.
[203]Guarente L. Mitochondria--a nexus for aging, calorie restriction, and sirtuins?. Cell,2008,132(2):171–176.
[204]Tupe RS, Tupe SG, Agte VV. Dietary nicotinic acid supplementation improves hepaticzinc uptake and offers hepatoprotection against oxidative damage. Br J Nutr,2011,25:1–9.
[205]Bonda DJ, Wang X, Perry G, et al. Oxidative stress in Alzheimer disease: a possibilityfor prevention. Neuropharmacology,2010,59(4–5):290–294.
[206]Hüttemann M, Pecina P, Rainbolt M, et al. The multiple functions of cytochrome cand their regulation in life and death decisions of the mammalian cell: fromrespiration to apoptosis. Mitochondrion,2011,11(3):369–381.
[207]Wang X. The expanding role of mitochondria in apoptosis. Genes Dev,2001,15(22):2922-2933.
[208]Caito S, Rajendrasozhan S, Cook S, et al. SIRT1is a redox-sensitive deacetylase thatis post-translationally modified by oxidants and carbonyl stress. FASEB J,2010,24:3145–3159.
[209]Maiese K, Chong ZZ, Hou J, et al. New strategies for Alzheimer’s disease andcognitive impairment. Oxid Med Cell Longev,2009,2(5):279–289.
[210]Zhang G, Zhao Z, Gao L, et al. Gypenoside attenuates white matter lesions induced bychronic cerebral hypoperfusion in rats. Pharmacol Biochem Behav,2011,99(1):42–51.
[211]Chong ZZ, Shang YC, Hou J, et al. Wnt1neuroprotection translates into improvedneurological function during oxidant stress and cerebral ischemia through AKT1andmitochondrial apoptotic pathways. Oxid Med Cell Longev,2010,3(2):153–165.
[212]Khan MM, Ahmad A, Ishrat T, et al. Resveratrol attenuates6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson’sdisease. Brain Res,2010,1328:139–151.
[213]Cardaci S, Filomeni G, Ciriolo, MR. Redox implications of AMPK-mediated signaltransduction beyond energetic clues. J. Cell Sci,2012,125:2115–2125.
[214]Canto C, Gerhart-Hines Z, Feige JN, et al. AMPK regulates energy expenditure bymodulating NAD+metabolism and SIRT1activity. Nature,2009,458:1056–1060.
[215]Furukawa A, Tada-Oikawa S, Kawanishi S, et al. H2O2accelerates cellular senescenceby accumulation of acetylated p53via decrease in the function of SIRT1by NAD+depletion. Cell. Physiol. Biochem,2007,20:45–54.
[216]Rajendrasozhan S, Yang SR, Kinnula, et al. SIRT1, an antiinflammatory and antiagingprotein, is decreased in lungs of patients with chronic obstructive pulmonary disease.Am. J. Respir. Crit. Care Med.2008,177:861–870.
[217]Hou J, Chong ZZ, Shang YC, et al. Early apoptotic vascular signaling is determinedby Sirt1through nuclear shuttling, forkhead trafficking, bad, and mitochondrialcaspase activation. Curr Neurovasc Res,2010;7(2):95–112.
[218]Ota H, Akishita M, Akiyoshi T, et al. Testosterone Deficiency Accelerates Neuronaland Vascular Aging of SAMP8Mice: Protective Role of eNOS and SIRT1. PLoS One,2012,7(1): e29598.
[219]Chen SD, Wu HY, Yang DI, et al. Effects of rosiglitazone on global ischemia-inducedhippocampal injury and expression of mitochondrial uncoupling protein2. Biochem.Biophys. Res. Commun,2006,351,198–203.
[220]Chan PH. Mitochondria and neuronal death/survival signaling pathways in cerebralischemia. Neurochem. Res,2004,29,1943–1949.
[221]Castellani RJ, Rolston RK, Smith MA. Alzheimer disease. Dis Mon,2010,56(9):484–546.
