绞股蓝皂甙干预慢性脑缺血性大鼠认知功能障碍的实验研究
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摘要
随着老龄化社会的到来，老年期痴呆已逐渐成为一个重要的医疗和社会问题。老年期痴呆主要由阿尔茨海默病（AD,Alzheimer’s disease）和血管性痴呆（VD,vascular dementia）这两种血管性相关疾病构成。血管性痴呆(VD)的发病率，各国报告不完全一致。据WHO统计，欧美的痴呆以AD为多，约占全部痴呆的50%－60%，VD仅占10%-20%，其他原因导致的痴呆占30%。我国和日本的情况相似，其中VD占62%，其它占38%，提示VD是我国老年性痴呆的主要组成部分。血管性痴呆的主要临床表现：记忆力、执行力、信息处理下降，以及行为、情绪异常。血管性痴呆发病机制十分复杂，各种原因引起的脑动脉硬化、狭窄或闭塞，使脑组织慢性缺血，神经细胞代谢率下降，兴奋性降低，引起脑思维过程迟缓，认知能力下降。以往研究表明脑血流下降程度与痴呆的严重程度密切相关，尤易是缺血累海马及前额叶皮质下环路。目前,对血管性痴呆的治疗，临床上暂无特效药物。本实验通过对大鼠双侧颈总动脉永久性结扎，建立血管性痴呆大鼠模型。通过Morris水迷宫、生化检测、HE染色、勒克司坚牢蓝染色、免疫组织化学染色、免疫印迹分析，研究绞股蓝皂甙（GP）对血管性痴呆模型大鼠皮质、海马、胼胝体及视束缺血性损伤的保护作用，探讨其在血管性痴呆大鼠治疗中的影响。研究结果发现血管性痴呆模型大鼠皮层、海马、胼胝体及视束中MDA、TNF-α、IL-６含量增加，SOD下降，8-OHdG、4-HNE、GFAP~+标记阳性细胞明显增多，血管性痴呆模型大鼠皮层、海马、胼胝体及视束组织形态学受到损伤，学习记忆能力下降。绞股蓝皂能够降低血管性痴呆模型大鼠皮层、海马、胼胝体及视束中MDA、TNF-α、IL-６含量，提高SOD含量，抑制8-OHdG、4-HNE、GFAP+抗体表达，GP对血管性痴呆模型大鼠皮层、海马、胼胝体及视束具有神经保护作用，并且能改善血管性痴呆模型大鼠的学习记忆能力，提示GP对血管性痴呆有潜在的治疗效果，未来有可能成为一种有效的治疗血管性痴呆药物。
Senile dementia has become an increasingly important medical and socialproblem as a result of the increasing size of the elderly population. Alzheimer’sdisease (AD) and vascular dementia (VD), which are also vascular dysfunctiondiseases, are the two main types of dementia prevalent in the elderly population.For the incidence of vascular dementia (VD), different report results are notcompletely the same. According to WHO statistics, in Europe and America, ADis given priority to VD, VD accounts for about50%-60%of dementia that areprevalent in the elderly population, VD accounts for10%-20%, other types ofdementia accounts for30%. However, in Japan, the incidence of vasculardementia is different, VD accounts for about62%of dementia that are veryprevalent in the elderly population, other types of dementia accounts for10%-20%. The case of vascular dementia in china is similar to that in Japan, VDis the primary types of dementia that are very prevalent in the elderly population.The major clinical manifestations of VD include prominent loss in memory,difficulty in following instructions, lack of verbal fluency, a slowing of theprocessing ability and hampered abstract thinking. VD pathogenesis is very complicated, the formation of cerebral arteriosclerosis, intracranial vascularnarrow or block cause the hypoperfusion of brain tissue, which also lead to thereduction of the central nerve cells metabolism, excitability, the slow of brainthinking process, the cognitive decline. It was reported that the decrease incerebral blood flow relates to the cognitive impairment found in AD and VD, theseverity of the cognitive impairment is closely related to the degree of thedecrease in cerebral blood flow, especially when the hippocampus and prefrontalcortex loop appear ischemic changes. At present, there is no effective drugtreatment for vascular dementia. We aimed to establish the vascular dementiamodel in the rat with the permanen bilateral carotid artery ligation. We used a ratmodel of chronic cerebral hypoperfusion, with the application of the Morriswater maze tests, biochemical examinations,, HE dying, Luxol fast blue staining,immunohistochemical assays and Western blotting analysis, to investigate theprotective effects of GP on the cortex, hippocampal CA1region, corpuscallosum and optic tract, and the underlying mechanisms for its inhibition ofcognitive decline. In the present study, we found that the MDA, TNF-α and IL-６contents are significantly increased in the hypoperfused saline groupcompared to the sham-operated group, but the SOD activity in the hypoperfusedsaline group was significantly decreased after chronic cerebral hypoperfusion;the4-HNE,8-OHdG and GFAP+positive cells are significantly increased in thehypoperfused saline group. The nomal morphology of organization of the cortex,hippocampal CA1region, corpus callosum and optic tract in rats after chroniccerebral hypoperfusion were damaged, chronic cerebral hypoperfusion alsosignificantly induced memory deficits in the hypoperfused saline group rats. GPgiven at200mg/kg per day markedly attenuated these morphological changes inthe cortex, hippocampal CA1region, corpus callosum and optic tract in rats after chronic cerebral hypoperfusion, Rats receiving200mg/kg GP had betterspatial learning and memory than saline-treated rats. Our results suggest that GPmay have therapeutic potential for the treatment of dementia caused by chroniccerebral hypoperfusion, and may serve as a potential new anti-dementia agent.
