TLR4信号通路在老龄大鼠术后认知功能下降中的作用研究
摘要
目的：通过比较老龄大鼠麻醉和手术前后行为学的变化,探讨麻醉和手术对术后认知功能的影响；检测麻醉和手术前后老龄大鼠海马区TLR4及其下游关键因子的表达,探讨TLR4信号通路在麻醉手术后老龄大鼠术后认知功能下降的发生机制中的作用。
方法：(1)22-23月龄雌性SD大鼠70只,随机分为对照组(C组),手术组(S1、S3、S7,即麻醉术后1、3、7天组,n=10),麻醉组(A1、A3、A7,即麻醉后1、3、7天组,n=10)。造模前进行6天Morris水迷宫重复空间记忆训练。在第7天,对手术组使用3%异氟烷诱导后行气管插管术,以2%异氟烷维持麻醉2小时,行脾脏切除术；对麻醉组仅给予3%异氟烷诱导后气管插管术及2%异氟烷维持麻醉2小时；对C组给予空氧混合气体吸入2小时。造模过程中监测各项生命体征。在手术/麻醉后第1、3、7天分别对S1和A1组、S3和A3组、S7和A7组进行反向测试,将平台移至对侧,比较各组与对照组潜伏时间、位移和游泳速度的差异。行为学测试完毕后立即处死,每组随即选5只取海马液氮保存,其余5只灌注固定后取大脑叠氮化钠保存备用。
(2)应用免疫组化、免疫荧光双标、western blot及RT-PCR等方法检测麻醉手术前后大鼠海马区CA3区TLR4及其下游通路主要因子MyD88、TRIF、NF-κB及炎症因子TNF-α、IL-1β、IL-6等的表达,尼氏染色法观察海马区神经元的数量和形态改变。
结果：(1)反向测试的结果显示,手术组的潜伏时间与位移明显增加,以S1组表现最为显著,这种增加在S3组虽然有所下降,但与对照组相比仍具有统计学差异。麻醉组也表现为潜伏时间与位移增加,但程度与持续时间均不及手术组,仅A1组的潜伏时间和位移与对照组相比有统计学差异。各组的游泳速度无明显差异。(2)免疫组化结果显示,手术后海马区小胶质细胞被激活,激活形态的小胶质细胞数量S1组最多。麻醉组海马区小胶质细胞也被激活,但数量少于对应时间点的手术组。免疫荧光显示TLR4在海马CA3区主要表达于小胶质细胞和神经细胞表面。手术后,TLR4在此两种细胞上均呈现高表达状态,在S1组出现表达高峰,此后逐渐下调至正常水平；麻醉后TLR4表达亦上调,但在对应时间点均低于手术组。Western blot和RT-PCR结果显示,海马CA3区TLR4、MyD88、TRIF、NF-κB及炎症因子TNF-α、IL-1β、IL-6等在手术及麻醉后都呈现表达增高的趋势,其高峰都出现在S1组和A1组,但麻醉组整体表达都明显弱于手术组。尼氏染色发现麻醉和手术前后海马CA3区神经元数量无明显变化。
结论：(1)麻醉和手术都能引起老龄大鼠认知功能下降,手术所导致的认知功能下降程度更为严重；(2)手术引起TLR4信号通路激活导致中枢炎症的形成,损害神经元,这可能是引起老龄大鼠术后认知功能下降的机制之一。图11幅,表5个,参考文献106篇。
Object:(1) discuss which has predominant effect on postoperative cognitive deficits between surgery and anesthesia by observing the change of behavior in aged rats after surgery;(2) explain the effects of TLR4signaling on postoperative cognitive deficits in aged rats by detecting and comparing the expression of TLR4and the key factors downstream before and after surgery and/or anesthesia.
Method:(1) Part1:70female Sprague Dawley rats (22-23-month-old) were divided into7groups (n=10) randomly after6-day-training in Morris Water Maze. Rats in Group S1, S3and S7received splenectomy under2%isoflurane inhalation anesthesia for2hs; Group A1, A3and A7underwent2%isoflurane inhalation anesthesia for2hs only; Group Control inhaled mixed oxygen for2hs. Vital signs were monitored during surgery and/or anesthesia. Group S1and A1, Group S3and A3and Group S7and A7were killed on Day1,3and7after surgery/anesthesia respectively after reversal test. The platform was located in opposite zone in reversal test. Latency, distance and speed were recorded and analyzed.5of the rat's brains in each group were acquired without any additional treatment and stored in liquid nitrogen, and the rest were stored in1%sodium azide solution after perfusion with4%paraformaldehyde solution.(2) Part2:locate TLR4and detect the expressions of TLR4, the downstream factors MyD88, TRIF, NF-κB and pro-inflammatory cytokines TNF-α, IL-1β and IL-6in hippocampal CA3area, by the way of immunohistochemistry, immunofluorescence, western blot and RT-PCR. Observe the neurons change in number and morphology in hippocampal CA3area by Nissl's staining.
Results:(1) The rats underwent splenectomy showed noticed prolonged latency and increased distance. This increasing in S1and S3was statistically significant. Although the rats received inhalation anesthesia showed prolonged latency and increased distance too, the degree and duration were apparently less than those in Group S.(2) In hippocampal CA3area, microglia was activated both after splenectomy and inhalation anesthesia, but the surgery-induced activation was more serious. Immunofluorescence technique was utilized to locate TLR4and found TLR4mainly expressed on microglia and neuron. Splenectomy lead to prominent high expression of TLR4both on microglia and neuron, and the peak appeared in Group S1. The increased expression was also significant in Group S3. Anesthesia-induce increased expression of TLR4was not so remarkable as that in Group S. The results of western blot and RT-PCR showed the same change as immunofluorescence. As downstream key factors in TLR4signaling, MyD88、TRIF and NF-κB showed parallel changes as TLR4, as well as pro-inflammatory factors TNF-α, IL-1β and IL-6. The number of neuron in hippocampal CA3area showed no significant change.
Conclusion:(1) Both surgery and anesthesia result in cognitive deficits in aged rats, and surgery seems to play a more important role in this procedure.(2) TLR4signaling activates microglia to produce multiple pro-inflammatory cytokines, which lead to CNS inflammation and ultimately damage neurons. This is a possible mechanism of surgery-induced cognitive deficits in aged rats. Figures11, tables5, references106.
方法：(1)22-23月龄雌性SD大鼠70只,随机分为对照组(C组),手术组(S1、S3、S7,即麻醉术后1、3、7天组,n=10),麻醉组(A1、A3、A7,即麻醉后1、3、7天组,n=10)。造模前进行6天Morris水迷宫重复空间记忆训练。在第7天,对手术组使用3%异氟烷诱导后行气管插管术,以2%异氟烷维持麻醉2小时,行脾脏切除术；对麻醉组仅给予3%异氟烷诱导后气管插管术及2%异氟烷维持麻醉2小时；对C组给予空氧混合气体吸入2小时。造模过程中监测各项生命体征。在手术/麻醉后第1、3、7天分别对S1和A1组、S3和A3组、S7和A7组进行反向测试,将平台移至对侧,比较各组与对照组潜伏时间、位移和游泳速度的差异。行为学测试完毕后立即处死,每组随即选5只取海马液氮保存,其余5只灌注固定后取大脑叠氮化钠保存备用。
(2)应用免疫组化、免疫荧光双标、western blot及RT-PCR等方法检测麻醉手术前后大鼠海马区CA3区TLR4及其下游通路主要因子MyD88、TRIF、NF-κB及炎症因子TNF-α、IL-1β、IL-6等的表达,尼氏染色法观察海马区神经元的数量和形态改变。
结果：(1)反向测试的结果显示,手术组的潜伏时间与位移明显增加,以S1组表现最为显著,这种增加在S3组虽然有所下降,但与对照组相比仍具有统计学差异。麻醉组也表现为潜伏时间与位移增加,但程度与持续时间均不及手术组,仅A1组的潜伏时间和位移与对照组相比有统计学差异。各组的游泳速度无明显差异。(2)免疫组化结果显示,手术后海马区小胶质细胞被激活,激活形态的小胶质细胞数量S1组最多。麻醉组海马区小胶质细胞也被激活,但数量少于对应时间点的手术组。免疫荧光显示TLR4在海马CA3区主要表达于小胶质细胞和神经细胞表面。手术后,TLR4在此两种细胞上均呈现高表达状态,在S1组出现表达高峰,此后逐渐下调至正常水平；麻醉后TLR4表达亦上调,但在对应时间点均低于手术组。Western blot和RT-PCR结果显示,海马CA3区TLR4、MyD88、TRIF、NF-κB及炎症因子TNF-α、IL-1β、IL-6等在手术及麻醉后都呈现表达增高的趋势,其高峰都出现在S1组和A1组,但麻醉组整体表达都明显弱于手术组。尼氏染色发现麻醉和手术前后海马CA3区神经元数量无明显变化。
结论：(1)麻醉和手术都能引起老龄大鼠认知功能下降,手术所导致的认知功能下降程度更为严重；(2)手术引起TLR4信号通路激活导致中枢炎症的形成,损害神经元,这可能是引起老龄大鼠术后认知功能下降的机制之一。图11幅,表5个,参考文献106篇。
Object:(1) discuss which has predominant effect on postoperative cognitive deficits between surgery and anesthesia by observing the change of behavior in aged rats after surgery;(2) explain the effects of TLR4signaling on postoperative cognitive deficits in aged rats by detecting and comparing the expression of TLR4and the key factors downstream before and after surgery and/or anesthesia.
Method:(1) Part1:70female Sprague Dawley rats (22-23-month-old) were divided into7groups (n=10) randomly after6-day-training in Morris Water Maze. Rats in Group S1, S3and S7received splenectomy under2%isoflurane inhalation anesthesia for2hs; Group A1, A3and A7underwent2%isoflurane inhalation anesthesia for2hs only; Group Control inhaled mixed oxygen for2hs. Vital signs were monitored during surgery and/or anesthesia. Group S1and A1, Group S3and A3and Group S7and A7were killed on Day1,3and7after surgery/anesthesia respectively after reversal test. The platform was located in opposite zone in reversal test. Latency, distance and speed were recorded and analyzed.5of the rat's brains in each group were acquired without any additional treatment and stored in liquid nitrogen, and the rest were stored in1%sodium azide solution after perfusion with4%paraformaldehyde solution.(2) Part2:locate TLR4and detect the expressions of TLR4, the downstream factors MyD88, TRIF, NF-κB and pro-inflammatory cytokines TNF-α, IL-1β and IL-6in hippocampal CA3area, by the way of immunohistochemistry, immunofluorescence, western blot and RT-PCR. Observe the neurons change in number and morphology in hippocampal CA3area by Nissl's staining.
Results:(1) The rats underwent splenectomy showed noticed prolonged latency and increased distance. This increasing in S1and S3was statistically significant. Although the rats received inhalation anesthesia showed prolonged latency and increased distance too, the degree and duration were apparently less than those in Group S.(2) In hippocampal CA3area, microglia was activated both after splenectomy and inhalation anesthesia, but the surgery-induced activation was more serious. Immunofluorescence technique was utilized to locate TLR4and found TLR4mainly expressed on microglia and neuron. Splenectomy lead to prominent high expression of TLR4both on microglia and neuron, and the peak appeared in Group S1. The increased expression was also significant in Group S3. Anesthesia-induce increased expression of TLR4was not so remarkable as that in Group S. The results of western blot and RT-PCR showed the same change as immunofluorescence. As downstream key factors in TLR4signaling, MyD88、TRIF and NF-κB showed parallel changes as TLR4, as well as pro-inflammatory factors TNF-α, IL-1β and IL-6. The number of neuron in hippocampal CA3area showed no significant change.
Conclusion:(1) Both surgery and anesthesia result in cognitive deficits in aged rats, and surgery seems to play a more important role in this procedure.(2) TLR4signaling activates microglia to produce multiple pro-inflammatory cytokines, which lead to CNS inflammation and ultimately damage neurons. This is a possible mechanism of surgery-induced cognitive deficits in aged rats. Figures11, tables5, references106.
引文
[1]Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery[J]. Anesthesiology,2008,108(1):18-30
[2]Petersen RC, Doody R, Kurz A, et al., Current concepts in mild cognitive impairment[J]. Arch Neurol,2001,58(12):1985-92
[3]张文超,汪赛赢,欧阳文.吸入麻醉诱导下大鼠气管插管的应用研究[J].现代医药卫生,2010,16：2401-2
[4]Abildstrom H, Rasmussen LS, Rentowl P, et al. Cognitive dysfunction 1-2 years after non-cardiac surgery in the elderly:ISPOCD group. International Study of Post-Operative Cognitive Dysfunction[J]. Acta Anaesthesiol Scand,2000,44(10): 1246-51
[5]Moller JT, Cluitmans P, Rasmussen LS, et al, Long-term postoperative cognitive dysfunction in the elderly:ISPOCD1 study[J]. The Lancet,1998.351(9106): 857-61
[6]Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery[J]. Anesthesiology,2008,108(1):18-30
[7]Culley DJ, Baxter MG, Crosby CA, et al. Impaired acquisition of spatial memory 2 weeks after isoflurane and isoflurane-nitrous oxide anesthesia in aged rats[J]. Anesth Analg,2004,99(5):1393-7
[8]Culley DJ, Baxter MG, Yukhananov R, et al. Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats[J]. Anesthesiology,2004,100(2):309-14
[9]Crosby C, Culley DJ, Baxter MG, et al. Spatial memory performance 2 weeks after general anesthesia in adult rats[J]. Anesth Analg,2005,101(5):1389-92
[10]Hunter KF, D Cyr. Pharmacotherapeutics in older adults. J Wound Ostomy Continence Nurs,2006,33(6):630-35
[11]Jeanne Stemmelin, Jean-Christophe Cassel, Bruno Will, et al. Sensitivity to cholinergic drug treatments of aged rats with variable degrees of spatial memory impairment[J]. Behav Brain Res,1999,98(1):53-66
[12]张洁,欧阳文.异氟醚对老年大鼠脑组织神经元凋亡的影响[J].中华麻醉学杂志,2009,29(7)：610-2
[13]Newman MF, Grocott HP, Mathew JP, et al. Report of the Substudy Assessing the Impact of Neurocognitive Function on Quality of Life 5 Years After Cardiac Surgery Editorial Comment[J]. Stroke,2001,32(12):2874-81
[14]Wan Y, Xu J, Ma D, et al. Postoperative impairment of cognitive function in rats:a possible role for cytokine-mediated inflammation in the hippocampus[J]. Anesthesiology,2007,106(3):436-43
[15]Rosczyk HA, NL Sparkman, RW Johnson. Neuroinflammation and cognitive function in aged mice following minor surgery [J]. Exp Gerontol,2008. 43(9):840-6
[16]Westaby S, Saatvedt K, White S, et al. Is there a relationship between cognitive dysfunction and systemic inflammatory response after cardiopulmonary bypass? [J] Ann Thorac Surg,2001,71(2):667-72
[17]Hu Z, Ou Y, Duan K, et al. Inflammation:a bridge between postoperative cognitive dysfunction and Alzheimer's disease[J]. Med Hypotheses,2010,74(4): 722-4.