[222]Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science,1992,256(5054):184–185.
[223]Kehoe P, Wavrant-De Vrieze F, Crook R, et al. A full genome scan for late onsetAlzheimer's disease. Hum Mol Genet,1999,8:237-245.
[224]Bertram L, Blacker D, Mullin K, et al. Evidence for genetic linkage of Alzheimer'sdisease to chromosome10q. Science,2000,290:2302-2303.
[225]Kojro E, Fahrenholz F. The non-amyloidogenic pathway: structure and function ofalpha-secretases. Subcell Biochem,2005,38:105–127.
[226]Qin W, Yang T, Ho L, et al. Neuronal SIRT1activation as a novel mechanismunderlying the prevention of Alzheimer disease amyloid neuropathology by calorierestriction. J Biol Chem,2006,281:21745–21754.
[227]Kim D, Nguyen MD, Dobbin MM, Fischer A, et al. SIRT1deacetylase protectsagainstneurodegeneration in models for Alzheimer’s disease and amyotrophic lateralsclerosis. Embo J,2007,26:3169–3179.
[228]Helisalmi S, Vepsalainen S, Hiltunen M, et al. Genetic study between SIRT1, PPARD,PGC-1alpha genes and Alzheimer's disease. J Neurol,2008,255:668-673.
[229]Julien C, Tremblay C, Emond V, et al. SIRT1Decrease Parallels the Accumulation oftau in Alzheimer Disease. J Neuropathol Exp Neurol,2009,68(1):48-58.
[230]Spilman P, Podlutskaya N, Hart M J, et al. Inhibition of mTOR by rapamycinabolishes cognitive deficits and reduces amyloid beta levels in a mouse model ofAlzheimer’s disease. Plos ONE,2010,5(4):e9979.
[231]Potente M, Ghaeni L, Baldessari D, et al. SIRT1controls endothelial angiogenicfunctions during vascular growth. GENES&DEVELOPMENT,2007,21:2644–2658.
[232]Csiszar A, Labinskyy N, Podlutsky A, et al. Vasoprotective effects of resveratrol andSIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatoryphenotypic alterations. Am J Physiol Heart Circ Physiol,2008,294(6):H2721–H2735.
[233]Oomen CA, Farkas E, Roman V, et al. Resveratrol preserves cerebrovascular densityand cognitive function in aging mice. Front Aging Neurosci,2009,1:1-8.
[234]Raval AP, Dave KR, Perez-Pinzon MA. Resveratrol mimics ischemic preconditioningin the brain. J Cereb Blood Flow Metab,2006,26:1141–1147.
[235]Raval AP, Lin HW, Dave KR, et al. Resveratrol and ischemic preconditioning in thebrain. Curr Med Chem,2008;15:1545–1551.
[236]Chong ZZ, Maiese K. Enhanced tolerance against early and late apoptotic oxidativestress in mammalian neurons through nicotinamidase and sirtuin mediated pathways.Curr Neurovasc Res,2008,5:159–170.
[237]Wang S, Xing Z, Vosler PS, et al. Cellular NAD replenishment confers markedneuroprotection against ischemic cell death: role of enhanced DNA repair. Stroke,2008,39:2587–2595.
[238]Wang S, Vosler PS, Gan Y, et al. NAD protects neurons from NMDA-induced toxicityin vitro by a SIRT1-dependent mechanism.39th annual meeting of SFN; Chicago, IL.2009. p. Online.2009, Neuroscience Meeting.
[239]Ying W, Wei G, Wang D, et al. Intranasal administration with NAD+profoundlydecreases brain injury in a rat model of transient focal ischemia. Front Biosci,2007,12:2728–2734.
[240]Tsai SK, Hung LM, Fu YT, et al. Resveratrol neuroprotective effects during focalcerebral ischemia injury via nitric oxide mechanism in rats. Journal of VascularSurgery,2007,46:346–353.