Senile dementia has become an increasingly important medical and socialproblem as a result of the increasing size of the elderly population. Alzheimer’sdisease (AD) and vascular dementia (VD), which are also vascular dysfunctiondiseases, are the two main types of dementia prevalent in the elderly population.For the incidence of vascular dementia (VD), different report results are notcompletely the same. According to WHO statistics, in Europe and America, ADis given priority to VD, VD accounts for about50%-60%of dementia that areprevalent in the elderly population, VD accounts for10%-20%, other types ofdementia accounts for30%. However, in Japan, the incidence of vasculardementia is different, VD accounts for about62%of dementia that are veryprevalent in the elderly population, other types of dementia accounts for10%-20%. The case of vascular dementia in china is similar to that in Japan, VDis the primary types of dementia that are very prevalent in the elderly population.The major clinical manifestations of VD include prominent loss in memory,difficulty in following instructions, lack of verbal fluency, a slowing of theprocessing ability and hampered abstract thinking. VD pathogenesis is very complicated, the formation of cerebral arteriosclerosis, intracranial vascularnarrow or block cause the hypoperfusion of brain tissue, which also lead to thereduction of the central nerve cells metabolism, excitability, the slow of brainthinking process, the cognitive decline. It was reported that the decrease incerebral blood flow relates to the cognitive impairment found in AD and VD, theseverity of the cognitive impairment is closely related to the degree of thedecrease in cerebral blood flow, especially when the hippocampus and prefrontalcortex loop appear ischemic changes. At present, there is no effective drugtreatment for vascular dementia. We aimed to establish the vascular dementiamodel in the rat with the permanen bilateral carotid artery ligation. We used a ratmodel of chronic cerebral hypoperfusion, with the application of the Morriswater maze tests, biochemical examinations,, HE dying, Luxol fast blue staining,immunohistochemical assays and Western blotting analysis, to investigate theprotective effects of GP on the cortex, hippocampal CA1region, corpuscallosum and optic tract, and the underlying mechanisms for its inhibition ofcognitive decline. In the present study, we found that the MDA, TNF-α and IL-６contents are significantly increased in the hypoperfused saline groupcompared to the sham-operated group, but the SOD activity in the hypoperfusedsaline group was significantly decreased after chronic cerebral hypoperfusion;the4-HNE,8-OHdG and GFAP+positive cells are significantly increased in thehypoperfused saline group. The nomal morphology of organization of the cortex,hippocampal CA1region, corpus callosum and optic tract in rats after chroniccerebral hypoperfusion were damaged, chronic cerebral hypoperfusion alsosignificantly induced memory deficits in the hypoperfused saline group rats. GPgiven at200mg/kg per day markedly attenuated these morphological changes inthe cortex, hippocampal CA1region, corpus callosum and optic tract in rats after chronic cerebral hypoperfusion, Rats receiving200mg/kg GP had betterspatial learning and memory than saline-treated rats. Our results suggest that GPmay have therapeutic potential for the treatment of dementia caused by chroniccerebral hypoperfusion, and may serve as a potential new anti-dementia agent.
引文
[1]贾建军，王鲁宁，汤洪川.血管性痴呆的发病机制.中华老年心脑血管病杂志.2000;2(2):139-142
[2] DeLa Torre, Jack C. Alzheimers disease is a vasocognopathy: a new termto describe its nature[J]. Neurol Res.2004;26(5):517-524.
[3] Micieli G.Vascular dementia. Neurol Sci.2004;27:37-39.
[4]平井俊策.平成元年度厚生省循环器病研究委托班研究报告集[R].国立循病.1990:80.
[5] Liu HX, Zhang JJ, Zheng P, Zhang Y. Altered expression of MAP-2,GAP-43, and synaptophysin in the hippocampus of rats with chroniccerebral hypoperfusion correlates with cognitive impairment. Brain ResMol Brain Res.2005;139:169-77.
[6]谢玉丰.神经胶质细胞与突触可塑性研究新进展[J].生理科学进展.2007;38:111-114.
[7] Koistinaho M, Koistinaho J. Interactions between Alzheimer's disease andcerebral ischemia focus on inflammation. Brain Res Rev.2005;48:240-250.
[8] Guo M, Cox B, Mahale S, Davis W, Carranza A, Hayes K. Pre-ischemicexercise reduces matrix metalloproteinase-9expression and amelioratesblood-brain barrier dysfunction in stroke. Neuroscience.2008;151:340-351.
[9] Otori T, Katsumata T, Muramatsu H, Kashiwagi F, Katayama Y, TerashiA. Long-term measurement of cerebral blood flow and metabolism in a ratchronic hypoperfusion model. Clin Exp Pharmacol Physiol.2003;30:266–72.
[10]Kumaran D, Udayabanu M, Kumar M, Aneja R, Katyal A. Involvement ofangiotensin converting enzyme in cerebral hypoperfusion inducedanterograde memory impairment and cholinergic dysfunction in rats.Neuroscience.2008;155:626-39.
[11]Humpel C, Marksteiner J. Cerebrovascular damage as a cause forAlzheimer's disease. Curr Neurovasc Res.2005;2:341-7.
[12]Gunstad J, Brickman AM, Paul RH. Progressive morphometrie andcognitive changes in vascular dementia. Arch Clin Neuro psychol.2005;20:229–241.
[13]Dohmen C, Kumura E, Rosner G. Extracellular correlates of glutamatetoxicity in short-term cerebral ischemia and reperfusion: a direct in vivocomparison between white and gray matter. Brain Research.2005;1037:43–51.
[14]Cada A,delaTorre JC, Gonzalez-Lima F. Chronic cerebrovascularischemia in aged rats: Effects on brain metabolic capacity and behavior[J].Neurobiol Aging.2000;21(2):225-233.
[15]Ueda M, Muramatsu H, Kamiya T. Pyruvatedehydrogena,activity,andenergy metabolite levels following bilateral common carotidarteryocclusion in rat brain[J]. Life Sci2000;67(7):821-827.
[16]Chan PH.Reactive oxygen radicals in signaling and damage in theischemic brain [J].Cereb Blood Flow Metab.2001;65(1),21:25.45.姚丹丹,等.绞股蓝对衰老大鼠下丘脑的抗衰老作用研究[J].医学理论与实践,2007,20(10):1119-1120.
[17]Farkas E, Luiten PG,BariF. Permanent,bilateral common carotid arteryocclusion In the rat:a model for chronic cerebral hypoperfusion-relatedneurodegenerative diseases. BrainRes Rev.2007;54:162–80.
[18]Cui J, Holmes EH, Greene TG,et al·Oxidative DNA damage precedes DNAfragmentation after experimental stroke in rat brain[J].FASEB J.2000;14(7):955-6.
[19]InalF, GunesO, EraslanA,etal·Changes in antioxidative system andmembrane damage of lettuce in response to salinity and borontoxicity[J].Scientia Horticulturae.2007;114:5-10·
[20]Solaroglu I, Solaroglu A, Kaptanoglu E,et al·Erythropoietin preventsischemia-reperfusion from inducing oxidative damage in fetal rat brain[J].Child Nerv Syst.2003;19:19-22·
[21]Deguchi K, Hayashi T, Nagotani S, Sehara Y, Zhang H, Tsuchiya A.Reduction of cerebral infarction in rats by biliverdin associated withamelioration of oxidative stress. Brain Res.2008;1188:1–8.