[18]Morris RG, Hagan JJ, Rawlins JN. Allocentric spatial learning by hippocampectomised rats:a further test of the "spatial mapping" and "working memory" theories of hippocampal function[J]. Q J Exp Psychol B,1986,38(4): 365-95
[19]Morris RG. Spatial localization does not require the presence of local cues[J]. Learning and Motivation,1981,12(2):239-60
[20]Kallai J, Makany T, Karadi K, et al. Spatial orientation strategies in Morris-type virtual water task for humans[J]. Behav. Brain Res,2005,159(2):187-96
[21]Morris RG Developments of a water-maze procedure for studying spatial learning in the rat[J]. J Neurosci Methods,1984,11(1):47-60
[22]Cravens, R.W. Effects of maternal undernutrition on offspring behavior: Incentive value of a food reward and ability to escape from water[J]. Dev Psychobiol, 1974,7(1):61-9
[23]Morris RG, Garrud P, Rawlins JN, et al. Place navigation impaired in rats with hippocampal lesions[J]. Nature,1982,297(5868):681-3
[24]Fitzgerald LW, Dokla CP. Morris water task impairment and hypoactivity following cysteamine-induced reductions of somatostatin-like immunoreactivity[J]. Brain Res,1989,505(2):246-50
[25]Vorhees CV, MT Williams. Morris water maze:procedures for assessing spatial and related forms of learning and memory[J]. Nat Protoc,2006,1(2):848-58
[26]庄心良,曾因明,陈伯奎主编.现代麻醉学,第三版[M].北京：人民卫生出版社,2003.450-61
[27]Miller RD. Anesthesia. sthed[M]. New York:ChurehillLivingstone, 2000:506-51
[28]Terrando N, Monaco C, Ma D, et al. Tumor necrosis factor-a triggers a cytokine cascade yielding postoperative cognitive decline[J]. Proc Natl Acad Sci U S A,2010,107(47):20518-22
[29]张瑜,金芬华,任志鹏,等.脑缺血后TLR4作用与小胶质细胞的激活[J].国际病理科学与临床杂志,2008,28(4)：13-338
[30]Chen YC, Yip PK, Huang YL, et al. Sequence variants of toll like receptor 4 and late-onset Alzheimer's disease[J]. PLoS One,2012,7(12):e50771
[31]夏月峰,欧阳文,段开明,等.异氟醚对老龄大鼠海马CA3区突触机构的影响[J].中华麻醉学杂志,2008,28(2)：149-51
[32]段开明,欧阳文,陈满红,等.异氟烷对成龄和老龄大鼠海马蛋白质组延迟相的差异性影响[J].中南大学学报(医学版).2009,34(7)：589-94
[33]李丹,欧阳文,段开明.异氟醚对老龄大鼠海马CA3区突触素表达的影响[J].中华麻醉学杂志.2009,29(10)：899-902
[34]Cao XZ, Ma H, Wang JK, et al. Postoperative cognitive deficits and neuroinflammation in the hippocampus triggered by surgical trauma are exacerbated in aged rats[J]. Prog Neuropsychopharmacol Biol Psychiatry,2010,34(8):1426-32
[35]Wan Y, Xu J, Ma D, et al. Maze, Postoperative impairment of cognitive function in rats:a possible role for cytokine-mediated inflammation in the hippocampus[J]. Anaesthesiology,2007,106(3):436-43
[36]Fidalgo AR, Cibelli M, White JP, et al. Systemic inflammation enhances surgery-induced cognitive dysfunction in mice[J]. Neurosci Lett,2011,498(1):63-6
[37]孟凡珍,万燕杰,徐静,等.中枢神经胶质细胞与认知功能[J].实用医学杂志.2008,24(23)：4145-6
[38]Hashimoto C, Hudson KL, Anderson KV. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein[J]. Cell,1988,52(2):269-79
[39]Maria Fischer, Marc Ehlers. Toll-like receptors in autoimmunity[J]. Annals of the New York Academy of Sciences,2008,1143:21-34
[40]Piccinini AM, Midwood KS. DAMPening inflammation by modulating TLR signalling[J]. Mediators Inflamm.2010, pⅱ:672395
[41]Palsson-McDermott EM, O'Neill LA. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4[J]. Immunology,2004,113(2): 153-62
[42]Li Y, Si R, Feng Y, et al. Myocardial Ischemia Activates an Injurious Innate Immune Signaling via Cardiac Heat Shock Protein 60 and Toll-like Receptor 4[J]. J Biol Chem,2011,286(36):31308-19
[43]Asea A, Rehli M, Kabingu E, et al. Novel signal transduction pathway utilized by extracellular HSP70:role of toll-like receptor (TLR) 2 and TLR4[J]. J Biol Chem,2002,277(17):15028-34
[44]Roelofs MF, Boelens WC, Joosten LA, et al. Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis[J]. J Immunol,2006,176(11):7021-7
[45]Yang Z, Deng Y, Su D, et al. TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury[J]. Lab Invest,2013 Apr 29. doi: 10.1038
[46]Shi H,Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fattyacid 2 induced insulin resistance[J]. J ClinInvest,2006,116(11):3015-25
[47]王海坤,韩代书.Toll样受体(TLRs)的信号转导与免疫调节[J].生物化学与生物物理进展,2006,33(9)：820-7
[48]Hines DJ, Choi HB, Hines RM, et al. Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides[J]. PLoS One,2013,8(3):e60388
[49]He, H.J., et al., Surgery upregulates high mobility group box-1 and disrupts the blood-brain barrier causing cognitive dysfunction in aged rats[J]. CNS Neurosci Ther,2012.18(12):p.994-1002.
[50]徐发良，李磊,吕凤林,等.手术创伤后Toll样受体4/髓样分化蛋白-2的表达[J].中华实验外科杂志,2005年,7：810-2
[51]Rogove AD, Lu W, Tsirka SE. Microglial activation and recruitment, but not proliferation, suffice to mediate neurodegeneration[J]. Cell Death and Differentiation,2002,9(8):801-6
[52]Dilger RN, Johnson RW. Aging, microglial cell priming,and the discordant central inflammatory response to signals fromthe peripheral immune system[J]. J Leukoc Biol,2008,84(4):932-9
[53]杨玉荣,佘锐萍,梁宏德.Toll-NF-κB信号途径及其介导的功能[J].细胞生物学杂志,2007,29：483-6
[54]Xia MZ, Liang YL, Wang H, et al. Melatonin modulates TLR4-mediated inflammatory genes through MyD88-and TRIF-dependent signaling pathways in lipopolysaccharide-stimulated RAW264.7 cells[J]. J Pineal Res,2012,53(4):325-34
[55]Babcock AA, Toft-Hansen H, Owens T. Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury[J]. J Immunol.2008,181(9): 6481-90
[56]Eckle T, Eltzschig HK. Toll-like Receptor Signaling during Myocardial Ischemia[J]. Anesthesiology,2011,114(3):490-2
[57]Falahati S, BM, Waickman AT, et al. Ischemia-Induced Neuroinflammation Is Associated with Disrupted Development of Oligodendrocyte Progenitors in a Model of Periventricular Leukomalacia[J]. Dev Neurosci,2013, Feb 27. [Epub ahead of print].
[58]Boutin H, LeFeuvre RA, Horai R, et al. Role of IL-lalpha and IL-lbeta in ischemic brain damage[J]. J Neurosci,2001,21(15):5528-34
[59]张伟伟,周辰,齐翠,等.白介素1p时间依赖性地抑制大鼠皮层神经元钾电流[J].生物物理学报,2009,6：415-22
[60]Raivich G, Banati R. Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease[J]. Brain Res Brain Res Rev,2004,46(3):261-81
[61]Holmin S, Mathiesen T. Intracerebral administration of interleukin-lbeta and induction of inflammation, apoptosis and vasogenic edema[J]. J Neurosurg,2000, 92(1):108-20
[62]李欣,李海红,方泽漫,等.白介素-1β对原代培养海马神经元毒性的研究[J].中华行为医学与脑科学杂志,2009,18(12)：1061-3
[63]Mrak R E, Griffin W S. Glia and their cytokines in progression of neurodegeneration[J]. Neurobiol Aging,2005,26(3):349-54
[64]Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis[J]. Annu Rev Immunol,1996,14(1):397-440
[65]Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family[J]. Annu Rev Immunol,2009,27(2):519-50
[66]Van Wagoner NJ, Benveniste EN. lnterleukin-6 expression and regulation in astrocytes[J]. J Neuroimmunol,1999,100(122):124-39
[67]Penkowa M,Molinero A,Carrasco J,et al. Interleukin-6 deifciency reduces the brain inflammatory response and increases oxidaitve stress and neurodegeneration after kianic acid-induced seizuers[J]. Neuroscience,2001,102(4): 805-18
[68]Rizzi M, Perego C, Aliprandi M, et al. Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development[J]. Neurobiol Dis,2003,14:494-503
[69]Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty[J]. Annu Rev Med,2000,51(6):245-70
[70]孙冰,韩代书.Toll样受体信号通路的负调控[J].生物化学与生物物理进展,2009,36(12)：1516-22
[71]Jurgens HA, RW Johnson. Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation[J]. Exp Neurol,2012,233(1):40-8
[72]丁力,严国章,石翊飒,等.手术创伤对老龄大鼠海马CA3区突触结构的影响[J].中华麻醉学杂志,2010,1：67-70
[73]Leow-Dyke S, Allen C, Denes A, et al. Neuronal toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro [J]. J Neuroinflammation,2012,9(5):230
[74]Zhang Z, Zhang ZY, Wu Y, et al. Immunolocalization of Toll-likereceptors 2 and 4 as well as their endogenous ligand, heat shockprotein 70, in rat traumatic brain injury [J]. Neuroimmunomodulation,2012,19(1):10-9
[75]Qiu J, Nishimura M, Wang Y, et al. Early release of HMGB-1 from neurons after the onset ofbrain ischemia[J]. J Cereb Blood Flow Metab,2008,28(2):927-38
[76]Franceschi C. Inflammaging as a major characteristic of old people:can it be prevented or cured? [J] Nutr Rev,2007,65(12):173-6
[77]Mattson MP, T Magnus. Ageing and neuronal vulnerability[J]. Nature Reviews Neuroscience,2006,7(4):278-94
[78]Cibelli M, Fidalgo AR, Terrando N, et al.Role of interleukin-lbeta in postoperative cognitive dysfunction[J]. Ann Neurol,2010,68(3):360-8
[79]Dean JM, Wang X, Kaindl AM, et al. Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro[J]. Brain Behav Immun, 2010,24(5):776-83
[80]Letiembre M, Hao W, Liu Y, et al. Innate immune receptor expression in normal brain aging[J]. Neuroscience,2007,146(1):248-54
[81]Rivest S. Regulation of innate immune responses in the brain[J]. Nat Rev Immunol.2009.9(6):429-39.