[241]Alano CC, Ying W, Swanson RA. Poly(ADP-ribose) polymerase-1-mediated celldeath in astrocytes requires NAD+depletion and mitochondrial permeabilitytransition. J Biol Chem,2004,279:18895–18902.
[242]Liu D, Gharavi R, Pitta M, et al. Nicotinamide Prevents NAD+Depletion andProtects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+Consumptionby SIRT1may Endanger Energetically Compromised Neurons. Neuromolecular Med.2009,11(1):28–42.
[243]Liu D, Smith CL, Barone FC, et al. Astrocytic demise precedes delayed neuronaldeath in focal ischemic rat brain. Molecular Brain Research,1999,68:29–41.
[244] Sim o F, Matté A, Matté C, et al. Resveratrol prevents oxidative stress and inhibitionof Na(+)K(+)-ATPase activity induced by transient global cerebral ischemia in rats. JNutr Biochem,2011,22(10):921–928.
[245]Wang T, Gu J, Wu PF, et al. Protection by tetrahydroxystilbene glucoside againstcerebral ischemia: involvement of JNK, SIRT1, and NF-[kappa]B pathways andinhibition of intracellular ROS/RNS generation. Free Radical Biology and Medicine,2009,47:229–240.
[246]Avraham Y, Davidi N, Porat M, et al. Leptin reduces infarct size in association withenhanced expression of CB2, TRPV1, SIRT-1and leptin receptor. Curr NeurovascRes,2010,7:136–143.
[247]Zhu HR, Wang ZY, Zhu XL, et al. Icariin protects against brain injury by enhancingSIRT1-dependent PGC-1alpha expression in experimental stroke. Neuropharmacology,2010,59:70–76.
[248]Valerio A, Dossena M, Bertolotti P, et al. Leptin is induced in the ischemic cerebralcortex and exerts neuroprotection through NF-kappaB/c-Rel-dependent transcription.Stroke,2009,40:610–617.
[249]Zhang F, Chen J. Leptin protects hippocampal CA1neurons against ischemic injury. JNeurochem,2008,107:578–587.
[250]Zhang F, Wang S, Signore AP, et al. Neuroprotective effects of leptin against ischemicinjury induced by oxygen-glucose deprivation and transient cerebral ischemia. Stroke,2007,38:2329–2336.
[251]Kakefuda K, Fujita Y, Oyagi A, et al. Sirtuin1overexpression mice show a referencememory deficit, but not neuroprotection. Biochemical and Biophysical ResearchCommunications,2009,387:784–788.
[252]Chong ZZ, Lin SH, Li F, et al. The sirtuin inhibitor nicotinamide enhances neuronalcell survival during acute anoxic injury through AKT, BAD, PARP, and mitochondrialassociated “anti-apoptotic” pathways. Curr Neurovasc Res,2005,2:271–285.
[253]Dubois MF, Hebert R. The incidence of vascular dementia in Canada: a comparisonwith Europe and East Asia. Neuroepidemiology,2001,20:179-187.
[254]De Deyn PP, D’Hooge R, van Zutphen LFM. Animal models of human disorders—General aspects, Neurosci. Res. Commun.2000,26:141–148.
[255]Tsuchiya M, Sako K, Yura S, et al. Local cerebral glucose utilization following acuteand chronic bilateral carotid artery ligation in Wistar rat: relation to change in localcerebral blood flow. Exp Brain Res,1993,95:17.
[256]Sarti C, Pantoni L, Bartolini L, et al. Cognitive impairment and chronic cerebralhypoperfusion: what can be learned from experimental models. J Neurol Sci,2002,203204:263266.
[257]Wakita H, Tomimoto H, Akiguchi I, et al. Glial activation and white matter changes inthe rat brain induced by chronic cerebral hypoperfusion: an immunohistochemicalstudy. Acta Neuropathol,1994,87:484492,
[258]Tomimoto H, Akiguchi I, Suenaga T, et al.Alterations of the blood brain barrier andglial cells in white-matter lesions in cerebro-vascular and Alzheimer’s disease patients.Stroke,1996,27:2069-2074.