[22]de la Torre JC, Aliev G. Inhibition of vascular nitric oxide after rat chronicbrain hypoperfusion: spatial memory and immunocytochemical changes. JCereb Blood Flow Metab.2005;25:663-72.
[23]Hamel E, Nicolakakis N, Aboulkassim T, Ongali B, Tong XK. Oxidativestress and cerebrovascular dysfunction in mouse models of Alzheimersdisease. Exp Physiol.2008;93:116-20.
[24]Hallenbeck JM. The many faces of tumor necrosis factor in stroke. NatMed,2002;8:1363-8.
[25]Huang L, He Z, Guo L, Wang H. Improvement of cognitive deficit andneuronal damage in rats with chronic cerebral ischemia via relativelong-term inhibition of rho-kinase. Cell Mol Neurobiol.2008;28:757-68.
[26]Kim JS, Yun IJ, Choi YB, Lee KS, Kim YI. Ramipril protects from freeradical induced white matter damage in chronic hypoperfusion in the rat.Journal of Clinical Neuroscience.2008;15:174-178.
[27]O'Callaghan JP, Sriram K. Glial fibrillary acidic protein and related glialproteins as biomarkers of neurotoxicity. Expert Opin DrugSaf.2005;4:433-42.
[28]Shibata M, Ohtani R, Ihara M. Tomimoto,H.,.White matter lesions andglial activation in a novel mouse model of chronic cerebral hypoperfusion.Stroke.2004;35:2598-2603.
[29]Tateishi N, Mori T, Kagamiishi Y. Astrocytic activation and delayedinfarct expansion after permanent focal ischemia in rats. Part II:suppression of astrocytic activation by a novel agent(R)-(-)-2-propyloctanoic acid (ONO-2506) leads to mitigation of de-layedinfarct expansion and early improvement of neurologic deficits. J CerebBlood Flow Metab.2002;22:723-734.
[30]Vicente é, Degerone D, Bohn L, Francisco S, Pimentel A, Leite MC,Swarowsky A, Rodrigues L, Nardin P, de Gottfried C, Souza DO, NettoCA, Alberto Gon alves CA. Astroglial and cognitive effects of chroniccerebral hypoperfusion in the rat. Brain R.2009;1251:204-212.
[31]von Bernhardi R. Glial cell dysregulation: a new perspective on Alzheimerdisease. Neurotox Res.2007;12,215-32.
[32]Liu C, Wu J, Gu J, Xiong Z, Wang F, Wang J, et al. Baicalein improvescognitive deficits induced by chronic cerebral hypoperfusion in rats.Pharmacol Biochem Behav.2007,86:423-30.
[33]de la Torre JC. Is Alzheimer’s a neurodegenerative or a vascular disorder?Data, dogma and dialectics. Lancet Neurol.2004;3:184–190.
[34]李瑞岭,高南南,亚少敏,等.绞股蓝的药理和临床研究.中医药研究.1996,(5):55-57.
[35]姚丹丹,等.绞股蓝对衰老大鼠下丘脑的抗衰老作用研究[J].医学理论与实践,2007,20(10):1119-1120.
[36]肖东,顾振纶,钱曾年,等.绞股蓝的药理作用.中成药研究.1992;14(1):36-38.
[37]王旭平,等.绞股蓝总苷对谷氨酸诱导的胎鼠大脑皮层神经元氧化性损伤保护机制的研究[J].山东大学学报(医学版).2006;44(6):564-567.
[38]张莉,等.绞股蓝总皂苷对血管性痴呆大鼠大脑皮层及海马的影响[J].中草药研究.2002;33(4):330-331.
[39]韦登明,饶广勋,扬文辉.绞股蓝总甙对实验性脑缺血损伤的保护作用[J].中药药理与临床.2005;21(1):20-22.
[40]Vagnucci AH, Li WW. Alzheimer’s disease and angiogenesis [J].Lancet.2003;361(9357):605-608.
[41]Royall DR. Alzheimer disease as a vascular disorder: nosological evidence.Stroke.2002;33:2147-8.
[42]Zlokovic BV. Vascular disorder in Alzheimer's disease: role inpathogenesis of dementia and therapeutic targets. Adv Drug DelivRev.2002;54:1553-9.
[43]von Bernhardi R Immunotherapy in Alzheimer's disease: where do westand? Where should we go? J Alzheimers Dis.2010;19:405-21.
[44]CASTRO Jessiea, MOLANO Ana, ZARRANZ Juan Jose etal. Prevalenceof neuropsyehiatrie symptoms in Alzheimer's disease and vasculardementia[J].Cur:Alzheimer Res.2008;5(l):61-69.
[45]叶翠飞，白容，刘汇波等.双侧颈总动脉结扎对大鼠学习记忆相关脑区血流量的影响.中国实验动物学报.1999;7(1):23-25
[46]Sarti, C, Pantoni, L, Bartolini, L, Inzitari, D. Persistent impairment of gaitperformances and working memory after bilateral common carotid arteryocclusion in the adult Wistar rat. Behav. Brain Res.2002;136,13-20.
[47]Otori T, Katsumata T, Muramatsu H, Kashiwagi F, Katayama Y, Terashi A.Long-term measurement of cerebral blood flow and metabolism in a ratchronic hypoperfusion model. Clin Exp PharmacolPhysiol.2003;30:266-72.
[48]Sarti C, Pantoni L, Bartolini L, et al. Cognitive impairment and chroniccerebral hypoperfusion: what can be learned from experimental models [J].J Neurol Sci.2002;204(15):263-266.
[49] M,et al. A new model of bilateral hemispheric ischmia in the ratthree vessel occlusion model[J].Stroke.1985;16:489-495.
[50]Pulsinelli WA，Brierley JB.A new model of bilateral hemispheric ischemiain the unanesthetized rat[J].Stroke.1979;10(3):267-269.
[51]李胜，雷征霖.大鼠大脑中动脉区局灶性脑缺血模型[J].国外医学.脑血管疾病分册.1998;6(1):3-6
[52]Watson BD.Induction of reproducible brain infarction by photochemicallyinitiated thrombosis[J].Ann Neurol.1985;17:497-501.
[53]陈俊抛，田时周，于薇薇等.多发性脑梗塞痴呆动物模型的研究.中华神经精神科杂志.1994;27(5):311-317.
[54]唐启盛，黄启福，郭建文.高脂血症大鼠缺血再灌流诱发行为学障碍模型的实验研究.北京中医药大学学报.1997;20(5):34-36.