[82]Rosczyk HA, Sparkman NL, Johnson RW. Neuroinflammation and cognitive function in aged mice following minor surgery[J]. Exp Gerontol.2008, 43(9):840-6
[82]Cibelli M, Fidalgo AR, Terrando N, et al. Role of Interleukin-lb in Postoperative Cognitive Dysfunction[J]. Ann Neurol,2010,68(3):360-8
[83]Chen J, Buchanan JB, Sparkman NL, et al. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system[J]. Brain Behav Immun,2008,22(3):301-11
[84]Salminen A, Ojala J, Kauppinen A, et al. Inflammation in Alzheimer's disease:Amyloid-β oligomers trigger innate immunity defence via pattern recognition receptors [J]. Prog Neurobiol.2009,87(3):181-94
[85]Zhang W, Wang LZ, Yu JT, et al. Increased expressions of TLR2 and TLR4 on peripheral blood mononuclear cells from patients with Alzheimer's disease[J]. J Neurol Sci,2012,315(1-2):67-71
[86]张亮,李金莲,庞有旺.小胶质细胞和炎症作用参与老年痴呆症的研究进展[J].神经解剖学杂志.2006,22(5)：583-5
[87]Planel E, Richter KE, Nolan CE, et al. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia[J]. J Neurosci,2007,27(12):3090-7
[88]Xie Z, Culley DJ, Dong Y, et al. The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo[J]. Ann Neurol,2008,64(6):618-27
[89]Bianchi SL, Tran T, Liu C, Lin S, et al. Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics[J]. Neurobiol Aging,2008,29(7):1002-10
[90]Nussmeier NA, Searles BE. Inflammatory brain injury after cardiopulmonary bypass:is it real? [J] Anesth Analg,2010,110(2):288-90
[91]贺晓生,费舟.Toll样受体在创伤性脑损伤中的作用与调控研究[J].创伤外科杂志,2009,11(4)：289-92
[92]Song M, Jin J, Lim JE, et al. TLR4 mutation reduces microglial activation, increases Abeta deposits andexacerbates cognitive deficits in a mouse model of Alzheimer's disease[J]. J Neuroinflammation,2011,8:92
[93]Sofat N, Robertson SD, Wait R. Fibronectin Ⅲ 13-14 domains induce joint damage via Toll-like receptor 4 activation and synergize with interleukin-1 and tumour necrosis factor[J]. J Innate Immun,2012; 4(1):69-79
[94]Lehnardt S, Massillon L, Follett P, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway[J].Proc Natl Acad Sci U S A,2003,100(14):8514-9
[95]Costello DA, Lyons A, Denieffe S, et al. Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice:a role for Toll-like receptor activation[J]. J Biol Chem,2011,286(40):34722-32
[96]张瑜,金芬华,任志鹏,等.脑缺血后TLR4作用与小胶质细胞的激活[J].国际病理科学与临床杂志,2008,28(4)：334-8
[97]Okun E, Barak B, Saada-Madar R, et al. Evidence for a developmental role for TLR4 in learning and memory[J]. PLoS One,2012,7(10):e47522
[98]Ginhoux F, Lim S, Hoeffel G, et al. Origin and differentiation of microglia[J]. Front Cell Neurosci,2013,7:45
[99]Vacas S, Degos V, Feng X, et al. The neuroinflammatory response of postoperative cognitive decline[J]. Br Med Bull,2013 Apr 4. [Epub ahead of print]
[100]Van Harten AE, Scheeren TW, Absalom AR. A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia[J]. Anaesthesia,2012,67(3):280-93
[101]Zhang L, Zhang J, Yang L, et al. Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells[J]. Br J Anaesth,2013 Apr 19. [Epub ahead of print]
[102]Barrientos RM, Hein AM, Frank MG, et al. Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats[J]. J Neurosci,2012,32(42):14641-8
[103]Haruhiko Akiyama, Steven Barger, Scott Barnum, et al. Inflammation and Alzheimer's disease[J]. Neurobiology of Aging,2000,21(3):383-421
[104]Tang SC, Arumugam TV, Xu X, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits[J]. Proc Natl Acad Sci U S A, 2007,104(34):13798-803
[105]Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease[J]. Trends Neurosci,2011,34(5):269-81
[106]Rolls A, Shechter R, London A, et al. Toll-like receptors modulate adult hippocampal neurogenesis[J]. Nat Cell Biol,2007,9(9):1081-8
[1]Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction[J]. Br J Anaesth,2009,103(Suppl 1):i41-46
[2]Burkhart CS, Steiner LA. Can postoperative cognitive dysfunction be avoided? [J] Hosp Pract (1995),2012,40(1):214-23
[3]Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators[J]. N Engl J Med,1996,335(25):1857-63
[4]Kat MG, Vreeswijk R, de Jonghe JF, et al. Long-term cognitive outcome of delirium in elderly hip surgery patients. A prospective matched controlled study over two and a half years[J]. Dement Geriatr Cogn Disord,2008,26(1):1-8
[5]Lowery DP, Wesnes K, Ballard CG. Subtle attentional deficits in the absence of dementia are associated with an increased risk of post-operative delirium[J]. Dement Geriatr Cogn Disord,2007,23(6):390-4
[6]Steinmetz J, Christensen KB, Lund T, et al. Long-term consequences of postoperative cognitive dysfunction[J]. Anesthesiology,2009,110(3):548-55
[7]Van Dijk D, Kalkman CJ. Why are cerebral microemboli not associated with cognitive decline? [J] Anesth Analg,2009,109(4):1006-8
[8]Newman MF, Grocott HP, Mathew JP, et al. Report of the substudy assessing the impact of neurocognitive function on quality of life 5 years after cardiac surgery[J]. Stroke,2001,32(12):2874-81
[9]Price CC, Garvan CW, Monk TG. Type and severity of cognitive decline in older adults after noncardiac surgery[J]. Anesthesiology,2008,108(1):8-17
[10]Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery[J]. Anesthesiology,2008; 108(1):18-30
[11]Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction[J]. Lancet,1998, 351(9106):857-61
[12]Bekker AY, Weeks EJ. Cognitive function after anaesthesia in the elderly[J]. Best Pract Res Clin Anaesthesiol,2003,17(2):259-72
[13]Boos GL, Soares LF, Oliveira Filho GR. Postoperative cognitive dysfunction:prevalence and associated factors[J]. Rev Bras Anestesiol,2005,55(5): 517-24
[14]Rudolph JL, Schreiber KA, Culley DJ, et al. Measurement of post-operative cognitive dysfunction after cardiac surgery:a systematic review[J]. Acta Anaesthesiol Scand,2010,54(6):663-77
[15]Coburn M, Fahlenkamp A, Zoremba N, et al. Postoperative cognitive dysfunction:Incidence and prophylaxis[J]. Anaesthesist,2010,59(2):177-84
[16]Hartholt KA, van der Cammen TJ, Klimek M. Postoperative cognitive dysfunction in geriatric patients[J]. Z Gerontol Geriatr,2012,45(5):411-6
[17]Rasmussen LS, Siersma VD, ISPOCD GROUP. Postoperative cognitive dysfunction:true deterioration versus random variation[J]. Acta Anaesthesiol Scand, 2004,48(9):1137-43
[18]Lewis MS, Maruff P, Silbert BS, et al. The influence of different error estimates in the detection of postoperative cognitive dysfunction using reliable change indices with correction for practice effects[J]. Arch Clin Neuropsychol,2007,22(2): 249-57
[19]Rasmussen LS, Larsen K, Houx P, et al. The assessment of postoperative cognitive function[J]. Acta Anaesthesiol Scand,2001,45(3):275-89
[20]Funder KS, Steinmetz J, Rasmussen LS. Methodological issues of postoperative cognitive dysfunction research[J]. Semin Cardiothorac Vase Anesth, 2010,14(2):119-22
[21]Steinmetz J, Rasmussen LS, ISPOCD GROUP. Choice reaction time in patients with post-operative cognitive dysfunction[J]. Acta Anaesthesiol Scand,2008, 52(1):95-8
[22]Abildstrom H, Rasmussen LS, Rentowl P, et al. Cognitive dysfunction 1-2 years after non-cardiac surgery in the elderly. ISPOCD group. International Study of Post-Operative Cognitive Dysfunction[J]. Acta Anaesthesiol Scand,2000,44(10): 1246-51
[23]Zhu J, Jiang X, Shi E, et al. Sevoflurane preconditioning reverses impairment of hippocampal long-term potentiation induced by myocardial ischaemia-reperfusion injury[J]. Eur J Anaesthesiol,2009,26(11):961-8
[24]Johnson T, Monk T, Rasmussen LS, et al. Postoperative cognitive dysfunction in middle-aged patients[J]. Anesthesiology,2002,96(6):1351-7
[25]Cui QT, Fu QL, Han PL, et al. Risk factors of cognitive impairment after off-pump coronary artery bypass grafting[J]. Chinese Journal of Cardiology,2012, 40(2):104-7
[26]Silbert BS, Scott DA, Evered LA, et al. A comparison of the effect of high-and low-dose fentanyl on the incidence of postoperative cognitive dysfunction after coronary artery bypass surgery in the elderly[J]. Anesthesiology,2006,104(6): 1137-45
[27]Evered L, Scott DA, Silbert B, et al. Postoperative cognitive dysfunction is independent of type of surgery and anesthetic[J]. Anesth Analg,2011,112(5):1179-85
[28]Lee TA, Wolozin B, Weiss KB, et al. Assessment of the emergence of Alzheimer's disease following coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty[J]. J Alzheimers Dis,2005,7(4):319-24
[29]Canet J, Raeder J, Rasmussen LS, et al. Cognitive dysfunction after minor surgery in the elderly[J]. Acta Anaesthesiol Scand,2003,47(10):1204-10
[30]Jildenstal PK, Hallen JL, Rawal N, et al. Effect of auditory evoked potential-guided anaesthesia on consumption of anaesthetics and early postoperative cognitive dysfunction:a randomised controlled trial[J]. Eur J Anaesthesiol,2011, 28(3):213-9
[31]Puskas JD, Stringer A, Hwang SN, et al. Neurocognitive and neuroanatomic changes after off-pump versus on-pump coronary artery bypass grafting:long-term follow-up of a randomized trial[J]. J Thorac Cardiovasc Surg,2011,141(5):1116-27
[32]Boodhwani M, Rubens FD, Wozny D, et al. Predictors of early neurocognitive deficits in low-risk patients undergoing on-pump coronary artery bypass surgery [J]. Circulation,2006,114(1 Suppl):1461-6
[33]Van Dijk D, Spoor M, Hijman R, et al. Cognitive and cardiac outcomes 5 years after off-pump vs on-pump coronary artery bypass graft surgery[J]. JAMA, 2007,297(7):701-8
[34]Hudetz JA, Patterson KM, Amole O, et al. Postoperative cognitive dysfunction after noncardiac surgery:effects of metabolic syndrome[J]. J Anesth, 2011,25(3):337-44
[35]Li M, Bertout JA, Ratcliffe SJ, et al. Acute anemia elicits cognitive dysfunction and evidence of cerebral cellular hypoxia in older rats with systemic hypertension[J].Anesthesiology,2010,113(4):845-58
[36]Messerotti Benvenuti S, Zanatta P, Longo C, et al. Preoperative cerebral hypoperfusion in the left, not in the right, hemisphere is associated with cognitive decline after cardiac surgery[J]. Psychosom Med,2012,74(1):73-80
[37]Williams-Russo P, Sharrock NE, Mattis S, et al. Randomized trial of hypotensive epidural anesthesia in older adults[J]. Anesthesiology,1999,91(4): 926-35
[38]Salazar F, Donate M, Boget T, Bogdanovich A, et al. Intraoperative warming and post-operative cognitive dysfunction after total knee replacement[J]. Acta Anaesthesiol Scand,2011,55(2):216-22
[39]Bisschops LL, Hoedemaekers CW, Mollnes TE, et al. Rewarming after hypothermia after cardiac arrest shifts the inflammatory balance[J]. Crit Care Med, 2012,40(4):1136-42
[40]de Lange F, Jones WL, Mackensen GB, et al. The effect of limited rewarming and postoperative hypothermia on cognitive function in a rat cardiopulmonary bypass model[J]. Anesth Analg,2008,106(3):739-45
[41]Rasmussen LS, Johnson T, Kuipers HM, et al. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients[J]. Acta Anaesthesiol Scand,2003,47(3):260-6
[42]Mracek J, Holeckova I, Chytra I, et al. The impact of general versus local anesthesia on early subclinical cognitive function following carotid endarterectomy evaluated using P3 event-related potentials[J]. Acta Neurochir (Wien),2012,154(3): 433-8
[43]Guay J. General anaesthesia does not contribute to long-term post-operative cognitive dysfunction in adults:A meta-analysis[J]. Indian J Anaesth,2011,55(4): 358-63
[44]Enlund M, Mentell O, Flenninger A, et al. Evidence of cerebral dysfunction associated with isoflurane-or propofol based anaesthesia for orthognathic surgery, as assessed by biochemical and neuropsychological methods[J]. Ups J Med Sci,1998, 103(1):43-59
[45]Hocker J, Stapelfeldt C, Leiendecker J, et al. Postoperative neurocognitive dysfunction in elderly patients after xenon versus propofol anesthesia for major noncardiac surgery:a double-blinded randomized controlled pilot study[J]. Anesthesiology,2009,110(5):1068-76
[46]Coburn M, Baumert JH, Roertgen D, et al. Emergence and early cognitive function in the elderly after xenon or desflurane anaesthesia:a double-blinded randomized controlled trial[J]. Br J Anaesth,2007,98(6):756-62.
[47]Fujita Y, Nakamura K, Horiguchi Y, et al. Effect of different perioperative analgesic methods on postoperative cognitive dysfunction in elderly patients undergoing upper abdominal surgery[J]. Masui,2011,60(10):1153-8
[48]Rasmussen LS, Steentoft A, Rasmussen H, et al. Benzodiazepines and postoperative cognitive dysfunction in the elderly. ISPOCD Group. International Study of Postoperative Cognitive Dysfunction[J]. Br J Anaesth,1999,83(4):585-9
[49]Rortgen D, Kloos J, Fries M, et al. Comparison of early cognitive function and recovery after desflurane or sevoflurane anaesthesia in the elderly:a double-blinded randomized controlled trial [J]. Br J Anaesth,2010,104():167-74
[50]Poirier J, Davignon J, Bouthillier D, et al. Apolipoprotein E polymorphism and Alzheimer's disease[J]. Lancet,1993,342(8837):697-9
[51]McDonagh DL, Mathew JP, White WD, et al. Cognitive function after major noncardiac surgery, apolipoprotein E4 genotype, and biomarkers of brain injury[J]. Anesthesiology,2010,112(4):852-9
[52]Abildstrom H, Christiansen M, Siersma VD, et al. Apolipoprotein E genotype and cognitive dysfunction after noncardiac surgery[J]. Anesthesiology,2004, 101(4):855-61
[53]Bryson GL, Wyand A, Wozny D, et al. A prospective cohort study evaluating associations among delirium, postoperative cognitive dysfunction, and apolipoprotein E genotype following open aortic repair[J]. Can J Anaesth,2011,58(3): 246-55
[54]Steinmetz J, Jespersgaard C, Dalhoff K, et al. Cytochrome P450 polymorphism and postoperative cognitive dysfunction[J]. Minerva Anestesiol,2012, 78(3):303-9
[55]Ologunde R, Ma D. Do inhalational anesthetics cause cognitive dysfunction? [J] Acta Anaesthesiol Taiwan,2011,49(4):149-53
[56]Brownrigg TD, Theisen CS, Fibuch EE, et al. Carnosine protects against the neurotoxic effects of a serotonin-derived melanoid[J]. Neurochem Res,2011,36(3): 467-75
[57]Mawhinney LJ, de Rivero Vaccari JP, Alonso OF, et al. Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain[J]. Brain Res,2012,1431:23-34
[58]Wang H, Xu Z, Feng C, et al. Changes of learning and memory in aged rats after isoflurane inhalational anaesthesia correlated with hippocampal acetylcholine level[J]. Ann Fr Anesth Reanim,2012,31(3):e61-6
[59]Yan XB, Ouyang W, Li G, et al. Involvement of neuronal nitric oxide synthase in cognitive impairment in isoflurane-treated rats[J]. Neurosci Lett,2012, 506(2):240-4