[259]Otori T, Katsumata T, Muramatsu H, et al. Long-term measurement of cerebral bloodflow and metabolism in a rat chronic hypoperfusion model. Clin Exp PharmacolPhysiol,2003,30:266-272.
[260]Farkas E, Luiten PG and Bari F. Permanent, bilateral common carotid artery occlusionin the rat: a model for chronic cerebral hypoperfusion-related neurodegenerativediseases. Brain Res Rev,2007,54:162-180.
[261]De la Torre JC, Fortin T, Park GA, et al.Chronic cerebrovascular insuffciency inducesdementia-like defcits in aged rats, Brain Res,1992,582:186–195.
[262]Block F. Global ischemia and behavioural defcits, Prog. Neurobiol,1999,58:279–295.
[263]Pappas BA, de la Torre JC, Davidson CM, et al. Chronic reduction of cerebral bloodfow in the adult rat: late emerging CA1cell loss and memory dysfunction. Brain Res,1996,708:50–58.
[264]Silva AJ, Giese KP, Fedorov NB, et al. Molecular, cellular, and neuroanatomicalsubstrates of place learning, Neurobiol. Learn. Mem,1998,70:44–61.
[265]Brandeis R, Brandys Y, Yehuda S. The use of the Morris water maze in the study ofmemory and learning, Int. J. Neurosci,1989,48:29–69.
[266]Poucet b, Save e, Lenck-Santini P.-P. Sensory and memory properties of hippocampalplace cells, Rev. Neurosci,2000,11:95–111.
[267]Schmidt-Kastner R. and Freund T. Selective vulnerability of the hippocampus in brainischemia. Neuroscience,1991,40599–636.
[268]Olsen G.M, Scheel-Kruger J, Moller A, et al. Relation of spatial learning of rats in theMorris water maze task to the number of viable CA1neurons following four-vesselocclusion, Behav. Neurosci,1994,108:681–690.
[269]Nunn J A, LePeillet E, Netto C A, et al. Global ischaemia: hippocampal pathology andspatial defcits in the water maze, Behav. Brain Res,1994,62:41–54.
[270]Mogensen J, Pedersen TK, Holm S, et al. Prefrontal cortical mediation of rats’ placelearning in a modifed water maze, Brain Res. Bull,1995,38:425–434.
[271]Ohtaki H, Fujimoto T, Sato T, et al. Progressive expression of vascular endothelialgrowth factor (VEGF) and angiogenesis after chronic ischemic hypoperfusion in rat.Acta Neurochir,2006, Suppl.96:283–287.
[272]De Jong G, Farkas E, Stienstra CM, et al. Cerebral hypoperfusion yields capillarydamage in the hippocampal CA1area that correlates with spatial memory impairment[J].Neuroscience,1999,91(1):203-210.
[273]Liu HX, Zhang JJ, Zheng P, et al. Altered expression of MAP-2, GAP-43, andsynaptophysin in the hippocampus of rats with chronic cerebral hypoperfusioncorrelates with cognitive impairment. Brain Res. Mol. Brain Res,2005,139:169–177.
[274]Wahlund LET, Gauthier S. Vascular Cognitive Impairment in Clinical Practice.Cambridge, UK: Cambridge University Press,2009.
[275]Farkasa E, Luiten PG, Bari F.Permanent, bilateral common carotid artery occlusion inthe rat: A model for chronic cerebral hypoperfusion-related neurodegenerative diseases.BRAIN RESEARCH REVIEWS,2007,54:162–180
[276]Ni J, Ohm H,‘Matsumoto K, et al. Progressive cognitive impairment followingchronic cerebral hypoperfusion induced by permament occlusion of bilateral carotidarteries in rats. Brain Res,1994,653:231-236.