[55] Cheng KC, Cahill DS, Kasai H.8-Hy-droxyguanine, an abundant form ofoxidative DNA damage, causes G-T and A-C substitutions. J BiolChem.1992;267:166-172.
[56]Chong ZZ, Li F, Maiese K. Oxidative stress in the brain: novel cellulartargets that govern survival during neurodegenerative disease. ProgNeurobiol2005;75:207-46.
[57]Aliev, G., Smith, M.A., Obrenovich, M.E., de la Torre, J.C., Perry, G.,Role of vascular hypoperfusion-induced oxidative stress and mitochondriafailure in the pathogenesis of Alzheimer disease. Neurotox. Res.2003；5：491-504.
[58]Saito H，Togashi H，Yoshioka M，etal.Animal model of vascular dementiawith emphasis on stroke-prone spontaneously hypertension rats[J].Clin.Exp. Pharmacol.Physiol.1995;22:257-259.
[59]CJover T, McCulloch J, Dewar D. The lipid peroxidation by-product4-hydroxynonenal is toxic to axons and oligodendrocytes. J Cereb BloodFlow Metab.2000;20:1529-36.
[60]Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E,Vescovi A, Bagetta G, Kollias G,Meldolesi J, Volterra A.CXCR4-activated astrocyte glutamate release via TNF alpha:amplificationby microglia triggers neurotoxicity. NatNeurosci.2001;4:702-10.
[61]Chamorro, A, Hallenbeck, J. The harms and benefits of inflammatory andimmune responses in vascular disease. Stroke.2006,37,291-293.Vargas MR, Pehar M, Cassina P, et al. Stimulation of nerve growth factorexpression in astrocytes by peroxynitrite. In Vivo.2004;18(3):269-274.
[62]Meeuwsen S, BsibsiM, Pers oon Deen C, et al. Cultured human adultmicroglia from different donors display stable cytokine, chemokine andgrowth factor gene Profilesbut respond differently to aproinflammatorystimulus[J]. Neuroimmunomo dulation,2005,12(4):235-245.
[63]Morioka T, Kalehua AN, Streit WJ. Progressive expression ofimmunomolecules on microglia cells in rat dorsalhippocampus followingtransient forebrain ischemia[J]. Acta Neuropatho,1992,83:149-157.
[64] Streit WJ,Walter SA,Pennell NA. Reactive microgliosis[J]. ProgNeurobiol,1999,57(6):563-581.
[65]Von Bernhardi R. Participation of glial cells in the pathogenesis of AD: adifferent view on neuroinflammation. Biomedical and Life Sciences2009;4:1-18.
[66]Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. JNeuroimmunol,2007,184:53-68.
[67] Badan I, Buchhold B, Hamm A, Gratz M, Walker LC, Platt D. Acceleratedglial reactivity to stroke in aged rats correlates with reduced functionalrecovery. J of Cerebral Blood Flow&Metabolism,2003;23:845-854..
[68]Yancopoulos GD, Davis S, Gate NW,et al. Vascular specific growth factorsand blood vessel formation [J].Nature,2000,407(14):242-247.
[69]Leonoudakis D, Braithwaite SP, Beattie MS, Beattie EC. TNFalpha-induced AMPA-receptor trafficking in CNS neurons; relevance toexcitotoxicity? Neuron Glia Biol,2004;1:263-73.
[70]Ridet Jl, Malhotra SK, Privat A, et al. Reactive astrocytes: cellulr andmolecular cues to biological funtion[J].Trends Neurosxi,2006,20:570-577.
[71]Shibata, M, Ohtani, R, Ihara,M, Tomimoto,H.White matter lesions andglial activation in a novel mouse model of chronic cerebral hypoperfusion.Stroke,2004,35,2598–2603.
[72]Maragakis NJ, Rothstein JD. Mechanisms of disease: astrocytes inneurodegenerative disease. Nat. Clin. Pract.Neurol,2006;2:679–689.
[73]Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive astrocytes: cellularand molecular cues to biological function. Trends Neurosci,1997,20:570-577.
[74]Norris, CM, Kadish, I, Blalock, EM, Chen, KC, Thibault, V,Porter, NM,Landfield, PW, Kraner, SD. Calcineurin triggers reactive/inflammatoryprocesses in astrocytes and is upregulated in aging and Alzheimer's models.J. Neurosci.2005,25:4649-4658.
[75]O'Callaghan, JP, Sriram, K. Glial fibrillary acidic protein and related glialproteins as biomarkers of neurotoxicity. Expert Opin. Drug Saf.2005,4:433-442.
[76]Chen Yong, Hallenbeck, John M, et al. Overexpression of MonocyteChemoat t ractant Protein1in t he Brain Exacer bates Ischemic BrainInjury and Is Associated With Recruitment of Inflammatory Cells [J].Journal of Cerebral Blood Flow&Metabolism.2003,23(6):748-755.
[77]Hanisch U K. Microglia as a source and target of cytokines [J]. Glia.2002,40:140-155.
[78]Gdel Zoppo, I. Ginis, JM. Hallenbeck, C. Iadecola, X. Wang,GZ.Feuerstein, Inflammation and troke: putative role forcytokines,adhesion molecules and iNOS in brain response toischemia.Brain Pathol.2000,10:95-112.
[79]J Yrjanheikki, R Keinnen, M Pellikka, THfkfelt, J Koistinaho.Tetracyclines inhibit microglial ctivation and are neuroprotective inglobalbrain ischemia, Proc. Natl. Acad. Sci. U. S. A.1998,5:15769-15774.
[80]H. Akiyama, T. Arai, H. Kondo, E. Tanno, C. Haga, K. Ikeda, Cellmediators of inflammation in the Alzheimer disease brain, Alzheimer Dis.Assoc. Disord.2000;14:47-53.
[81]Gregersen R., Lambertsen K. and Finsen B. Microglia and macrophagesare the major source of tumor necrosis factor in permanent middle cerebralartery occlusion in mice. J. Cereb.Blood Flow Metab,2000,20:53-65.
[82]Rossi DJ，Oshima T，Attwell D.Glutamate release in severe brain ischaemiais mainly by reversed uptake[J].Nature.2000;403(6767):316-321.
[83]Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA. Peroxynitritegenerated by inducible nitric oxide synthase and NADPHoxidase mediatesmicroglial toxicity to oligodendrocytes. Proc Natl Acad Sci USA,2005,102:9936–9941.
[84]Iadecola C. Neurovascular regulation in the normal brain and inAlzheimer’s disease.Nat Rev Neurosci2004;5:347–360.