[60]Lin D, Cao L, Wang Z, et al. Lidocaine attenuates cognitive impairment after isoflurane anesthesia in old rats[J]. Behav Brain Res,2012,228(2):319-27
[61]Zhang B, Tian M, Zhen Y, et al. The effects of isoflurane and desflurane on cognitive function in humans[J]. Anesth Analg,2012,114(2):410-5
[62]Seitz DP, Shah PS, Herrmann N, et al. Exposure to general anesthesia and risk of Alzheimer's disease:a systematic review and meta-analysis[J]. BMC Geriatr, 2011,11:83
[63]Hu Z, Ou Y, Duan K, et al. Inflammation:a bridge between postoperative cognitive dysfunction and Alzheimer's disease[J]. Med Hypotheses,2010,74(4): 722-4
[64]Xie Z, Tanzi RE. Alzheimer's disease and post-operative cognitive dysfunction[J]. Exp Gerontol,2006,41(4):346-59
[65]Kalenka A, Gross B, Maurer MH, et al. Isoflurane anesthesia elicits protein pattern changes in rat hippocampus[J]. J Neurosurg Anesthesiol,2010,22(2):144-54
[66]Lin D, Zuo Z. Isoflurane induces hippocampal cell injury and cognitive impairments in adult rats[J]. Neuropharmacology,2011,61(8):1354-9
[67]Rasmussen LS, O'Brien JT, Silverstein JH, et al. Is peri-operative cortisol secretion related to post-operative cognitive dysfunction?[J] Acta Anaesthesiol Scand, 2005,49(9):1225-31
[68]Cerejeira J, Nogueira V, Luis P, Vaz-Serra A, Mukaetova-Ladinska EB. The cholinergic system and inflammation:common pathways in delirium pathophysiology[J]. J Am Geriatr Soc,2012,60(4):669-75
[69]Li YC, Xi CH, An YF, et al. Perioperative inflammatory response and protein S-100beta concentrations-relationship with post-operative cognitive dysfunction in elderly patients[J]. Acta Anaesthesiol Scand,2012,56(5):595-600
[70]Kamer AR, Galoyan SM, Haile M, et al. Meloxicam improves object recognition memory and modulates glial activation after splenectomy in mice[J]. Eur J Anaesthesiol,2012,29(7):322-7
[71]Tveita AA, Dietrichs ES, Tveita T. Myocardial gene expression profiling of rewarming shock in a rodent model of accidental hypothermia[J]. Cryobiology,2012, 64(3):201-10
[72]Sta Maria N, Eckmann DM. Model predictions of gas embolism growth and reabsorption during xenon anesthesia[J]. Anesthesiology,2003,99(3):638-45
[73]Yon JH, Daniel-Johnson J, Carter LB, et al. Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways[J]. Neuroscience,2005,135(3):815-27
[74]Linstedt U, Meyer O, Kropp P, et al. Serum concentration of S-100 protein in assessment of cognitive dysfunction after general anesthesia in different types of surgery[J]. Acta Anaesthesiol Scand,2002,46(4):384-9
[75]Norkiene I, Samalavicius R, Ivaskevicius J, et al. Asymptomatic carotid artery stenosis and cognitive outcomes after coronary artery bypass grafting[J]. Scand Cardiovasc J,2011,45(3):169-73
[76]Fudickar A, Peters S, Stapelfeldt C, et al. Postoperative cognitive deficit after cardiopulmonary bypass with preserved cerebral oxygenation:a prospective observational pilot study[J]. BMC Anesthesiol,2011,11:7
[77]Twomey C, Corrigan M, Burlacu C, et al. Nitric oxide index is not a predictor of cognitive dysfunction following laparotomy[J]. J Clin Anesth,2010, 22(1):22-8
[78]Bryson GL, Wyand A. Evidence-based clinical update:general anesthesia and the risk of delirium and postoperative cognitive dysfunction[J]. Can J Anaesth, 2006,53(7):669-77
[79]Cohendy R, Brougere A, Cuvillon P. Anaesthesia in the older patient[J]. Curr Opin Clin Nutr Metab Care,2005,8(1):17-21
[80]Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and cognitive decline in elderly patients:a systematic review[J]. Anesth Analg,2006,102(4):1255-66
[81]Vizcaychipi MP, Lloyd DG, Wan Y, et al. Xenon pretreatment may prevent early memory decline after isoflurane anesthesia and surgery in mice[J]. PLoS One, 2011,6(11):e26394
[82]Cai ZY, Yan Y, Chen R. Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model[J]. Neurosci Bull,2010,26(1):28-36
[83]Fan L, Wang TL, Xu YC, et al. Minocycline may be useful to prevent/treat postoperative cognitive decline in elderly patients[J]. Med Hypotheses,2011,76(5): 733-6
[84]Djaiani G, Katznelson R, Fedorko L, et al. Early benefit of preserved cognitive function is not sustained at one-year after cardiac surgery:a longitudinal follow-up of the randomized controlled trial[J]. Can J Anaesth,2012,59(5):449-55
[85]Schwarz N, Schonburg M, Kastaun S, et al. Cognitive deterioration after cardiosurgery[J].Nervenarzt,2011,82(2):190,192-7
[86]Ge YY, Xu Y, Cheng JQ, et al. Case-control study on the effect of ulinastatin on postoperative complications in elderly patients undergoing hip joint replacement[J]. Zhongguo Gu Shang,2011,24(6):459-62
[87]Wang Y, Sands LP, Vaurio L, et al. The effects of postoperative pain and its management on postoperative cognitive dysfunction[J]. Am J Geriatr Psychiatry,2007, 15(1):50-9
[1]Kawai T and Akira S. TLR signaling[J]. Cell Death Differ,2006,13(5): 816-25
[2]Valanne S, Wang JH, Ramet M. The Drosophila toll signaling pathway[J]. J Immunol,2011,186(2):649-56
[3]Okun E, Griffioen KJ, Lathia JD, et al. Toll-like receptors in neurodegeneration[J]. Brain Res Rev,2009; 59(2):278-92
[4]Leulier F, Lemaitre B. Toll-like receptors:taking an evolutionary approach[J]. Nat Rev Genet,2008,9(3):165-178
[5]Matam Vijay-Kumar, Jesse D. Aitken, Frederic A. Carvalho, et al.Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5[J]. Science, 2010,328(5975):228-31
[6]Gerondakis S, Grumont RJ, Banerjee A. Regulating B-cell activation and survival in response to TLR signals[J]. Immunol. Immunol Cell Biol,2007,85(6): 471-5
[7]Chiaki Iwamura and Toshinori Nakayama. Toll-like receptors in the respiratory system:their roles in inflammation[J]. Current Allergy and Asthma Reports,2008,8(1):7-13
[8]Eriksson M, Meadows SK, Basu S, et al. TLRs mediate IFN-gamma production by human uterine NK cells in endometrium[J]. J Immunol,2006,176(10): 6219-24
[9]Roger Sutmuller, Anja Garritsen, and Gosse J Adema. Regulatory T cells and n toll-like receptors:regulating the regulators[J]. Ann Rheum Dis.2007,66(3):91-5
[10]Kaisho T and Akira S. Toll-like receptor function and signaling[J]. J Allergy Clin Immunol,2006,117(5):979-87
[11]Sabroe I, Whyte MK. Toll-like receptor (TLR)-based networks regulate neutrophilic inflammation in respiratory disease[J]. Biochem Soc Trans,2007,35(6): 14-95
[12]Tomohiro Yoshimoto and Kenji Nakanishi. Roles of IL-18 in basophils and mast cells[J]. Allergology International,2006,55:105-13
[13]Gibson FC 3rd, Ukai T, Genco CA. Engagement of specific innate immune signaling pathways during Porphyromonas gingival is induced chronic inflammation and atherosclerosis[J]. Front Biosci,2008,13:2041-59
[14]Julie K. Olson and Stephen D. Miller. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs[J]. J Immunol, 2004,173:3916-24
[15]Bowman CC, Rasley A, Tranguch SL, et al. Cultured astrocytes express toll-like receptors for bacterial products[J]. Glia,2003,43(3):281-91
[16]Aravalli RN, Peterson PK, Lokensgard JR. Toll-like receptors in defense and damage of the central nervous system[J]. J Neuroimmune Pharmacol.2003,2(4): 297-312
[17]Tang SC, Arumugam TV, Xu X, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits[J]. Proc Natl Acad Sci U.S.A, 2007,104(34):13798-803
[18]Uematsu S, Fujimoto K, Jang MH, et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5[J]. Nat Immunol,2008,9(7):769-76
[19]Smith KD, Andersen-Nissen E, Hayashi F, et al. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility[J]. Nat Immunol,2003,4(12):1247-53
[20]Kucera K, Koblansky AA, Saunders LP, et al. Structure-based analysis of Toxoplasma gondii profilin:a parasite-specific motif is required for recognition by Toll-like receptor 11[J]. J Mol Biol,2010,403(4):616-29
[21]Miyake, K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors[J]. Semin Immunol,2007,19(1):3-10
[22]Schon MP, Schon M. TLR7 and TLR8 as targets in cancer therapy[J]. Oncogene,2008,27(2):190-9
[23]Pandey S, Agrawal DK. Immunobiology of Toll-like receptors:emerging trends[J]. Immunol Cell Biol,2006,84(4):333-41
[24]Lehnardt S, Schott E, Trimbuch T, et al. A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS[J]. J Neurosci,2008,28(10):2320-31
[25]Liu Y, Chen GY, Zheng P. CD24-Siglec G/10 discriminates danger-from pathogen-associated molecular patterns[J]. Trends Immunol,2009,30(12):557-61
[26]Shimada M, Yanai Y, Okazaki T, et al. Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine/chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization[J]. Development,2008,135(11):2001-11
[27]Hemmi H, Akira S. TLR signalling and the function of dendritic cells[J]. Chem Immunol Allergy,2005,86:120-35
[28]Gorina R, Font-Nieves M, Marquez-Kisinousky L, et al. Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NF-κB signaling, MAPK, and Jakl/Statl pathways[J]. Glia,2011, 59(2):242-55
[29]Jung DY, Lee H, Jung BY, et al. TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia:a critical role of IFN-beta as a decision maker[J]. J Immunol,2005,174(10):6467-76
[30]Divanovic S, Trompette A, Atabani SF, et al. Inhibition of TLR-4/MD-2 signaling by RP105/MD-1[J]. J Endotoxin Res,2005,11(6):363-8
[31]Mattson MP, Maudsley S, Martin B. A neural signaling triumvirate that influences ageing and age-related disease:insulin/IGF-1, BDNF and serotonin[J]. Ageing Res Rev,2004,3(4):445-64
[32]Mattson MP, Barger SW, Begley JG, et al. Calcium, free radicals, and excitotoxic neuronal death in primary cell culture[J]. Methods Cell Biol,1995,46: 187-216
[33]Mattson MP, Goodman Y, Luo H, et al. Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis:evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration[J]. J Neurosci Res,1997,49(6):681-97
[34]Lathia JD, Rao MS, Mattson MP, et al. The microenvironment of the embryonic neural stem cell:lessons from adult niches? [J] Dev Dyn,2007,236(12): 3267-82
[35]Xin Duan, Eunchai Kang, Cindy Y Liu, et al. Development of neural stem cell in the adult brain[J]. Curr Opin Neurobiol,2008,18(1):108-15
[36]Lathia JD, Okun E, Tang SC, et al. Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation[J]. J Neurosci,2008, 28,(51):13978-84
[37]Okun E, Griffioen KJ, Son TG, et al. TLR2 activation inhibits embryonic neural progenitor cell proliferation[J]. J Neurochem,2010,114(2):462-74
[38]Rolls A, Shechter R, London A, et al. Toll-like receptors modulate adult hippocampal neurogenesis[J]. Nat Cell Biol,2007,9(9):1081-8
[39]Shechter R, Ronen A, Rolls A, et al. Toll-like receptor 4 restricts retinal progenitor cell proliferation[J]. J Cell Biol,2008,183(3):393-400
[40]Covacu R, Arvidsson L, Andersson A, et al. TLR activation induces TNF-alpha production from adult neural stem/progenitor cells[J]. J Immunol,2009, 182(11):6889-95
[41]Sloane JA, Batt C, Ma Y, et al. Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2[J]. Proc Natl Acad Sci U S A, 2010,107(25):11555-60
[42]Okun E, Griffioen K, Barak B, et al. Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis[J]. Proc Natl Acad Sci U S A, 2010,107(35):15625-30
[43]Ma Y, Li J, Chiu I, et al. Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis[J]. J Cell Biol,2006, 175(2):209-15
[44]Ma Y, Haynes RL, Sidman RL, et al. TLR8:an innate immune receptor in brain, neurons and axons[J]. Cell Cycle,2007,6(23):2859-68
[45]Cameron JS, Alexopoulou L, Sloane JA, et al. Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals[J]. J Neurosci,2007,27(47): 13033-41
[46]Acosta C, Davies A. Bacterial lipopolysaccharide regulates nociceptin expression in sensory neurons[J]. J Neurosci Res,2008,86(5):1077-86
[47]Iliev Al, Stringaris AK, Nau R, et al. Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9) [J]. FASEB J,2003,18(2):412-4
[48]Okun E, Lathia JD, Mattson MP. Adhesion-and migration-related side effects of phosphothioated CpG oligodeoxynucleotides. Cell Adh Migr,2009,3(3): 272-4
[49]Okun E, Mattson MP. Phosphothioated oligodeoxynucleotides induce nonspecific effects on neuronal cell adhesion in a growth substrate-dependent manner[J]. J Neurosci Res,2009,87(8):1947-52
[50]Trudler D, Farfara D, Frenkel D. Toll-like receptors expression and signaling in glia cells in neuro-amyloidogenic diseases:towards future therapeutic application[J]. Mediators Inflamm,2010, DOI:10.1155/2010/497987
[51]Kariko K, Ni H, Capodici J, et al. mRNA is an endogenous ligand for Toll-like receptor 3[J]. J Biol Chem,2004,279(13),12542-50
[52]Bsibsi M, Bajramovic JJ, Vogt MH, et al. The microtubule regulator stathmin is an endogenous protein agonist for TLR3[J], J Immunol,2010,184(12): 6929-37
[53]Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis[J]. Brain Behav Immun,2011,25(2):181-213
[54]Howard L. Weiner, Dan Frenkel. Immunology and immunotherapy of Alzheimer's disease[J]. Nat Rev Immunol,2006,6:404-16
[55]Tanaka S, Ide M, Shibutani T, et al. Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats[J]. J Neurosci Res,2006,83(4):557-66
[56]Palin K, Bluthe RM, McCusker RH, et al. The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFalpha-induced sickness behavior[J]. Psychopharmacology,2009,201(4):549-56
[57]Tauber SC, Ebert S, Weishaupt JH, et al. Stimulation of Toll-like receptor 9 by chronic intraventricular unmethylated cytosine-guanine DNA infusion causes neuroinflammation and impaired spatial memory[J]. J Neuro pathol Exp Neurol,2009, 68(10):1116-24
[58]Stefan Bauer, Thomas Muller, Svetlana Hamm. Pattern recognition by Toll-like receptors[J]. Adv Exp Med Biol,2009,653:15-34
[59]Schaffler A, Scholmerich J. Innate immunity and adipose tissue biology[J]. Trends Immunol,2010,31(6):228-35
[60]Lehnard t, S. Innate immunity and neuroinflammation in the CNS:the role of microglia in Toll-like receptor-mediated neuronal injury[J]. Glia,2010,58(3): 253-63
[61]Suh HS, Brosnan CF, Lee SC. Toll-like receptors in CNS viral infections [J]. Curr Top Microbiol Immunol,2009,336:63-81
[62]Baker BJ, Park KW, Qin H, et al. IL-27 inhibits OSM-mediated TNF-alpha and iNOS gene expression in microglia[J]. Glia,2010,58(9):1082-93
[63]Bsibsi M, Persoon-Deen C, Verwer RW, et al. Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators[J]. Glia,2006, 53(7):688-95
[64]Kim H, Yang E, Lee J, et al. Double-stranded RNA mediates interferon regulatory factor 3 activation and interleukin-6 production by engaging Toll-like receptor 3 in human brain astrocytes[J]. Immunology,2008,124(4):480-8