[277]Driscoll I, Hamilton D A, Petropoulos H, et al. The aging hippocampus: cognitive,biochemical and structural findings. Cerebral cortex,2003,13:1344-351.
[278]Burke SN, Barnes CA. Neural plasticity in the aging brain. Nature Rev Neurosci,2006,7:30-40.
[279]Sarangi S, San Pedro EC, Mountz J M. Antrior choroidal artery infarction presentingas Proressive cognitive deficit. Clin Nucl Med,2000,25（3）：187-190.
[280]Lojkowska W, Ryglewicz D, Jedrzejczak T, et a. SPECT as a diagnosticestint in theinvestigation of dementia. Neurol Sci,2002,15:215-219.
[281]Yang DW, Kim BS, Park JK, et al.Analysis of cerebral blood flow of subcorticalvascular dementia with single photon emission computered tomography: adaptationof statistical parametric mapping.Neurol Sci,2002,15:199-205.
[282]Bennett SA, Tenniswood M, Chen JH, et al. Chronic cerebral hypoperfusion elicitsneuronal apoptosis and behavioral impairment. Neuroreport,1998,9:161-166.
[283]Bennett SA, Tenniswood M, Chen JH, et al. Chronic cerebral hypoperfusion elicitsneuronal apoptosis and behavioral impairment. NeuroReport,1998,9:161–166.
[284]Ni JW, MatsumotoK, Li HB, et al.Neuronal damage and decrease of centralAcetylcholine level following permanent occlusion of bilateral common carotidarteries in rat.Brain Res,1995,673(2):290-296.
[285]Nanti M, Watanabe H. Availability of2VO rats as a model for chroniccerebrovascular disease [J].Nippon Yakurigaku Zasshi,1999,113(2):85-95.
[286]Ramadori G, Lee CE, Bookout AL, et al. Brain SIRT1: Anatomical distribution andregulation by energy availability. J Neurosci,2008,28(40):9989–9996.
[287]Samuel SM, Thirunavukkarasu M, Penumathsa SV, et al. Akt/FOXO3a/SIRT1Mediated Cardioprotection by n-Tyrosol against Ischemic Stress in Rat In vivo modelof Myocardial Infarction: Switching Gears towards Survival and Longevity. J AgricFood Chem,2008,56(20):9692–9698.
[288]Yan W, Fang ZP, Yang QZ, et al. SirT1mediates hyperbaric oxygen preconditioning-induced ischemic tolerance in rat brain. J Cereb Blood Flow Metab,2013,33(3):396–406.
[289]Harman D.Aging: A theory based on free radical and radiation chemistry. J Gerontol,1956,11:298–300.
[290]Barbara Shukitt-Hale.The effects of aging and oxidative stress on psychomotor andbehavior. Age,1999,22:9-17.
[291]Kim JS, Yun I, Choi YB, et a1．Ramipril protects from free radical induced whitematter damage in chronic hypoporfusion in the rat[J]．J Clin Neurosci,2008,15(2):174-178.
[292]Smith MA, Nunomura A, Lee HG, et al. Chronological primacy of oxidative stress inAlzheimer disease. Neurobiology of aging,2005,26:579–580.
[293]W rtwein G, Stackman RW, Walsh TJ. Vitamin E prevents the place learning defcitand the cholinergic hypofunction induced by AF64A. Exp. Neurol,125(1994)15–21.
[294]Chan PH. Role of oxidants in ischemic brain damage. Stroke,1996,27:1124–1129.
[295]Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. JCereb Blood Flow Metab,2001,21:2–14.
[296]Tanaka K, Wada-Tanaka N, Miyazaki I, Nomura M, Ogawa N.Chronic cerebralhypoperfusion induces striatal alterations due to the transient increase of NOproduction and the depression of glutathione content.Neurochem Res,2002,27(4):331-336.