[85]Imai H, Masayasu H, Dewar D, Graham DI, Macrae IM. Ebselen protectsboth gray and white matter in a rodent model of focal cerebral ischemia.Stroke2001;32:2149–54.
[86]Farkas E, Luiten PG. Cerebral microvascular pathology in aging andAlzheimer'sdisease. Prog Neurobio,2001;64:575-611
[87]Fagan SC, Hess DC, Hohnadel EJ, Pollock DM, Ergul A. Targets forvascular protection after acute ischemic stroke. Stroke,2004,35:2220-5.
[88]Ni JW, Matsumoto K, Li HB,et al. Neuronal damage and decrease ofCentral Acetylcholine level following permanent occlusion of bilateralcommon carotid arteries in rat[J]. Brain Res,1995,673(2):290-296.
[89]Otori T, Katsumata T, Katayama Y, Terashi A. Measurement of regionalcerebral blood flow and glucose utilization in rat brain under chronichypoperfusion conditions following bilateral carotid artery occlusion.Analyzed by autoradiographical methods. Nippon Ika DaigakuZasshi,1997,64:428-39.
[90]Morris RG. Developments of water-maze procedure for studying spatiallearning in the rat. J Neurosci Methods,1984;11:47–60.
[91]Tanaka K,Wada N, Hori K,et al. Chronic cerebral hypoperfusion disruptsdiscrininatine behavior in acquired-learning rats[J]. J Neurosci Methods,1998,84:63-68.
[92]Dela Torre JC, Cada A, Nelson N,et al. Reduced cytochrome oxidace andmemory dysfunction after chronic brain ischemia in aged rats[J]. NeurosciLett,1997,223(2):165-168.
[93]Jong GT, Farkas E, Stienstra CM,et al. Cerebral hypoperfusion yieldscapillary damage in the hypocampal CAl area that correlates with spatialmemory impairment [J]. Neuroscience,1999,91(1):203-210.
[94]Meguro K, LeMestric C Landeau B,et al. Relations betweenhypometabolism in the posterior association neocortex and hippocampalAtrophy in Alzheimer’ disease:PET/MRI correlative study[J].JNeurolNeurosurg Psychiatry,2001,71:315-32.
[95]Pantoni, L, Leys, D, Fazekas, F, Longs treth Jr, WT, Inzitari, D, Wallin, A,Filippi, M, Scheltens, P, Erkinjuntti, T, Hachinski, V. Role of whitematter lesions in cognitive impairment of vascular origin. Alzheimer Dis.Assoc. Disord.1999,13, S49–S54.
[96]孙莉,张昱,邹昕颖.慢性前脑缺血致痴呆大鼠皮质及皮质下白质区病理学变化的对比研究[J].中风与神经疾病杂志,2004,21(5):403-405.
[97]扈荣,钟晓明.血管性痴呆动物模型的研究概况[J].浙江中医药大学学报,2008,32(1):137-140.
[98]He Z, Liao Y, Zheng M, Zeng FD, Guo LJ. Piracetam improves cognitivedeficits caused by chronic cerebral hypoperfusion in rats. Cell MolNeurobiol2008,28:613-27.
[99]Ohtaki H, Fujimoto T, Sato T, Kishimoto K, Fujimoto M, Moriya M, et al.Progressive expression of vascular endothelial growth factor (VEGF) andangiogenesis after chronic ischemic hypoperfusion in rat. Acta NeurochirSuppl,2006,96:283-7.
[100]Gerlai R. Behavioral tests of hippocampal function: simple paradigmscomplex problems. Behav Brain Res,2001,125:269-77.
[101]Peng Y, Xu S, Chen G, Wang L, Feng Y, Wang X. l-3-n-Butylphthalideimproves cognitive impairment induced by chronic cerebralhypoperfusion in rats. J Pharmacol Exp Ther,2007;321:902–10.
[102]Watanabe T, Zhang N, Liu M, Tanaka R, Mizuno Y, Urabe T. Cilostazolprotects against brain white matter damage and cognitive impairment in arat model of chronic cerebral hypoperfusion. Stroke,2006,37:1539-45.
[103]Yenari MA, Xu L, Tang XN, Qiao Y, Giffard RG. Microglia potentiatedamage to blood-brain barrier constituents: improvement by minocyclinein vivo and in vitro. Stroke,2006,37:1087-1093.
[104]Matsui T, Mori T, Tateishi N, Kagamiishi Y, Satoh S, Katsube N, et al.Astrocytic activation and delayed infarct expansion after permanent focalischemia in rats. Part I: enhanced astrocytic synthesis of s-100beta in theperi infarct area precedes delayed infarct expansion. J Cereb Blood FlowMetab,2002,22:711-22.
[105]Liu X, Sullivan KA, Madl JE, Legare M, Tjalkens RB.Manganese-induced neurotoxicity: the role of astroglial-derived nitricoxide in striatal interneuron degeneration. Toxicol Sci,2006,91:521-31.
[106]Abraham H, Lazar G. Early microglial reaction following mild forebrainischemia induced by common carotid artery occlusion in rats. Brain Res,2000,862:63-73.
[107]Cai ZY, Yan Y, Chen R. Minocycline reduces astrocytic reactivation andneuroinflammation in the hippocampus of a vascular cognitiveimpairment rat model. Neurosci Bull,2010,26:28-36.
[108]Clarke WE, Berry M, Smith C, Kent A, Logan A. Coordination offibroblast growth factor receptor1(FGFR1) and fibroblast growthfactor-2(FGF-2) trafficking to nuclei of reactive astrocytes aroundcerebral lesions in adult rats. Mol Cell Neurosci,2001,17:17-30.
[109]Buskila Y, Farkash S, Hershfinkel M, Amitai Y. Rapid and reactive nitricoxide production by astrocytes in mouse neocortical slices. Glia,2005;52:169-176.
[110]Pappas BA, de la Torre JC, Davidson CM, Keyes MT, Fortin T. Chronicreduction of cerebral blood flow in the adult rat: late-emerging CA1cellloss and memory dysfunction. Brain Res,1996,708:50-8.
[111]龙大宏，杨丹迪，李佳拥，许孟杰，汪华侨。弯隆海马伞损伤对大鼠学习记忆和海马GFAP阳性神经胶质细胞的影响。神经解剖学杂志，2002，18(1):63-66.
[112]Farkas E, Luiten PG, Bari F. Permanent, bilateral common carotid arteryocclusion in the rat: a model for chronic cerebral hypoperfusion-relatedneurodegenerative diseases. Brain Res Rev,2007,54:162-80.