[65]Klein M, Obermaier B, Angele B, et al. Innate immunity to pneumococcal infection of the central nervous system depends on toll-like receptor (TLR) 2 and TLR4[J]. J Infect Dis,2008,198(7):1028-36
[66]S(?)rensen LN, Reinert LS, Malmgaard L, et al. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain[J]. J Immunol,2008, 181(12):8604-12
[67]Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis[J]. Science,2007,317(5844):1522-7
[68]Wang T, Town T, Alexopoulou L, et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis[J]. Nat Med,2004,10(12): 1366-73
[69]Daffis S, Samuel MA, Suthar MS, et al. Toll-like receptor 3 has a protective role against West Nile virus infection[J]. J Virol,2008,82(21):10349-58
[70]Szretter KJ, Daffis S, Patel J, et al. The innate immune adaptor molecule MyD88 restricts West Nile virus replication and spread in neurons of the central nervous system[J]. J Virol,2010,84(23):12125-38
[71]Szretter KJ, Samuel MA, Gilfillan S, et al. The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis[J]. J Virol,2009,83(18): 9329-38
[72]O'Neill LA. DisSARMing Toll-like receptor signaling[J]. Nat Immunol, 2006,7(10):1023-25
[73]Erridge C. Endogenous ligands of TLR2 and TLR4:agonists or assistants? [J] J Leukoc Biol,2010,87(6):989-99
[74]Boksa P. Effects of prenatal infection on brain development and behavior:a review of findings from animal models[J]. Brain Behav Immun,2010,24(6):881-97
[75]Caso JR, Pradillo JM, Hurtado O, et al. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke[J]. Circulation,2007, 115(12):1599-08
[76]Hua F, Ma J, Ha T, et al. Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion[J]. J Neuroimmunol,2007,190(1-2):101-11
[77]Lehnardt S, Lehmann S, Kaul D, et al. Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia[J]. J Neuroimmunol,2007,190(1-2):28-33
[78]Kilic U, Kilic E, Matter CM, et al. TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration[J]. Neurobiol Dis,2008, 31(1):33-40
[79]Hyakkoku K, Hamanaka J, Tsuruma K, et al. Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia[J]. Neuroscience,2010,171(1):258-67
[80]Pradillo JM, Fernandez-Lopez D, et al. Toll-like receptor 4 is involved in neuroprotection afforded by ischemic preconditioning[J]. J Neurochem,2009,109(1): 287-94
[81]Yang QW, Lu FL, Zhou Y, et al. HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling[J]. J Cereb Blood Flow Metab,2010,31(2):593-605
[82]Park C, Cho IH, Kim D, et al. Toll-like receptor 2 contributes to glial cell activation and heme oxygenase-1 expression in traumatic brain injury [J]. Neurosci Lett,431(2):123-8
[83]Clark AK, Staniland AA, Marchand F, et al. P2X7-dependent release of interleukin-lbeta and nociception in the spinal cord following lipopolysaccharide[J]. J Neurosci,2010,30(2):573-82
[84]Liu T, Xu ZZ, Park CK, et al. Toll-like receptor 7 mediates pruritus[J]. Nat Neurosci,2010,13(12):1460-2
[85]Mattson, MP. Pathways towards and away from Alzheimer's disease[J]. Nature,2004,430(7000):631-9
[86]Richard KL, Filali M, Prefontaine P, et al. Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease[J]. J Neurosci,2008,28(22): 5784-93
[87]Tahara K, Kim HD, Jin JJ, et al. (2006) Activation of Toll-1 ike receptor 2 on microglia promotes cell uptake of Alzheimer dise ase-associated amyloid beta peptide[J]. J Biol Chem,2006,281(6):3651-9
[88]Tahara, K. et al. Role of toll-like receptor signalling in Abeta uptake and clearance[J]. Brain,2006,129 (Pt 11):3006-19
[89]Reed-Geaghan EG, Savage JC, Hise AG, et al. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation[J]. J Neurosci,2009,29(38):11982-92
[90]Doi Y, Mizuno T, Maki Y, et al. Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer's disease[J]. Am J Pathol,2009,175(5):2121-32
[91]Scholtzova H, Kascsak RJ, Bates KA, et al. Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology[J]. Neurosci.2009,29(6):1846-54
[92]Jin JJ, Kim HD, Maxwell JA, et al. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease[J]. J Neuroinflammation,2008,5:23
[93]Walter S, Letiembre M, Liu Y, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease[J]. Cell Physiol Biochem,2007,20(6): 947-56
[94]Tang SC, Lathia JD, Selvaraj PK, et al. Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal[J]. Exp Neurol,2008,213(1):114-21
[95]Minoretti P, Gazzaruso C, Vito CD, et al. Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease[J]. Neurosci Lett,2006,391(3):147-9
[96]Soulika AM, Lee E, McCauley E, et al. Initiation and progression of axonopathy in experimental autoimmune encephalomyelitis[J]. J Neurosci,2009, 29(47):14965-79
[97]Marta M, Andersson A, Isaksson M, et al. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis[J]. Eur J Immunol, 2008,38(2):565-75
[98]Prinz M, Garbe F, Schmidt H, et al. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis[J]. J Clin Invest, 2006,116(2):456-64
[99]Ellestad KK, Tsutsui S, Noorbakhsh F, et al. Early life exposure to lipopolysaccharide suppresses experimental autoimmune encephalomyelitis by promoting tolerogenic dendritic cells and regulatory T cells[J]. J Immunol,2009, 183(1):298-09
[100]Herrmann I, Kellert M, Schmidt H, et al. Streptococcus pneumoniae Infection aggravates experimental autoimmune encephalomyelitis via Toll-like receptor 2[J], Infect Immun,2006,74(8):4841-8
[101]Farez MF, Quintana FJ, Gandhi R, et al. Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE[J]. Nature Immunol,2009,10(9):958-64
[102]Meyer U, Feldon J, Yee BK. A review of the fetal brain cytokine imbalance hypothesis of schizophrenia[J]. Schizophr Bull,2009,35(5):959-72
[103]Salaria S, Badkoobehi H, Rockenstein E, et al. Toll-like receptor pathway gene expression is associated with human immunodeficiency virus-associated neurodegeneration[J]. J Neurovirol,2007,13(6):496-503
[104]Marta M, Meier UC, Lobell A. Regulation of autoimmune encephalomyelitis by toll-like receptors[J]. Autoimmun Rev,2009,8(6):506-9
[2]Petersen RC, Doody R, Kurz A, et al., Current concepts in mild cognitive impairment[J]. Arch Neurol,2001,58(12):1985-92
[3]张文超,汪赛赢,欧阳文.吸入麻醉诱导下大鼠气管插管的应用研究[J].现代医药卫生,2010,16：2401-2
[4]Abildstrom H, Rasmussen LS, Rentowl P, et al. Cognitive dysfunction 1-2 years after non-cardiac surgery in the elderly:ISPOCD group. International Study of Post-Operative Cognitive Dysfunction[J]. Acta Anaesthesiol Scand,2000,44(10): 1246-51
[5]Moller JT, Cluitmans P, Rasmussen LS, et al, Long-term postoperative cognitive dysfunction in the elderly:ISPOCD1 study[J]. The Lancet,1998.351(9106): 857-61
[6]Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery[J]. Anesthesiology,2008,108(1):18-30
[7]Culley DJ, Baxter MG, Crosby CA, et al. Impaired acquisition of spatial memory 2 weeks after isoflurane and isoflurane-nitrous oxide anesthesia in aged rats[J]. Anesth Analg,2004,99(5):1393-7
[8]Culley DJ, Baxter MG, Yukhananov R, et al. Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats[J]. Anesthesiology,2004,100(2):309-14
[9]Crosby C, Culley DJ, Baxter MG, et al. Spatial memory performance 2 weeks after general anesthesia in adult rats[J]. Anesth Analg,2005,101(5):1389-92
[10]Hunter KF, D Cyr. Pharmacotherapeutics in older adults. J Wound Ostomy Continence Nurs,2006,33(6):630-35
[11]Jeanne Stemmelin, Jean-Christophe Cassel, Bruno Will, et al. Sensitivity to cholinergic drug treatments of aged rats with variable degrees of spatial memory impairment[J]. Behav Brain Res,1999,98(1):53-66
[12]张洁,欧阳文.异氟醚对老年大鼠脑组织神经元凋亡的影响[J].中华麻醉学杂志,2009,29(7)：610-2
[13]Newman MF, Grocott HP, Mathew JP, et al. Report of the Substudy Assessing the Impact of Neurocognitive Function on Quality of Life 5 Years After Cardiac Surgery Editorial Comment[J]. Stroke,2001,32(12):2874-81
[14]Wan Y, Xu J, Ma D, et al. Postoperative impairment of cognitive function in rats:a possible role for cytokine-mediated inflammation in the hippocampus[J]. Anesthesiology,2007,106(3):436-43
[15]Rosczyk HA, NL Sparkman, RW Johnson. Neuroinflammation and cognitive function in aged mice following minor surgery [J]. Exp Gerontol,2008. 43(9):840-6
[16]Westaby S, Saatvedt K, White S, et al. Is there a relationship between cognitive dysfunction and systemic inflammatory response after cardiopulmonary bypass? [J] Ann Thorac Surg,2001,71(2):667-72
[17]Hu Z, Ou Y, Duan K, et al. Inflammation:a bridge between postoperative cognitive dysfunction and Alzheimer's disease[J]. Med Hypotheses,2010,74(4): 722-4.
[18]Morris RG, Hagan JJ, Rawlins JN. Allocentric spatial learning by hippocampectomised rats:a further test of the "spatial mapping" and "working memory" theories of hippocampal function[J]. Q J Exp Psychol B,1986,38(4): 365-95
[19]Morris RG. Spatial localization does not require the presence of local cues[J]. Learning and Motivation,1981,12(2):239-60
[20]Kallai J, Makany T, Karadi K, et al. Spatial orientation strategies in Morris-type virtual water task for humans[J]. Behav. Brain Res,2005,159(2):187-96
[21]Morris RG Developments of a water-maze procedure for studying spatial learning in the rat[J]. J Neurosci Methods,1984,11(1):47-60
[22]Cravens, R.W. Effects of maternal undernutrition on offspring behavior: Incentive value of a food reward and ability to escape from water[J]. Dev Psychobiol, 1974,7(1):61-9
[23]Morris RG, Garrud P, Rawlins JN, et al. Place navigation impaired in rats with hippocampal lesions[J]. Nature,1982,297(5868):681-3
[24]Fitzgerald LW, Dokla CP. Morris water task impairment and hypoactivity following cysteamine-induced reductions of somatostatin-like immunoreactivity[J]. Brain Res,1989,505(2):246-50
[25]Vorhees CV, MT Williams. Morris water maze:procedures for assessing spatial and related forms of learning and memory[J]. Nat Protoc,2006,1(2):848-58
[26]庄心良,曾因明,陈伯奎主编.现代麻醉学,第三版[M].北京：人民卫生出版社,2003.450-61
[27]Miller RD. Anesthesia. sthed[M]. New York:ChurehillLivingstone, 2000:506-51
[28]Terrando N, Monaco C, Ma D, et al. Tumor necrosis factor-a triggers a cytokine cascade yielding postoperative cognitive decline[J]. Proc Natl Acad Sci U S A,2010,107(47):20518-22
[29]张瑜,金芬华,任志鹏,等.脑缺血后TLR4作用与小胶质细胞的激活[J].国际病理科学与临床杂志,2008,28(4)：13-338
[30]Chen YC, Yip PK, Huang YL, et al. Sequence variants of toll like receptor 4 and late-onset Alzheimer's disease[J]. PLoS One,2012,7(12):e50771
[31]夏月峰,欧阳文,段开明,等.异氟醚对老龄大鼠海马CA3区突触机构的影响[J].中华麻醉学杂志,2008,28(2)：149-51
[32]段开明,欧阳文,陈满红,等.异氟烷对成龄和老龄大鼠海马蛋白质组延迟相的差异性影响[J].中南大学学报(医学版).2009,34(7)：589-94
[33]李丹,欧阳文,段开明.异氟醚对老龄大鼠海马CA3区突触素表达的影响[J].中华麻醉学杂志.2009,29(10)：899-902
[34]Cao XZ, Ma H, Wang JK, et al. Postoperative cognitive deficits and neuroinflammation in the hippocampus triggered by surgical trauma are exacerbated in aged rats[J]. Prog Neuropsychopharmacol Biol Psychiatry,2010,34(8):1426-32
[35]Wan Y, Xu J, Ma D, et al. Maze, Postoperative impairment of cognitive function in rats:a possible role for cytokine-mediated inflammation in the hippocampus[J]. Anaesthesiology,2007,106(3):436-43
[36]Fidalgo AR, Cibelli M, White JP, et al. Systemic inflammation enhances surgery-induced cognitive dysfunction in mice[J]. Neurosci Lett,2011,498(1):63-6
[37]孟凡珍,万燕杰,徐静,等.中枢神经胶质细胞与认知功能[J].实用医学杂志.2008,24(23)：4145-6
[38]Hashimoto C, Hudson KL, Anderson KV. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein[J]. Cell,1988,52(2):269-79
[39]Maria Fischer, Marc Ehlers. Toll-like receptors in autoimmunity[J]. Annals of the New York Academy of Sciences,2008,1143:21-34
[40]Piccinini AM, Midwood KS. DAMPening inflammation by modulating TLR signalling[J]. Mediators Inflamm.2010, pⅱ:672395
[41]Palsson-McDermott EM, O'Neill LA. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4[J]. Immunology,2004,113(2): 153-62
[42]Li Y, Si R, Feng Y, et al. Myocardial Ischemia Activates an Injurious Innate Immune Signaling via Cardiac Heat Shock Protein 60 and Toll-like Receptor 4[J]. J Biol Chem,2011,286(36):31308-19
[43]Asea A, Rehli M, Kabingu E, et al. Novel signal transduction pathway utilized by extracellular HSP70:role of toll-like receptor (TLR) 2 and TLR4[J]. J Biol Chem,2002,277(17):15028-34
[44]Roelofs MF, Boelens WC, Joosten LA, et al. Identification of small heat shock protein B8 (HSP22) as a novel TLR4 ligand and potential involvement in the pathogenesis of rheumatoid arthritis[J]. J Immunol,2006,176(11):7021-7
[45]Yang Z, Deng Y, Su D, et al. TLR4 as receptor for HMGB1-mediated acute lung injury after liver ischemia/reperfusion injury[J]. Lab Invest,2013 Apr 29. doi: 10.1038
[46]Shi H,Kokoeva MV, Inouye K, et al. TLR4 links innate immunity and fattyacid 2 induced insulin resistance[J]. J ClinInvest,2006,116(11):3015-25
[47]王海坤,韩代书.Toll样受体(TLRs)的信号转导与免疫调节[J].生物化学与生物物理进展,2006,33(9)：820-7
[48]Hines DJ, Choi HB, Hines RM, et al. Prevention of LPS-Induced Microglia Activation, Cytokine Production and Sickness Behavior with TLR4 Receptor Interfering Peptides[J]. PLoS One,2013,8(3):e60388
[49]He, H.J., et al., Surgery upregulates high mobility group box-1 and disrupts the blood-brain barrier causing cognitive dysfunction in aged rats[J]. CNS Neurosci Ther,2012.18(12):p.994-1002.
[50]徐发良，李磊,吕凤林,等.手术创伤后Toll样受体4/髓样分化蛋白-2的表达[J].中华实验外科杂志,2005年,7：810-2
[51]Rogove AD, Lu W, Tsirka SE. Microglial activation and recruitment, but not proliferation, suffice to mediate neurodegeneration[J]. Cell Death and Differentiation,2002,9(8):801-6
[52]Dilger RN, Johnson RW. Aging, microglial cell priming,and the discordant central inflammatory response to signals fromthe peripheral immune system[J]. J Leukoc Biol,2008,84(4):932-9
[53]杨玉荣,佘锐萍,梁宏德.Toll-NF-κB信号途径及其介导的功能[J].细胞生物学杂志,2007,29：483-6
[54]Xia MZ, Liang YL, Wang H, et al. Melatonin modulates TLR4-mediated inflammatory genes through MyD88-and TRIF-dependent signaling pathways in lipopolysaccharide-stimulated RAW264.7 cells[J]. J Pineal Res,2012,53(4):325-34
[55]Babcock AA, Toft-Hansen H, Owens T. Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury[J]. J Immunol.2008,181(9): 6481-90
[56]Eckle T, Eltzschig HK. Toll-like Receptor Signaling during Myocardial Ischemia[J]. Anesthesiology,2011,114(3):490-2
[57]Falahati S, BM, Waickman AT, et al. Ischemia-Induced Neuroinflammation Is Associated with Disrupted Development of Oligodendrocyte Progenitors in a Model of Periventricular Leukomalacia[J]. Dev Neurosci,2013, Feb 27. [Epub ahead of print].