[297]Aytac E, Seymen HO, Uzun H, et al. Effects of iloprost on visual evoked potentialsand brain tissue oxidative stress after bilateral common carotid artery occlusion.Prostaglandins, Leukotrienes and Essential Fatty Acids.2006,74:373–378.
[298]Farkas E, Luiten PG, Bari F.Permanent, bilateral common carotid artery occlusion inthe rat: A model for chronic cerebral hypoperfusion-related neurodegenerativediseases. BRAIN RESEARCH REVIEWS,2007,54:162–180.
[299]Liu C, Wu J, Gu J, et a1．Baicalein improves cognitive deficits induced by chroniccerebral hypoperfusion in rats[J]. Pharmacol Biochem Behav,2007,86(3);423-430．
[300]Ozacmak VH, Sayan H, Cetin A, et al．ATl receptor blocker eandesartan-inducedaRenuation of brain injury of rats subjected to chronic cerebral hypoperfusion[J].Neurochem Res,2007,32(8);1314-1321．
[301]Chong ZZ, Shang YC, Wang S, et al. SIRT1: new avenues of discovery for disordersof oxidative stress. Expert Opin Ther Targets,2012,16(2):167–178.
[302] Wilcock G, M bius HJ, St ffler A, et al.A double-blind，placebo-controlled multicenterstudy of memantine in mild to moderate vascular dementia（MMM500）Int ClinPsychophamnacol,2002,17:297-305.
[303]Blander G, Guarente L. The Sir2family of protein deacetylases. Annual Review ofBiochemistry,2004,73:417-435.
[304]Hsu CP, Zhai P, Yamamoto T, et al. Sirt1Protects the Heart from Ischemia/Reperfusion. Circulation,2010,122(21):2170–2182.
[305]de Kreutzenberg SV, Ceolotto G, Papparella I, et al.Downregulation of theLongevity-Associated Protein Sirtuin1in Insulin Resistance and MetabolicSyndrome:Potential Biochemical Mechanisms. Diabetes,2010,59:1006–1015.
[306]Rajendrasozhan S, Yang SR, Kinnula VL, Rahman I.SIRT1, an antiinflammatory andantiaging protein, is decreased in lungs of patients with chronic obstructivepulmonary disease. Am J Respir Crit Care Med,2008,177(8):861-70.
[307]Clark D, Tuor UI, Thompson R, et al. Protection against Recurrent Stroke withResveratrol:Endothelial Protection. PLoS One,2012,7(10):e47792.
[308]Heyward FD, Walton RG, Carle MS, et al. Adult mice maintained on a high-fat dietexhibit object location memory deficits and reduced hippocampal SIRT1geneexpression. Neurobiol Learn Mem,2012,98(1):25-32.
[309]Yan WJ, Fang ZP, Yang QZ, et al. SirT1mediates hyperbaric oxygenpreconditioning-induced ischemic tolerance in rat brain. J Cereb Blood Flow Metab,2013,33(3):396–406.
[310]Zhu HR, Wang ZY, Zhu XL, et al. Icariin protects against brain injury by enhancingSIRT1-dependent PGC-1α Expression in experimental stroke. Neuropharmacology,2010,59(1-2):70-6.
[311]Dal-Pan A, Pifferi F, Marchal J, et al. Cognitive Performances Are SelectivelyEnhanced during Chronic Caloric Restriction or Resveratrol Supplementation in aPrimate. PLoS One,2011,6(1): e16581.
[312]Abraham J, Johnson RW.Consuming a Diet Supplemented with Resveratrol ReducedInfection-Related Neuroinflammation and Deficits in Working Memory in Aged Mice.Rejuvenation Res,2009,12(6):445–453.
[313]Schirmer H, Pereira TC, Rico EP, et al. Modulatory effect of resveratrol on SIRT1,SIRT3, SIRT4, PGC1α and NAMPT gene expression profiles in wild-type adultzebrafish liver.Mol Biol Rep,2012,39(3):3281-3289.