[113]Pappas BA, delaTorre JC, Davidson CM,et al. Chronic reduction ofcerebral blood flow in the adult rat: Late-emergatg CAl cell loss andmemory dysfunction[J]. Brain Res,1996,708(1):50-58.
[114]Ueno Y, Zhang N, Miyamoto N, Tanaka R, Hattori N, Urabe T.Edaravone attenuates white matter lesions through endothellal protectionin a rat chronic hypoperfusion model. Neuroscience,2009;16:2317-327.
[115]Wakita H, Tomimoto H, Akiguchi I, Matsuo A, Lin JX, Ihara M, et al.Axonal damage and demyelination in the white matter after chroniccerebral hypoperfusion in the rat. Brain Res,2002;924:63-70.
[116]Kim JE, Lee BR, Chun JE. Cognitive Dysfunction in16patients withcarotid stenosis: detailed neuropsychological Findings. J Clin Neurol,2007;3:9-17.
[117]Takamatsu J, Hirano A, Levy D, Henkind P. Experimental bilateralcarotid artery occlusion: a study of the optic nerve in the rat. NeuropatholAppl Neurol,1984;10:423-428.
[118]Goldberg MP, Ransom BR. New light on white matter. Stroke,2003;34:330–2.
[119]Kayoko Nakaji, Masafumi Ihara, Chiaki Takahashi. Matrix Metalloproteinase-2Plays a Critical Role in the Pathogenesis of White Matter LesionsAfter Chronic Cerebral Hypoperfusion in Rodents. Stroke,2006;37:2816–2823.
[120]Sarti C, Pantoni L, Bartolini L, Inzitari D. Persistent impairment of gaitperformances and working memory after bilateral common carotid arteryocclusion in the adult Wistar rat. Behav Brain Re,2002;136:13–20.
[121] Almkvist O, Tallberg IM. Cognitive decline from estimated premorbidstatus predicts neurodegeneration in Alzheimer disease. Neuropsychology,2009;23:117–124.
[122]Itoo BA, Al-Hawsawi ZM, Khan AH. Hypoxic ischemic encephalopathy:incidence and risk factors in North Western Saudi Arabia [J]. Saudi MedJ,2003,24(2):147-153.
[123]Karman J, Ling C, Sandor M, Fabry Z. Dendritic cells in the initiation ofimmune responses against central nervous system-derived antigens.Immunol Lett2004;92:107–15.
[124]Miyake T，okada M，Kitamura T. Reactive Proliferation of astrocytesstudied by immunohistoehemistry for proliferating cell nuclear antigen.Brain Res.1992, Sep11;590(1-2):300-2.
[125]Roman, GC. Brain hypoperfusion: a critical factor in vascular dementia.Neurol. Res.2004,26,454–458.
[126]Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, vanSwieten JC, Stijnen T, Hofman A., Witteman JC, Breteler, MM.Inflammatory proteins in plasma and the risk of dementia: the RotterdamStudy. Arch. Neurol.2004,61,668–672
[127]de Groot JC, de Leeuw, FEOudkerk M,Hofman A, Jolles J, Breteler MM.Cerebral white matter lesions and subjective cognitive dysfunction: theRotterdam Scan Study. Neurology,2001,56,1539–1545.
[128]Chamorro A, Hallenbeck J. The harms and benefits of inflammatory andimmune responses in vascular disease. Stroke,2006,37,291–293
[129]Plaschke K, Grant M, Weigand MA, Zuchner J, Martin E, BardenheuerHJ. Neuromodulatory effect of propentofylline on rat brain under acuteand long-term hypoperfusion. Br J Pharmacol.2001;133:107–116.
[130]Wakita, H, Tomimoto,H,Akiguchi, I,Kimura, J. Glial activation and whitematter changes in the rat brain induced by chronic cerebral hypoperfusion:an immunohistochemical study. Acta Neuropathol (Berl).1994,87,484–492.
[131]Leite MC, Galland F, Brolese G, Guerra MC, Bortolotto JW, Freitas,R,Almeida LM, Gottfried C, Goncalves CA. A simple, sensitive and widelyapplicable ELISA for S100B:methodological features of the measurementof this glial protein. J. Neurosci. Methods,2008,169,93–99.
[132]Wardlaw JM, Farrall A, Armitage PA, Carpenter T, Chappell F, Doubal F,Chowdhury D, Cvoro V, Dennis MS. Changes in background blood–brainbarrier integrity between lacunar and cortical ischemic stroke subtypes.Stroke,2008,39:1327–1332.
[133]Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of theblood–brain barrier responsible for lacunar stroke, leukoaraiosis, anddementia? Stroke,2003,34:806–812.
[134]Wei DM, Rao GQ, Yang WH. Effection of Gypenosides on braindamage induced by ischemic. Pharm and Clin Materia Medica,2005,21:20-2.
[135]Yao BC, Yuan H, Huang X, Zhang JJ. Gypenosides on the effect of COXand mitochondrial ultrastructure in the hippocampal in rats after theinjection of Aβ1-40. J Chin Gerontology,2005,10:1193-4.
[136]Wang XP, Zhao L, Feng YX, Shang LS, Liu JC, Cao WP, et al. Protectionof Gypenosides on glutamate-induced oxidation in the cultured corticalneurons of embryonic rats. J Shan Dong Med Univ,2006,44:564-7.
[137]Attawish A, Chivapat S, Phadungpat S, Bansiddhi J, Techadmrongsin Y,Mitrijit O, Chaorai B, Chavalittumrong P. Chronic toxicity ofGynostemma pentaphy llum. Fitoterapia,2004;75:539–551.
[138]Dong XH. Gypenosides and acetylsalicylic acid on the effect of theformation of platelet aggregation and blood clots. J Jining Med Univ,2006;29:47–48.
[2] DeLa Torre, Jack C. Alzheimers disease is a vasocognopathy: a new termto describe its nature[J]. Neurol Res.2004;26(5):517-524.
[3] Micieli G.Vascular dementia. Neurol Sci.2004;27:37-39.
[4]平井俊策.平成元年度厚生省循环器病研究委托班研究报告集[R].国立循病.1990:80.
[5] Liu HX, Zhang JJ, Zheng P, Zhang Y. Altered expression of MAP-2,GAP-43, and synaptophysin in the hippocampus of rats with chroniccerebral hypoperfusion correlates with cognitive impairment. Brain ResMol Brain Res.2005;139:169-77.
[6]谢玉丰.神经胶质细胞与突触可塑性研究新进展[J].生理科学进展.2007;38:111-114.