[58]Boutin H, LeFeuvre RA, Horai R, et al. Role of IL-lalpha and IL-lbeta in ischemic brain damage[J]. J Neurosci,2001,21(15):5528-34
[59]张伟伟,周辰,齐翠,等.白介素1p时间依赖性地抑制大鼠皮层神经元钾电流[J].生物物理学报,2009,6：415-22
[60]Raivich G, Banati R. Brain microglia and blood-derived macrophages: molecular profiles and functional roles in multiple sclerosis and animal models of autoimmune demyelinating disease[J]. Brain Res Brain Res Rev,2004,46(3):261-81
[61]Holmin S, Mathiesen T. Intracerebral administration of interleukin-lbeta and induction of inflammation, apoptosis and vasogenic edema[J]. J Neurosurg,2000, 92(1):108-20
[62]李欣,李海红,方泽漫,等.白介素-1β对原代培养海马神经元毒性的研究[J].中华行为医学与脑科学杂志,2009,18(12)：1061-3
[63]Mrak R E, Griffin W S. Glia and their cytokines in progression of neurodegeneration[J]. Neurobiol Aging,2005,26(3):349-54
[64]Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis[J]. Annu Rev Immunol,1996,14(1):397-440
[65]Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family[J]. Annu Rev Immunol,2009,27(2):519-50
[66]Van Wagoner NJ, Benveniste EN. lnterleukin-6 expression and regulation in astrocytes[J]. J Neuroimmunol,1999,100(122):124-39
[67]Penkowa M,Molinero A,Carrasco J,et al. Interleukin-6 deifciency reduces the brain inflammatory response and increases oxidaitve stress and neurodegeneration after kianic acid-induced seizuers[J]. Neuroscience,2001,102(4): 805-18
[68]Rizzi M, Perego C, Aliprandi M, et al. Glia activation and cytokine increase in rat hippocampus by kainic acid-induced status epilepticus during postnatal development[J]. Neurobiol Dis,2003,14:494-503
[69]Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty[J]. Annu Rev Med,2000,51(6):245-70
[70]孙冰,韩代书.Toll样受体信号通路的负调控[J].生物化学与生物物理进展,2009,36(12)：1516-22
[71]Jurgens HA, RW Johnson. Dysregulated neuronal-microglial cross-talk during aging, stress and inflammation[J]. Exp Neurol,2012,233(1):40-8
[72]丁力,严国章,石翊飒,等.手术创伤对老龄大鼠海马CA3区突触结构的影响[J].中华麻醉学杂志,2010,1：67-70
[73]Leow-Dyke S, Allen C, Denes A, et al. Neuronal toll-like receptor 4 signaling induces brain endothelial activation and neutrophil transmigration in vitro [J]. J Neuroinflammation,2012,9(5):230
[74]Zhang Z, Zhang ZY, Wu Y, et al. Immunolocalization of Toll-likereceptors 2 and 4 as well as their endogenous ligand, heat shockprotein 70, in rat traumatic brain injury [J]. Neuroimmunomodulation,2012,19(1):10-9
[75]Qiu J, Nishimura M, Wang Y, et al. Early release of HMGB-1 from neurons after the onset ofbrain ischemia[J]. J Cereb Blood Flow Metab,2008,28(2):927-38
[76]Franceschi C. Inflammaging as a major characteristic of old people:can it be prevented or cured? [J] Nutr Rev,2007,65(12):173-6
[77]Mattson MP, T Magnus. Ageing and neuronal vulnerability[J]. Nature Reviews Neuroscience,2006,7(4):278-94
[78]Cibelli M, Fidalgo AR, Terrando N, et al.Role of interleukin-lbeta in postoperative cognitive dysfunction[J]. Ann Neurol,2010,68(3):360-8
[79]Dean JM, Wang X, Kaindl AM, et al. Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro[J]. Brain Behav Immun, 2010,24(5):776-83
[80]Letiembre M, Hao W, Liu Y, et al. Innate immune receptor expression in normal brain aging[J]. Neuroscience,2007,146(1):248-54
[81]Rivest S. Regulation of innate immune responses in the brain[J]. Nat Rev Immunol.2009.9(6):429-39.
[82]Rosczyk HA, Sparkman NL, Johnson RW. Neuroinflammation and cognitive function in aged mice following minor surgery[J]. Exp Gerontol.2008, 43(9):840-6
[82]Cibelli M, Fidalgo AR, Terrando N, et al. Role of Interleukin-lb in Postoperative Cognitive Dysfunction[J]. Ann Neurol,2010,68(3):360-8
[83]Chen J, Buchanan JB, Sparkman NL, et al. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system[J]. Brain Behav Immun,2008,22(3):301-11
[84]Salminen A, Ojala J, Kauppinen A, et al. Inflammation in Alzheimer's disease:Amyloid-β oligomers trigger innate immunity defence via pattern recognition receptors [J]. Prog Neurobiol.2009,87(3):181-94
[85]Zhang W, Wang LZ, Yu JT, et al. Increased expressions of TLR2 and TLR4 on peripheral blood mononuclear cells from patients with Alzheimer's disease[J]. J Neurol Sci,2012,315(1-2):67-71
[86]张亮,李金莲,庞有旺.小胶质细胞和炎症作用参与老年痴呆症的研究进展[J].神经解剖学杂志.2006,22(5)：583-5
[87]Planel E, Richter KE, Nolan CE, et al. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia[J]. J Neurosci,2007,27(12):3090-7
[88]Xie Z, Culley DJ, Dong Y, et al. The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo[J]. Ann Neurol,2008,64(6):618-27
[89]Bianchi SL, Tran T, Liu C, Lin S, et al. Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics[J]. Neurobiol Aging,2008,29(7):1002-10
[90]Nussmeier NA, Searles BE. Inflammatory brain injury after cardiopulmonary bypass:is it real? [J] Anesth Analg,2010,110(2):288-90
[91]贺晓生,费舟.Toll样受体在创伤性脑损伤中的作用与调控研究[J].创伤外科杂志,2009,11(4)：289-92
[92]Song M, Jin J, Lim JE, et al. TLR4 mutation reduces microglial activation, increases Abeta deposits andexacerbates cognitive deficits in a mouse model of Alzheimer's disease[J]. J Neuroinflammation,2011,8:92
[93]Sofat N, Robertson SD, Wait R. Fibronectin Ⅲ 13-14 domains induce joint damage via Toll-like receptor 4 activation and synergize with interleukin-1 and tumour necrosis factor[J]. J Innate Immun,2012; 4(1):69-79
[94]Lehnardt S, Massillon L, Follett P, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway[J].Proc Natl Acad Sci U S A,2003,100(14):8514-9
[95]Costello DA, Lyons A, Denieffe S, et al. Long term potentiation is impaired in membrane glycoprotein CD200-deficient mice:a role for Toll-like receptor activation[J]. J Biol Chem,2011,286(40):34722-32
[96]张瑜,金芬华,任志鹏,等.脑缺血后TLR4作用与小胶质细胞的激活[J].国际病理科学与临床杂志,2008,28(4)：334-8
[97]Okun E, Barak B, Saada-Madar R, et al. Evidence for a developmental role for TLR4 in learning and memory[J]. PLoS One,2012,7(10):e47522
[98]Ginhoux F, Lim S, Hoeffel G, et al. Origin and differentiation of microglia[J]. Front Cell Neurosci,2013,7:45
[99]Vacas S, Degos V, Feng X, et al. The neuroinflammatory response of postoperative cognitive decline[J]. Br Med Bull,2013 Apr 4. [Epub ahead of print]
[100]Van Harten AE, Scheeren TW, Absalom AR. A review of postoperative cognitive dysfunction and neuroinflammation associated with cardiac surgery and anaesthesia[J]. Anaesthesia,2012,67(3):280-93
[101]Zhang L, Zhang J, Yang L, et al. Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells[J]. Br J Anaesth,2013 Apr 19. [Epub ahead of print]
[102]Barrientos RM, Hein AM, Frank MG, et al. Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats[J]. J Neurosci,2012,32(42):14641-8
[103]Haruhiko Akiyama, Steven Barger, Scott Barnum, et al. Inflammation and Alzheimer's disease[J]. Neurobiology of Aging,2000,21(3):383-421
[104]Tang SC, Arumugam TV, Xu X, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits[J]. Proc Natl Acad Sci U S A, 2007,104(34):13798-803
[105]Okun E, Griffioen KJ, Mattson MP. Toll-like receptor signaling in neural plasticity and disease[J]. Trends Neurosci,2011,34(5):269-81
[106]Rolls A, Shechter R, London A, et al. Toll-like receptors modulate adult hippocampal neurogenesis[J]. Nat Cell Biol,2007,9(9):1081-8
[1]Deiner S, Silverstein JH. Postoperative delirium and cognitive dysfunction[J]. Br J Anaesth,2009,103(Suppl 1):i41-46
[2]Burkhart CS, Steiner LA. Can postoperative cognitive dysfunction be avoided? [J] Hosp Pract (1995),2012,40(1):214-23
[3]Roach GW, Kanchuger M, Mangano CM, et al. Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators[J]. N Engl J Med,1996,335(25):1857-63
[4]Kat MG, Vreeswijk R, de Jonghe JF, et al. Long-term cognitive outcome of delirium in elderly hip surgery patients. A prospective matched controlled study over two and a half years[J]. Dement Geriatr Cogn Disord,2008,26(1):1-8
[5]Lowery DP, Wesnes K, Ballard CG. Subtle attentional deficits in the absence of dementia are associated with an increased risk of post-operative delirium[J]. Dement Geriatr Cogn Disord,2007,23(6):390-4
[6]Steinmetz J, Christensen KB, Lund T, et al. Long-term consequences of postoperative cognitive dysfunction[J]. Anesthesiology,2009,110(3):548-55
[7]Van Dijk D, Kalkman CJ. Why are cerebral microemboli not associated with cognitive decline? [J] Anesth Analg,2009,109(4):1006-8
[8]Newman MF, Grocott HP, Mathew JP, et al. Report of the substudy assessing the impact of neurocognitive function on quality of life 5 years after cardiac surgery[J]. Stroke,2001,32(12):2874-81
[9]Price CC, Garvan CW, Monk TG. Type and severity of cognitive decline in older adults after noncardiac surgery[J]. Anesthesiology,2008,108(1):8-17
[10]Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery[J]. Anesthesiology,2008; 108(1):18-30
[11]Moller JT, Cluitmans P, Rasmussen LS, et al. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction[J]. Lancet,1998, 351(9106):857-61
[12]Bekker AY, Weeks EJ. Cognitive function after anaesthesia in the elderly[J]. Best Pract Res Clin Anaesthesiol,2003,17(2):259-72
[13]Boos GL, Soares LF, Oliveira Filho GR. Postoperative cognitive dysfunction:prevalence and associated factors[J]. Rev Bras Anestesiol,2005,55(5): 517-24
[14]Rudolph JL, Schreiber KA, Culley DJ, et al. Measurement of post-operative cognitive dysfunction after cardiac surgery:a systematic review[J]. Acta Anaesthesiol Scand,2010,54(6):663-77
[15]Coburn M, Fahlenkamp A, Zoremba N, et al. Postoperative cognitive dysfunction:Incidence and prophylaxis[J]. Anaesthesist,2010,59(2):177-84
[16]Hartholt KA, van der Cammen TJ, Klimek M. Postoperative cognitive dysfunction in geriatric patients[J]. Z Gerontol Geriatr,2012,45(5):411-6
[17]Rasmussen LS, Siersma VD, ISPOCD GROUP. Postoperative cognitive dysfunction:true deterioration versus random variation[J]. Acta Anaesthesiol Scand, 2004,48(9):1137-43
[18]Lewis MS, Maruff P, Silbert BS, et al. The influence of different error estimates in the detection of postoperative cognitive dysfunction using reliable change indices with correction for practice effects[J]. Arch Clin Neuropsychol,2007,22(2): 249-57
[19]Rasmussen LS, Larsen K, Houx P, et al. The assessment of postoperative cognitive function[J]. Acta Anaesthesiol Scand,2001,45(3):275-89
[20]Funder KS, Steinmetz J, Rasmussen LS. Methodological issues of postoperative cognitive dysfunction research[J]. Semin Cardiothorac Vase Anesth, 2010,14(2):119-22
[21]Steinmetz J, Rasmussen LS, ISPOCD GROUP. Choice reaction time in patients with post-operative cognitive dysfunction[J]. Acta Anaesthesiol Scand,2008, 52(1):95-8
[22]Abildstrom H, Rasmussen LS, Rentowl P, et al. Cognitive dysfunction 1-2 years after non-cardiac surgery in the elderly. ISPOCD group. International Study of Post-Operative Cognitive Dysfunction[J]. Acta Anaesthesiol Scand,2000,44(10): 1246-51
[23]Zhu J, Jiang X, Shi E, et al. Sevoflurane preconditioning reverses impairment of hippocampal long-term potentiation induced by myocardial ischaemia-reperfusion injury[J]. Eur J Anaesthesiol,2009,26(11):961-8
[24]Johnson T, Monk T, Rasmussen LS, et al. Postoperative cognitive dysfunction in middle-aged patients[J]. Anesthesiology,2002,96(6):1351-7
[25]Cui QT, Fu QL, Han PL, et al. Risk factors of cognitive impairment after off-pump coronary artery bypass grafting[J]. Chinese Journal of Cardiology,2012, 40(2):104-7
[26]Silbert BS, Scott DA, Evered LA, et al. A comparison of the effect of high-and low-dose fentanyl on the incidence of postoperative cognitive dysfunction after coronary artery bypass surgery in the elderly[J]. Anesthesiology,2006,104(6): 1137-45
[27]Evered L, Scott DA, Silbert B, et al. Postoperative cognitive dysfunction is independent of type of surgery and anesthetic[J]. Anesth Analg,2011,112(5):1179-85
[28]Lee TA, Wolozin B, Weiss KB, et al. Assessment of the emergence of Alzheimer's disease following coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty[J]. J Alzheimers Dis,2005,7(4):319-24
[29]Canet J, Raeder J, Rasmussen LS, et al. Cognitive dysfunction after minor surgery in the elderly[J]. Acta Anaesthesiol Scand,2003,47(10):1204-10
[30]Jildenstal PK, Hallen JL, Rawal N, et al. Effect of auditory evoked potential-guided anaesthesia on consumption of anaesthetics and early postoperative cognitive dysfunction:a randomised controlled trial[J]. Eur J Anaesthesiol,2011, 28(3):213-9
[31]Puskas JD, Stringer A, Hwang SN, et al. Neurocognitive and neuroanatomic changes after off-pump versus on-pump coronary artery bypass grafting:long-term follow-up of a randomized trial[J]. J Thorac Cardiovasc Surg,2011,141(5):1116-27
[32]Boodhwani M, Rubens FD, Wozny D, et al. Predictors of early neurocognitive deficits in low-risk patients undergoing on-pump coronary artery bypass surgery [J]. Circulation,2006,114(1 Suppl):1461-6
[33]Van Dijk D, Spoor M, Hijman R, et al. Cognitive and cardiac outcomes 5 years after off-pump vs on-pump coronary artery bypass graft surgery[J]. JAMA, 2007,297(7):701-8
[34]Hudetz JA, Patterson KM, Amole O, et al. Postoperative cognitive dysfunction after noncardiac surgery:effects of metabolic syndrome[J]. J Anesth, 2011,25(3):337-44
[35]Li M, Bertout JA, Ratcliffe SJ, et al. Acute anemia elicits cognitive dysfunction and evidence of cerebral cellular hypoxia in older rats with systemic hypertension[J].Anesthesiology,2010,113(4):845-58
[36]Messerotti Benvenuti S, Zanatta P, Longo C, et al. Preoperative cerebral hypoperfusion in the left, not in the right, hemisphere is associated with cognitive decline after cardiac surgery[J]. Psychosom Med,2012,74(1):73-80
[37]Williams-Russo P, Sharrock NE, Mattis S, et al. Randomized trial of hypotensive epidural anesthesia in older adults[J]. Anesthesiology,1999,91(4): 926-35
[38]Salazar F, Donate M, Boget T, Bogdanovich A, et al. Intraoperative warming and post-operative cognitive dysfunction after total knee replacement[J]. Acta Anaesthesiol Scand,2011,55(2):216-22
[39]Bisschops LL, Hoedemaekers CW, Mollnes TE, et al. Rewarming after hypothermia after cardiac arrest shifts the inflammatory balance[J]. Crit Care Med, 2012,40(4):1136-42
[40]de Lange F, Jones WL, Mackensen GB, et al. The effect of limited rewarming and postoperative hypothermia on cognitive function in a rat cardiopulmonary bypass model[J]. Anesth Analg,2008,106(3):739-45
[41]Rasmussen LS, Johnson T, Kuipers HM, et al. Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients[J]. Acta Anaesthesiol Scand,2003,47(3):260-6
[42]Mracek J, Holeckova I, Chytra I, et al. The impact of general versus local anesthesia on early subclinical cognitive function following carotid endarterectomy evaluated using P3 event-related potentials[J]. Acta Neurochir (Wien),2012,154(3): 433-8
[43]Guay J. General anaesthesia does not contribute to long-term post-operative cognitive dysfunction in adults:A meta-analysis[J]. Indian J Anaesth,2011,55(4): 358-63
[44]Enlund M, Mentell O, Flenninger A, et al. Evidence of cerebral dysfunction associated with isoflurane-or propofol based anaesthesia for orthognathic surgery, as assessed by biochemical and neuropsychological methods[J]. Ups J Med Sci,1998, 103(1):43-59
[45]Hocker J, Stapelfeldt C, Leiendecker J, et al. Postoperative neurocognitive dysfunction in elderly patients after xenon versus propofol anesthesia for major noncardiac surgery:a double-blinded randomized controlled pilot study[J]. Anesthesiology,2009,110(5):1068-76
[46]Coburn M, Baumert JH, Roertgen D, et al. Emergence and early cognitive function in the elderly after xenon or desflurane anaesthesia:a double-blinded randomized controlled trial[J]. Br J Anaesth,2007,98(6):756-62.