[314]Anne Brunet, Lora B, Sweeney J, et al. Stress-Dependent Regulation of FOXOTranscription Factors by the SIRT1Deacetylase. SCIENCE,2004,303(26).
[315]Kenyon C, Murphy CT. Enrichment of regulatory motifs upstream of predictedDAF-16targets. Nat Genet,2006,38:397–398.
[316]Jacobs FM, van der Heide LP, Wijchers PJ, et al. FoxO6, a novel member of the FoxOclass of transcription factors with distinct shuttling dynamics. J Biol Chem,2003,278:35959–67.
[317]Anderson MJ, Viars CS, Czekay S, et al. Cloning and characterization of three humanforkhead genes that comprise an FKHR-like gene subfamily. Genomics,1998,47:187–99.
[318]Hoekman M F, Jacobs F M, Smidt M P, Burbach J P. Spatial and temporal expressionof FoxO transcription factors in the developing and adult murine brain. Gene ExprPatterns2006,6:134–140.
[319]Lehtinen MK, Yuan Z, Boag PR, et al. A Conserved MST-FOXO Signaling PathwayMediates Oxidative-Stress Responses and Extends Life Span. Cell,2006,125:987–1001.
[320]Bradley J. Willcox, Timothy A. Donlon, Qimei He, et al. FOXO3A genotype isstrongly associated with human longevity. PNAS,2008,105(37):13987–13992.
[321]Lam EW, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cellfate. Biochem Soc Trans,2006,34(Pt5):722–6.
[322]Fukunaga K, Ishigami T, Kawano T. Transcriptional regulation of neuronal genes andits effect on neural functions: expression and function of forkhead transcriptionfactors in neurons. J Pharmacol Sci,2005,98:205–11.
[323]Hillion JA, Li Y, Maric D, et al. Involvement of Akt in preconditioning-inducedtolerance to ischemia in PC12cells.J Cereb Blood Flow Metab,2006,26:1323–31.
[324]Won CK, Ji HH, Koh PO. Estradiol prevents the focal cerebral ischemicinjury-induced decrease of forkhead transcription factors phosphorylation. NeurosciLett,2006,398:39–43.
[325]Sherry M. Zakhary1, Diana Ayubcha1, Jeffery N. Dileo, et al.Distribution Analysis ofDeacetylase SIRT1in Rodent and Human Nervous Systems. Anat Rec (Hoboken),2010,293(6):1024–1032.
[326]Brunet A, Sweeney LB, Sturgill JF, et al.Greenberg ME.Stress-dependent regulationof FOXO transcription factors by the SIRT1deacetylase. Science,2004,303(5666):2011–5.
[327]Brunet A, Bonni A, Zigmond M J, et al.Akt promotes cell survival by phosphorylatingand inhibiting a Forkhead transcription factor.Cell,1999,96(6):857-68.
[328]Biggs WH3rd, Meisenhelder J, Hunter T, et al.Protein kinase B/Akt-mediatedphosphorylation promotes nuclear exclusion of the winged helix transcription factorFKHR1.Proc Natl Acad Sci U S A,1999,96(13):7421-6.
[329]Lam EW, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cellfate. Biochem Soc Trans,2006,34(Pt5):722–6.
[330]Fu Z, Tindall DJ. FOXOs, cancer and regulation of apoptosis. Oncogene,2008,27:2312–2319.
[331]Michishita E, Park JY, Burneskis JM, et al. Evolutionarily conserved andnonconserved cellular localizations and functions of human SIRT proteins. Mol BiolCell,2005,16(10):4623–35.
[332]Sugden MC, Caton PW, Holness MJ. PPAR control: it's SIRTainly as easy as PGC. JEndocrinol,2010,204:93–104.
[333]Nemoto S, Fergusson MM, Finkel T. SIRT1functionally interacts with the metabolicregulator and transcriptional coactivator PGC-1a. J Biol Chem,2005,280:16456–16460.