[7] Koistinaho M, Koistinaho J. Interactions between Alzheimer's disease andcerebral ischemia focus on inflammation. Brain Res Rev.2005;48:240-250.
[8] Guo M, Cox B, Mahale S, Davis W, Carranza A, Hayes K. Pre-ischemicexercise reduces matrix metalloproteinase-9expression and amelioratesblood-brain barrier dysfunction in stroke. Neuroscience.2008;151:340-351.
[9] Otori T, Katsumata T, Muramatsu H, Kashiwagi F, Katayama Y, TerashiA. Long-term measurement of cerebral blood flow and metabolism in a ratchronic hypoperfusion model. Clin Exp Pharmacol Physiol.2003;30:266–72.
[10]Kumaran D, Udayabanu M, Kumar M, Aneja R, Katyal A. Involvement ofangiotensin converting enzyme in cerebral hypoperfusion inducedanterograde memory impairment and cholinergic dysfunction in rats.Neuroscience.2008;155:626-39.
[11]Humpel C, Marksteiner J. Cerebrovascular damage as a cause forAlzheimer's disease. Curr Neurovasc Res.2005;2:341-7.
[12]Gunstad J, Brickman AM, Paul RH. Progressive morphometrie andcognitive changes in vascular dementia. Arch Clin Neuro psychol.2005;20:229–241.
[13]Dohmen C, Kumura E, Rosner G. Extracellular correlates of glutamatetoxicity in short-term cerebral ischemia and reperfusion: a direct in vivocomparison between white and gray matter. Brain Research.2005;1037:43–51.
[14]Cada A,delaTorre JC, Gonzalez-Lima F. Chronic cerebrovascularischemia in aged rats: Effects on brain metabolic capacity and behavior[J].Neurobiol Aging.2000;21(2):225-233.
[15]Ueda M, Muramatsu H, Kamiya T. Pyruvatedehydrogena,activity,andenergy metabolite levels following bilateral common carotidarteryocclusion in rat brain[J]. Life Sci2000;67(7):821-827.
[16]Chan PH.Reactive oxygen radicals in signaling and damage in theischemic brain [J].Cereb Blood Flow Metab.2001;65(1),21:25.45.姚丹丹,等.绞股蓝对衰老大鼠下丘脑的抗衰老作用研究[J].医学理论与实践,2007,20(10):1119-1120.
[17]Farkas E, Luiten PG,BariF. Permanent,bilateral common carotid arteryocclusion In the rat:a model for chronic cerebral hypoperfusion-relatedneurodegenerative diseases. BrainRes Rev.2007;54:162–80.
[18]Cui J, Holmes EH, Greene TG,et al·Oxidative DNA damage precedes DNAfragmentation after experimental stroke in rat brain[J].FASEB J.2000;14(7):955-6.
[19]InalF, GunesO, EraslanA,etal·Changes in antioxidative system andmembrane damage of lettuce in response to salinity and borontoxicity[J].Scientia Horticulturae.2007;114:5-10·
[20]Solaroglu I, Solaroglu A, Kaptanoglu E,et al·Erythropoietin preventsischemia-reperfusion from inducing oxidative damage in fetal rat brain[J].Child Nerv Syst.2003;19:19-22·
[21]Deguchi K, Hayashi T, Nagotani S, Sehara Y, Zhang H, Tsuchiya A.Reduction of cerebral infarction in rats by biliverdin associated withamelioration of oxidative stress. Brain Res.2008;1188:1–8.
[22]de la Torre JC, Aliev G. Inhibition of vascular nitric oxide after rat chronicbrain hypoperfusion: spatial memory and immunocytochemical changes. JCereb Blood Flow Metab.2005;25:663-72.
[23]Hamel E, Nicolakakis N, Aboulkassim T, Ongali B, Tong XK. Oxidativestress and cerebrovascular dysfunction in mouse models of Alzheimersdisease. Exp Physiol.2008;93:116-20.
[24]Hallenbeck JM. The many faces of tumor necrosis factor in stroke. NatMed,2002;8:1363-8.
[25]Huang L, He Z, Guo L, Wang H. Improvement of cognitive deficit andneuronal damage in rats with chronic cerebral ischemia via relativelong-term inhibition of rho-kinase. Cell Mol Neurobiol.2008;28:757-68.
[26]Kim JS, Yun IJ, Choi YB, Lee KS, Kim YI. Ramipril protects from freeradical induced white matter damage in chronic hypoperfusion in the rat.Journal of Clinical Neuroscience.2008;15:174-178.
[27]O'Callaghan JP, Sriram K. Glial fibrillary acidic protein and related glialproteins as biomarkers of neurotoxicity. Expert Opin DrugSaf.2005;4:433-42.
[28]Shibata M, Ohtani R, Ihara M. Tomimoto,H.,.White matter lesions andglial activation in a novel mouse model of chronic cerebral hypoperfusion.Stroke.2004;35:2598-2603.
[29]Tateishi N, Mori T, Kagamiishi Y. Astrocytic activation and delayedinfarct expansion after permanent focal ischemia in rats. Part II:suppression of astrocytic activation by a novel agent(R)-(-)-2-propyloctanoic acid (ONO-2506) leads to mitigation of de-layedinfarct expansion and early improvement of neurologic deficits. J CerebBlood Flow Metab.2002;22:723-734.
[30]Vicente é, Degerone D, Bohn L, Francisco S, Pimentel A, Leite MC,Swarowsky A, Rodrigues L, Nardin P, de Gottfried C, Souza DO, NettoCA, Alberto Gon alves CA. Astroglial and cognitive effects of chroniccerebral hypoperfusion in the rat. Brain R.2009;1251:204-212.
[31]von Bernhardi R. Glial cell dysregulation: a new perspective on Alzheimerdisease. Neurotox Res.2007;12,215-32.
[32]Liu C, Wu J, Gu J, Xiong Z, Wang F, Wang J, et al. Baicalein improvescognitive deficits induced by chronic cerebral hypoperfusion in rats.Pharmacol Biochem Behav.2007,86:423-30.
[33]de la Torre JC. Is Alzheimer’s a neurodegenerative or a vascular disorder?Data, dogma and dialectics. Lancet Neurol.2004;3:184–190.
[34]李瑞岭,高南南,亚少敏,等.绞股蓝的药理和临床研究.中医药研究.1996,(5):55-57.
[35]姚丹丹,等.绞股蓝对衰老大鼠下丘脑的抗衰老作用研究[J].医学理论与实践,2007,20(10):1119-1120.