[47]Fujita Y, Nakamura K, Horiguchi Y, et al. Effect of different perioperative analgesic methods on postoperative cognitive dysfunction in elderly patients undergoing upper abdominal surgery[J]. Masui,2011,60(10):1153-8
[48]Rasmussen LS, Steentoft A, Rasmussen H, et al. Benzodiazepines and postoperative cognitive dysfunction in the elderly. ISPOCD Group. International Study of Postoperative Cognitive Dysfunction[J]. Br J Anaesth,1999,83(4):585-9
[49]Rortgen D, Kloos J, Fries M, et al. Comparison of early cognitive function and recovery after desflurane or sevoflurane anaesthesia in the elderly:a double-blinded randomized controlled trial [J]. Br J Anaesth,2010,104():167-74
[50]Poirier J, Davignon J, Bouthillier D, et al. Apolipoprotein E polymorphism and Alzheimer's disease[J]. Lancet,1993,342(8837):697-9
[51]McDonagh DL, Mathew JP, White WD, et al. Cognitive function after major noncardiac surgery, apolipoprotein E4 genotype, and biomarkers of brain injury[J]. Anesthesiology,2010,112(4):852-9
[52]Abildstrom H, Christiansen M, Siersma VD, et al. Apolipoprotein E genotype and cognitive dysfunction after noncardiac surgery[J]. Anesthesiology,2004, 101(4):855-61
[53]Bryson GL, Wyand A, Wozny D, et al. A prospective cohort study evaluating associations among delirium, postoperative cognitive dysfunction, and apolipoprotein E genotype following open aortic repair[J]. Can J Anaesth,2011,58(3): 246-55
[54]Steinmetz J, Jespersgaard C, Dalhoff K, et al. Cytochrome P450 polymorphism and postoperative cognitive dysfunction[J]. Minerva Anestesiol,2012, 78(3):303-9
[55]Ologunde R, Ma D. Do inhalational anesthetics cause cognitive dysfunction? [J] Acta Anaesthesiol Taiwan,2011,49(4):149-53
[56]Brownrigg TD, Theisen CS, Fibuch EE, et al. Carnosine protects against the neurotoxic effects of a serotonin-derived melanoid[J]. Neurochem Res,2011,36(3): 467-75
[57]Mawhinney LJ, de Rivero Vaccari JP, Alonso OF, et al. Isoflurane/nitrous oxide anesthesia induces increases in NMDA receptor subunit NR2B protein expression in the aged rat brain[J]. Brain Res,2012,1431:23-34
[58]Wang H, Xu Z, Feng C, et al. Changes of learning and memory in aged rats after isoflurane inhalational anaesthesia correlated with hippocampal acetylcholine level[J]. Ann Fr Anesth Reanim,2012,31(3):e61-6
[59]Yan XB, Ouyang W, Li G, et al. Involvement of neuronal nitric oxide synthase in cognitive impairment in isoflurane-treated rats[J]. Neurosci Lett,2012, 506(2):240-4
[60]Lin D, Cao L, Wang Z, et al. Lidocaine attenuates cognitive impairment after isoflurane anesthesia in old rats[J]. Behav Brain Res,2012,228(2):319-27
[61]Zhang B, Tian M, Zhen Y, et al. The effects of isoflurane and desflurane on cognitive function in humans[J]. Anesth Analg,2012,114(2):410-5
[62]Seitz DP, Shah PS, Herrmann N, et al. Exposure to general anesthesia and risk of Alzheimer's disease:a systematic review and meta-analysis[J]. BMC Geriatr, 2011,11:83
[63]Hu Z, Ou Y, Duan K, et al. Inflammation:a bridge between postoperative cognitive dysfunction and Alzheimer's disease[J]. Med Hypotheses,2010,74(4): 722-4
[64]Xie Z, Tanzi RE. Alzheimer's disease and post-operative cognitive dysfunction[J]. Exp Gerontol,2006,41(4):346-59
[65]Kalenka A, Gross B, Maurer MH, et al. Isoflurane anesthesia elicits protein pattern changes in rat hippocampus[J]. J Neurosurg Anesthesiol,2010,22(2):144-54
[66]Lin D, Zuo Z. Isoflurane induces hippocampal cell injury and cognitive impairments in adult rats[J]. Neuropharmacology,2011,61(8):1354-9
[67]Rasmussen LS, O'Brien JT, Silverstein JH, et al. Is peri-operative cortisol secretion related to post-operative cognitive dysfunction?[J] Acta Anaesthesiol Scand, 2005,49(9):1225-31
[68]Cerejeira J, Nogueira V, Luis P, Vaz-Serra A, Mukaetova-Ladinska EB. The cholinergic system and inflammation:common pathways in delirium pathophysiology[J]. J Am Geriatr Soc,2012,60(4):669-75
[69]Li YC, Xi CH, An YF, et al. Perioperative inflammatory response and protein S-100beta concentrations-relationship with post-operative cognitive dysfunction in elderly patients[J]. Acta Anaesthesiol Scand,2012,56(5):595-600
[70]Kamer AR, Galoyan SM, Haile M, et al. Meloxicam improves object recognition memory and modulates glial activation after splenectomy in mice[J]. Eur J Anaesthesiol,2012,29(7):322-7
[71]Tveita AA, Dietrichs ES, Tveita T. Myocardial gene expression profiling of rewarming shock in a rodent model of accidental hypothermia[J]. Cryobiology,2012, 64(3):201-10
[72]Sta Maria N, Eckmann DM. Model predictions of gas embolism growth and reabsorption during xenon anesthesia[J]. Anesthesiology,2003,99(3):638-45
[73]Yon JH, Daniel-Johnson J, Carter LB, et al. Anesthesia induces neuronal cell death in the developing rat brain via the intrinsic and extrinsic apoptotic pathways[J]. Neuroscience,2005,135(3):815-27
[74]Linstedt U, Meyer O, Kropp P, et al. Serum concentration of S-100 protein in assessment of cognitive dysfunction after general anesthesia in different types of surgery[J]. Acta Anaesthesiol Scand,2002,46(4):384-9
[75]Norkiene I, Samalavicius R, Ivaskevicius J, et al. Asymptomatic carotid artery stenosis and cognitive outcomes after coronary artery bypass grafting[J]. Scand Cardiovasc J,2011,45(3):169-73
[76]Fudickar A, Peters S, Stapelfeldt C, et al. Postoperative cognitive deficit after cardiopulmonary bypass with preserved cerebral oxygenation:a prospective observational pilot study[J]. BMC Anesthesiol,2011,11:7
[77]Twomey C, Corrigan M, Burlacu C, et al. Nitric oxide index is not a predictor of cognitive dysfunction following laparotomy[J]. J Clin Anesth,2010, 22(1):22-8
[78]Bryson GL, Wyand A. Evidence-based clinical update:general anesthesia and the risk of delirium and postoperative cognitive dysfunction[J]. Can J Anaesth, 2006,53(7):669-77
[79]Cohendy R, Brougere A, Cuvillon P. Anaesthesia in the older patient[J]. Curr Opin Clin Nutr Metab Care,2005,8(1):17-21
[80]Fong HK, Sands LP, Leung JM. The role of postoperative analgesia in delirium and cognitive decline in elderly patients:a systematic review[J]. Anesth Analg,2006,102(4):1255-66
[81]Vizcaychipi MP, Lloyd DG, Wan Y, et al. Xenon pretreatment may prevent early memory decline after isoflurane anesthesia and surgery in mice[J]. PLoS One, 2011,6(11):e26394
[82]Cai ZY, Yan Y, Chen R. Minocycline reduces astrocytic reactivation and neuroinflammation in the hippocampus of a vascular cognitive impairment rat model[J]. Neurosci Bull,2010,26(1):28-36
[83]Fan L, Wang TL, Xu YC, et al. Minocycline may be useful to prevent/treat postoperative cognitive decline in elderly patients[J]. Med Hypotheses,2011,76(5): 733-6
[84]Djaiani G, Katznelson R, Fedorko L, et al. Early benefit of preserved cognitive function is not sustained at one-year after cardiac surgery:a longitudinal follow-up of the randomized controlled trial[J]. Can J Anaesth,2012,59(5):449-55
[85]Schwarz N, Schonburg M, Kastaun S, et al. Cognitive deterioration after cardiosurgery[J].Nervenarzt,2011,82(2):190,192-7
[86]Ge YY, Xu Y, Cheng JQ, et al. Case-control study on the effect of ulinastatin on postoperative complications in elderly patients undergoing hip joint replacement[J]. Zhongguo Gu Shang,2011,24(6):459-62
[87]Wang Y, Sands LP, Vaurio L, et al. The effects of postoperative pain and its management on postoperative cognitive dysfunction[J]. Am J Geriatr Psychiatry,2007, 15(1):50-9
[1]Kawai T and Akira S. TLR signaling[J]. Cell Death Differ,2006,13(5): 816-25
[2]Valanne S, Wang JH, Ramet M. The Drosophila toll signaling pathway[J]. J Immunol,2011,186(2):649-56
[3]Okun E, Griffioen KJ, Lathia JD, et al. Toll-like receptors in neurodegeneration[J]. Brain Res Rev,2009; 59(2):278-92
[4]Leulier F, Lemaitre B. Toll-like receptors:taking an evolutionary approach[J]. Nat Rev Genet,2008,9(3):165-178
[5]Matam Vijay-Kumar, Jesse D. Aitken, Frederic A. Carvalho, et al.Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5[J]. Science, 2010,328(5975):228-31
[6]Gerondakis S, Grumont RJ, Banerjee A. Regulating B-cell activation and survival in response to TLR signals[J]. Immunol. Immunol Cell Biol,2007,85(6): 471-5
[7]Chiaki Iwamura and Toshinori Nakayama. Toll-like receptors in the respiratory system:their roles in inflammation[J]. Current Allergy and Asthma Reports,2008,8(1):7-13
[8]Eriksson M, Meadows SK, Basu S, et al. TLRs mediate IFN-gamma production by human uterine NK cells in endometrium[J]. J Immunol,2006,176(10): 6219-24
[9]Roger Sutmuller, Anja Garritsen, and Gosse J Adema. Regulatory T cells and n toll-like receptors:regulating the regulators[J]. Ann Rheum Dis.2007,66(3):91-5
[10]Kaisho T and Akira S. Toll-like receptor function and signaling[J]. J Allergy Clin Immunol,2006,117(5):979-87
[11]Sabroe I, Whyte MK. Toll-like receptor (TLR)-based networks regulate neutrophilic inflammation in respiratory disease[J]. Biochem Soc Trans,2007,35(6): 14-95
[12]Tomohiro Yoshimoto and Kenji Nakanishi. Roles of IL-18 in basophils and mast cells[J]. Allergology International,2006,55:105-13
[13]Gibson FC 3rd, Ukai T, Genco CA. Engagement of specific innate immune signaling pathways during Porphyromonas gingival is induced chronic inflammation and atherosclerosis[J]. Front Biosci,2008,13:2041-59
[14]Julie K. Olson and Stephen D. Miller. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs[J]. J Immunol, 2004,173:3916-24
[15]Bowman CC, Rasley A, Tranguch SL, et al. Cultured astrocytes express toll-like receptors for bacterial products[J]. Glia,2003,43(3):281-91
[16]Aravalli RN, Peterson PK, Lokensgard JR. Toll-like receptors in defense and damage of the central nervous system[J]. J Neuroimmune Pharmacol.2003,2(4): 297-312
[17]Tang SC, Arumugam TV, Xu X, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits[J]. Proc Natl Acad Sci U.S.A, 2007,104(34):13798-803
[18]Uematsu S, Fujimoto K, Jang MH, et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5[J]. Nat Immunol,2008,9(7):769-76
[19]Smith KD, Andersen-Nissen E, Hayashi F, et al. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility[J]. Nat Immunol,2003,4(12):1247-53
[20]Kucera K, Koblansky AA, Saunders LP, et al. Structure-based analysis of Toxoplasma gondii profilin:a parasite-specific motif is required for recognition by Toll-like receptor 11[J]. J Mol Biol,2010,403(4):616-29
[21]Miyake, K. Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors[J]. Semin Immunol,2007,19(1):3-10
[22]Schon MP, Schon M. TLR7 and TLR8 as targets in cancer therapy[J]. Oncogene,2008,27(2):190-9
[23]Pandey S, Agrawal DK. Immunobiology of Toll-like receptors:emerging trends[J]. Immunol Cell Biol,2006,84(4):333-41
[24]Lehnardt S, Schott E, Trimbuch T, et al. A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS[J]. J Neurosci,2008,28(10):2320-31
[25]Liu Y, Chen GY, Zheng P. CD24-Siglec G/10 discriminates danger-from pathogen-associated molecular patterns[J]. Trends Immunol,2009,30(12):557-61
[26]Shimada M, Yanai Y, Okazaki T, et al. Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine/chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization[J]. Development,2008,135(11):2001-11
[27]Hemmi H, Akira S. TLR signalling and the function of dendritic cells[J]. Chem Immunol Allergy,2005,86:120-35
[28]Gorina R, Font-Nieves M, Marquez-Kisinousky L, et al. Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NF-κB signaling, MAPK, and Jakl/Statl pathways[J]. Glia,2011, 59(2):242-55
[29]Jung DY, Lee H, Jung BY, et al. TLR4, but not TLR2, signals autoregulatory apoptosis of cultured microglia:a critical role of IFN-beta as a decision maker[J]. J Immunol,2005,174(10):6467-76