[334]Finck BN, Kelly DP. PGC-1coactivators: Inducible regulators of energy metabolismin health and disease. J. Clin. Invest,2006,116:615–622.
[335]Lin J, Wu PH, Tarr PT, et al. Defects in adaptive energy metabolism with CNS-linkedhyperactivity in PGC-1alpha null mice. Cell,2004,119:121–135.
[336]Qin WP, Vahram H, Pavel K, et al. PGC-1α Expression Decreases in the AlzheimerDisease Brain as a Function of Dementia.Arch Neurol,2009,66(3):352-361.
[337]Liu L, Zhang P, Li Y, et al.Curcumin protects brain from oxidative stress throughinducing expression of UCP2in chronic cerebral hypoperfusion aging-rats.MolNeurodegener,2012,7(Suppl1): S10.
[338]Zhang GL, Deng JP, Wang BH, et al.Gypenosides improve cognitive impairmentinduced by chronic cerebral hypoperfusion in rats by suppressing oxidative stress andastrocytic activation. Behav Pharmacol,2011,22(7):633-44.
[339]Xu Y, Zhang JJ, Xiong L, et al.Green tea polyphenols inhibit cognitive impairmentinduced by chronic cerebral hypoperfusion via modulating oxidative stress. J NutrBiochem,2010,21(8):741-8.
[340]Wareski P, Vaarmann A, Choubey V, et al. PGC-1{alpha} and PGC-1{beta} regulatemitochondrial density in neurons. J. Biol. Chem,2009,284:21379–21385.
[341]Chinetti G., Fruchart JC, Staels B. Peroxisome proliferator-activated receptors(PPARs): Nuclear receptors at the crossroads between lipid metabolism andinflammation. Inflamm. Res,2000,49;497–505.
[342]Yin KJ, Deng Z, Hamblin M, et al. Peroxisome proliferator-activated receptor deltaregulation of miR-15a in ischemia-induced cerebral vascular endothelial injury. J.Neurosci,2010,30:6398–6408.
[343]Yin KJ, Deng Z, Hamblin M, et al. Vascular PPARdelta protects againststroke-induced brain injury. Arterioscler. Thromb. Vasc. Biol,2011,31:574–581.
[344]Li PF, Dietz R, and von Harsdorf R. Superoxide induces apoptosis in cardiomyocytes,but proliferation and expression of transforming growth factor-beta1in cardiacfbroblasts. FEBS Lett,1999,448:206–210.
[345]Lam EW, Francis RE, Petkovic M. FOXO transcription factors: key regulators of cellfate. Biochem Soc Trans,2006,34(Pt5):722–6.
[346]Giannakou ME, Partridge L. The interaction between FOXO and SIRT1: tipping thebalance towards survival. Trends Cell Biol,2004,14(8):408–12.
[347]Huang H, Tindall DJ. Dynamic FoxO transcription factors. J Cell Sci,2007,120:2479–2487.
[348]Essers, MA,Weijzen S, de Vries-Smits AM, et al. FOXO transcription factoractivation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J,2004,23:4802–4812.
[349]Kops GJ, Dansen TB, Polderman PE, et al. Forkhead transcription factor FOXO3aprotects quiescent cells from oxidative stress.Nature,2002,419(6904):316-21.
[350]Curtis C, Landis GN, Folk D, et al. Transcriptional profling of MnSOD-mediatedlifespan extension in Drosophila reveals a spe-cies-general network of aging andmetabolic genes. Genome Biol,2007,8:R262.
[351]Burgering BM, Medema RH. Decisions on life and death: FOXO Forkheadtranscription factors are in command when PKB/Akt is off duty. J Leukoc Biol,2003，73:689–701.
[352]Olmos Y, Sánchez-Gómez FJ, Wild B, et al. SirT1regulation of antioxidant genes isdependent on the formation of a FoxO3a/PGC-1α complex.Antioxid Redox Signal.2013Mar5.[Epub ahead of print]. online.liebertpub.com.