[30]Divanovic S, Trompette A, Atabani SF, et al. Inhibition of TLR-4/MD-2 signaling by RP105/MD-1[J]. J Endotoxin Res,2005,11(6):363-8
[31]Mattson MP, Maudsley S, Martin B. A neural signaling triumvirate that influences ageing and age-related disease:insulin/IGF-1, BDNF and serotonin[J]. Ageing Res Rev,2004,3(4):445-64
[32]Mattson MP, Barger SW, Begley JG, et al. Calcium, free radicals, and excitotoxic neuronal death in primary cell culture[J]. Methods Cell Biol,1995,46: 187-216
[33]Mattson MP, Goodman Y, Luo H, et al. Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis:evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration[J]. J Neurosci Res,1997,49(6):681-97
[34]Lathia JD, Rao MS, Mattson MP, et al. The microenvironment of the embryonic neural stem cell:lessons from adult niches? [J] Dev Dyn,2007,236(12): 3267-82
[35]Xin Duan, Eunchai Kang, Cindy Y Liu, et al. Development of neural stem cell in the adult brain[J]. Curr Opin Neurobiol,2008,18(1):108-15
[36]Lathia JD, Okun E, Tang SC, et al. Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation[J]. J Neurosci,2008, 28,(51):13978-84
[37]Okun E, Griffioen KJ, Son TG, et al. TLR2 activation inhibits embryonic neural progenitor cell proliferation[J]. J Neurochem,2010,114(2):462-74
[38]Rolls A, Shechter R, London A, et al. Toll-like receptors modulate adult hippocampal neurogenesis[J]. Nat Cell Biol,2007,9(9):1081-8
[39]Shechter R, Ronen A, Rolls A, et al. Toll-like receptor 4 restricts retinal progenitor cell proliferation[J]. J Cell Biol,2008,183(3):393-400
[40]Covacu R, Arvidsson L, Andersson A, et al. TLR activation induces TNF-alpha production from adult neural stem/progenitor cells[J]. J Immunol,2009, 182(11):6889-95
[41]Sloane JA, Batt C, Ma Y, et al. Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2[J]. Proc Natl Acad Sci U S A, 2010,107(25):11555-60
[42]Okun E, Griffioen K, Barak B, et al. Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis[J]. Proc Natl Acad Sci U S A, 2010,107(35):15625-30
[43]Ma Y, Li J, Chiu I, et al. Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis[J]. J Cell Biol,2006, 175(2):209-15
[44]Ma Y, Haynes RL, Sidman RL, et al. TLR8:an innate immune receptor in brain, neurons and axons[J]. Cell Cycle,2007,6(23):2859-68
[45]Cameron JS, Alexopoulou L, Sloane JA, et al. Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals[J]. J Neurosci,2007,27(47): 13033-41
[46]Acosta C, Davies A. Bacterial lipopolysaccharide regulates nociceptin expression in sensory neurons[J]. J Neurosci Res,2008,86(5):1077-86
[47]Iliev Al, Stringaris AK, Nau R, et al. Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9) [J]. FASEB J,2003,18(2):412-4
[48]Okun E, Lathia JD, Mattson MP. Adhesion-and migration-related side effects of phosphothioated CpG oligodeoxynucleotides. Cell Adh Migr,2009,3(3): 272-4
[49]Okun E, Mattson MP. Phosphothioated oligodeoxynucleotides induce nonspecific effects on neuronal cell adhesion in a growth substrate-dependent manner[J]. J Neurosci Res,2009,87(8):1947-52
[50]Trudler D, Farfara D, Frenkel D. Toll-like receptors expression and signaling in glia cells in neuro-amyloidogenic diseases:towards future therapeutic application[J]. Mediators Inflamm,2010, DOI:10.1155/2010/497987
[51]Kariko K, Ni H, Capodici J, et al. mRNA is an endogenous ligand for Toll-like receptor 3[J]. J Biol Chem,2004,279(13),12542-50
[52]Bsibsi M, Bajramovic JJ, Vogt MH, et al. The microtubule regulator stathmin is an endogenous protein agonist for TLR3[J], J Immunol,2010,184(12): 6929-37
[53]Yirmiya R, Goshen I. Immune modulation of learning, memory, neural plasticity and neurogenesis[J]. Brain Behav Immun,2011,25(2):181-213
[54]Howard L. Weiner, Dan Frenkel. Immunology and immunotherapy of Alzheimer's disease[J]. Nat Rev Immunol,2006,6:404-16
[55]Tanaka S, Ide M, Shibutani T, et al. Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats[J]. J Neurosci Res,2006,83(4):557-66
[56]Palin K, Bluthe RM, McCusker RH, et al. The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFalpha-induced sickness behavior[J]. Psychopharmacology,2009,201(4):549-56
[57]Tauber SC, Ebert S, Weishaupt JH, et al. Stimulation of Toll-like receptor 9 by chronic intraventricular unmethylated cytosine-guanine DNA infusion causes neuroinflammation and impaired spatial memory[J]. J Neuro pathol Exp Neurol,2009, 68(10):1116-24
[58]Stefan Bauer, Thomas Muller, Svetlana Hamm. Pattern recognition by Toll-like receptors[J]. Adv Exp Med Biol,2009,653:15-34
[59]Schaffler A, Scholmerich J. Innate immunity and adipose tissue biology[J]. Trends Immunol,2010,31(6):228-35
[60]Lehnard t, S. Innate immunity and neuroinflammation in the CNS:the role of microglia in Toll-like receptor-mediated neuronal injury[J]. Glia,2010,58(3): 253-63
[61]Suh HS, Brosnan CF, Lee SC. Toll-like receptors in CNS viral infections [J]. Curr Top Microbiol Immunol,2009,336:63-81
[62]Baker BJ, Park KW, Qin H, et al. IL-27 inhibits OSM-mediated TNF-alpha and iNOS gene expression in microglia[J]. Glia,2010,58(9):1082-93
[63]Bsibsi M, Persoon-Deen C, Verwer RW, et al. Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators[J]. Glia,2006, 53(7):688-95
[64]Kim H, Yang E, Lee J, et al. Double-stranded RNA mediates interferon regulatory factor 3 activation and interleukin-6 production by engaging Toll-like receptor 3 in human brain astrocytes[J]. Immunology,2008,124(4):480-8
[65]Klein M, Obermaier B, Angele B, et al. Innate immunity to pneumococcal infection of the central nervous system depends on toll-like receptor (TLR) 2 and TLR4[J]. J Infect Dis,2008,198(7):1028-36
[66]S(?)rensen LN, Reinert LS, Malmgaard L, et al. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain[J]. J Immunol,2008, 181(12):8604-12
[67]Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis[J]. Science,2007,317(5844):1522-7
[68]Wang T, Town T, Alexopoulou L, et al. Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis[J]. Nat Med,2004,10(12): 1366-73
[69]Daffis S, Samuel MA, Suthar MS, et al. Toll-like receptor 3 has a protective role against West Nile virus infection[J]. J Virol,2008,82(21):10349-58
[70]Szretter KJ, Daffis S, Patel J, et al. The innate immune adaptor molecule MyD88 restricts West Nile virus replication and spread in neurons of the central nervous system[J]. J Virol,2010,84(23):12125-38
[71]Szretter KJ, Samuel MA, Gilfillan S, et al. The immune adaptor molecule SARM modulates tumor necrosis factor alpha production and microglia activation in the brainstem and restricts West Nile Virus pathogenesis[J]. J Virol,2009,83(18): 9329-38
[72]O'Neill LA. DisSARMing Toll-like receptor signaling[J]. Nat Immunol, 2006,7(10):1023-25
[73]Erridge C. Endogenous ligands of TLR2 and TLR4:agonists or assistants? [J] J Leukoc Biol,2010,87(6):989-99
[74]Boksa P. Effects of prenatal infection on brain development and behavior:a review of findings from animal models[J]. Brain Behav Immun,2010,24(6):881-97
[75]Caso JR, Pradillo JM, Hurtado O, et al. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke[J]. Circulation,2007, 115(12):1599-08
[76]Hua F, Ma J, Ha T, et al. Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion[J]. J Neuroimmunol,2007,190(1-2):101-11
[77]Lehnardt S, Lehmann S, Kaul D, et al. Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia[J]. J Neuroimmunol,2007,190(1-2):28-33
[78]Kilic U, Kilic E, Matter CM, et al. TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration[J]. Neurobiol Dis,2008, 31(1):33-40
[79]Hyakkoku K, Hamanaka J, Tsuruma K, et al. Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia[J]. Neuroscience,2010,171(1):258-67
[80]Pradillo JM, Fernandez-Lopez D, et al. Toll-like receptor 4 is involved in neuroprotection afforded by ischemic preconditioning[J]. J Neurochem,2009,109(1): 287-94
[81]Yang QW, Lu FL, Zhou Y, et al. HMBG1 mediates ischemia-reperfusion injury by TRIF-adaptor independent Toll-like receptor 4 signaling[J]. J Cereb Blood Flow Metab,2010,31(2):593-605
[82]Park C, Cho IH, Kim D, et al. Toll-like receptor 2 contributes to glial cell activation and heme oxygenase-1 expression in traumatic brain injury [J]. Neurosci Lett,431(2):123-8
[83]Clark AK, Staniland AA, Marchand F, et al. P2X7-dependent release of interleukin-lbeta and nociception in the spinal cord following lipopolysaccharide[J]. J Neurosci,2010,30(2):573-82
[84]Liu T, Xu ZZ, Park CK, et al. Toll-like receptor 7 mediates pruritus[J]. Nat Neurosci,2010,13(12):1460-2
[85]Mattson, MP. Pathways towards and away from Alzheimer's disease[J]. Nature,2004,430(7000):631-9
[86]Richard KL, Filali M, Prefontaine P, et al. Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease[J]. J Neurosci,2008,28(22): 5784-93
[87]Tahara K, Kim HD, Jin JJ, et al. (2006) Activation of Toll-1 ike receptor 2 on microglia promotes cell uptake of Alzheimer dise ase-associated amyloid beta peptide[J]. J Biol Chem,2006,281(6):3651-9
[88]Tahara, K. et al. Role of toll-like receptor signalling in Abeta uptake and clearance[J]. Brain,2006,129 (Pt 11):3006-19
[89]Reed-Geaghan EG, Savage JC, Hise AG, et al. CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation[J]. J Neurosci,2009,29(38):11982-92
[90]Doi Y, Mizuno T, Maki Y, et al. Microglia activated with the toll-like receptor 9 ligand CpG attenuate oligomeric amyloid {beta} neurotoxicity in in vitro and in vivo models of Alzheimer's disease[J]. Am J Pathol,2009,175(5):2121-32
[91]Scholtzova H, Kascsak RJ, Bates KA, et al. Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology[J]. Neurosci.2009,29(6):1846-54
[92]Jin JJ, Kim HD, Maxwell JA, et al. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease[J]. J Neuroinflammation,2008,5:23
[93]Walter S, Letiembre M, Liu Y, et al. Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease[J]. Cell Physiol Biochem,2007,20(6): 947-56
[94]Tang SC, Lathia JD, Selvaraj PK, et al. Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal[J]. Exp Neurol,2008,213(1):114-21
[95]Minoretti P, Gazzaruso C, Vito CD, et al. Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset Alzheimer's disease[J]. Neurosci Lett,2006,391(3):147-9
[96]Soulika AM, Lee E, McCauley E, et al. Initiation and progression of axonopathy in experimental autoimmune encephalomyelitis[J]. J Neurosci,2009, 29(47):14965-79
[97]Marta M, Andersson A, Isaksson M, et al. Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis[J]. Eur J Immunol, 2008,38(2):565-75
[98]Prinz M, Garbe F, Schmidt H, et al. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis[J]. J Clin Invest, 2006,116(2):456-64
[99]Ellestad KK, Tsutsui S, Noorbakhsh F, et al. Early life exposure to lipopolysaccharide suppresses experimental autoimmune encephalomyelitis by promoting tolerogenic dendritic cells and regulatory T cells[J]. J Immunol,2009, 183(1):298-09
[100]Herrmann I, Kellert M, Schmidt H, et al. Streptococcus pneumoniae Infection aggravates experimental autoimmune encephalomyelitis via Toll-like receptor 2[J], Infect Immun,2006,74(8):4841-8
[101]Farez MF, Quintana FJ, Gandhi R, et al. Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE[J]. Nature Immunol,2009,10(9):958-64
[102]Meyer U, Feldon J, Yee BK. A review of the fetal brain cytokine imbalance hypothesis of schizophrenia[J]. Schizophr Bull,2009,35(5):959-72
[103]Salaria S, Badkoobehi H, Rockenstein E, et al. Toll-like receptor pathway gene expression is associated with human immunodeficiency virus-associated neurodegeneration[J]. J Neurovirol,2007,13(6):496-503
[104]Marta M, Meier UC, Lobell A. Regulation of autoimmune encephalomyelitis by toll-like receptors[J]. Autoimmun Rev,2009,8(6):506-9