[36]肖东,顾振纶,钱曾年,等.绞股蓝的药理作用.中成药研究.1992;14(1):36-38.
[37]王旭平,等.绞股蓝总苷对谷氨酸诱导的胎鼠大脑皮层神经元氧化性损伤保护机制的研究[J].山东大学学报(医学版).2006;44(6):564-567.
[38]张莉,等.绞股蓝总皂苷对血管性痴呆大鼠大脑皮层及海马的影响[J].中草药研究.2002;33(4):330-331.
[39]韦登明,饶广勋,扬文辉.绞股蓝总甙对实验性脑缺血损伤的保护作用[J].中药药理与临床.2005;21(1):20-22.
[40]Vagnucci AH, Li WW. Alzheimer’s disease and angiogenesis [J].Lancet.2003;361(9357):605-608.
[41]Royall DR. Alzheimer disease as a vascular disorder: nosological evidence.Stroke.2002;33:2147-8.
[42]Zlokovic BV. Vascular disorder in Alzheimer's disease: role inpathogenesis of dementia and therapeutic targets. Adv Drug DelivRev.2002;54:1553-9.
[43]von Bernhardi R Immunotherapy in Alzheimer's disease: where do westand? Where should we go? J Alzheimers Dis.2010;19:405-21.
[44]CASTRO Jessiea, MOLANO Ana, ZARRANZ Juan Jose etal. Prevalenceof neuropsyehiatrie symptoms in Alzheimer's disease and vasculardementia[J].Cur:Alzheimer Res.2008;5(l):61-69.
[45]叶翠飞，白容，刘汇波等.双侧颈总动脉结扎对大鼠学习记忆相关脑区血流量的影响.中国实验动物学报.1999;7(1):23-25
[46]Sarti, C, Pantoni, L, Bartolini, L, Inzitari, D. Persistent impairment of gaitperformances and working memory after bilateral common carotid arteryocclusion in the adult Wistar rat. Behav. Brain Res.2002;136,13-20.
[47]Otori T, Katsumata T, Muramatsu H, Kashiwagi F, Katayama Y, Terashi A.Long-term measurement of cerebral blood flow and metabolism in a ratchronic hypoperfusion model. Clin Exp PharmacolPhysiol.2003;30:266-72.
[48]Sarti C, Pantoni L, Bartolini L, et al. Cognitive impairment and chroniccerebral hypoperfusion: what can be learned from experimental models [J].J Neurol Sci.2002;204(15):263-266.
[49] M,et al. A new model of bilateral hemispheric ischmia in the ratthree vessel occlusion model[J].Stroke.1985;16:489-495.
[50]Pulsinelli WA，Brierley JB.A new model of bilateral hemispheric ischemiain the unanesthetized rat[J].Stroke.1979;10(3):267-269.
[51]李胜，雷征霖.大鼠大脑中动脉区局灶性脑缺血模型[J].国外医学.脑血管疾病分册.1998;6(1):3-6
[52]Watson BD.Induction of reproducible brain infarction by photochemicallyinitiated thrombosis[J].Ann Neurol.1985;17:497-501.
[53]陈俊抛，田时周，于薇薇等.多发性脑梗塞痴呆动物模型的研究.中华神经精神科杂志.1994;27(5):311-317.
[54]唐启盛，黄启福，郭建文.高脂血症大鼠缺血再灌流诱发行为学障碍模型的实验研究.北京中医药大学学报.1997;20(5):34-36.
[55] Cheng KC, Cahill DS, Kasai H.8-Hy-droxyguanine, an abundant form ofoxidative DNA damage, causes G-T and A-C substitutions. J BiolChem.1992;267:166-172.
[56]Chong ZZ, Li F, Maiese K. Oxidative stress in the brain: novel cellulartargets that govern survival during neurodegenerative disease. ProgNeurobiol2005;75:207-46.
[57]Aliev, G., Smith, M.A., Obrenovich, M.E., de la Torre, J.C., Perry, G.,Role of vascular hypoperfusion-induced oxidative stress and mitochondriafailure in the pathogenesis of Alzheimer disease. Neurotox. Res.2003；5：491-504.
[58]Saito H，Togashi H，Yoshioka M，etal.Animal model of vascular dementiawith emphasis on stroke-prone spontaneously hypertension rats[J].Clin.Exp. Pharmacol.Physiol.1995;22:257-259.
[59]CJover T, McCulloch J, Dewar D. The lipid peroxidation by-product4-hydroxynonenal is toxic to axons and oligodendrocytes. J Cereb BloodFlow Metab.2000;20:1529-36.
[60]Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E,Vescovi A, Bagetta G, Kollias G,Meldolesi J, Volterra A.CXCR4-activated astrocyte glutamate release via TNF alpha:amplificationby microglia triggers neurotoxicity. NatNeurosci.2001;4:702-10.
[61]Chamorro, A, Hallenbeck, J. The harms and benefits of inflammatory andimmune responses in vascular disease. Stroke.2006,37,291-293.Vargas MR, Pehar M, Cassina P, et al. Stimulation of nerve growth factorexpression in astrocytes by peroxynitrite. In Vivo.2004;18(3):269-274.
[62]Meeuwsen S, BsibsiM, Pers oon Deen C, et al. Cultured human adultmicroglia from different donors display stable cytokine, chemokine andgrowth factor gene Profilesbut respond differently to aproinflammatorystimulus[J]. Neuroimmunomo dulation,2005,12(4):235-245.
[63]Morioka T, Kalehua AN, Streit WJ. Progressive expression ofimmunomolecules on microglia cells in rat dorsalhippocampus followingtransient forebrain ischemia[J]. Acta Neuropatho,1992,83:149-157.
[64] Streit WJ,Walter SA,Pennell NA. Reactive microgliosis[J]. ProgNeurobiol,1999,57(6):563-581.
[65]Von Bernhardi R. Participation of glial cells in the pathogenesis of AD: adifferent view on neuroinflammation. Biomedical and Life Sciences2009;4:1-18.
[66]Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. JNeuroimmunol,2007,184:53-68.
[67] Badan I, Buchhold B, Hamm A, Gratz M, Walker LC, Platt D. Acceleratedglial reactivity to stroke in aged rats correlates with reduced functionalrecovery. J of Cerebral Blood Flow&Metabolism,2003;23:845-854..
[68]Yancopoulos GD, Davis S, Gate NW,et al. Vascular specific growth factorsand blood vessel formation [J].Nature,2000,407(14):242-247.
[69]Leonoudakis D, Braithwaite SP, Beattie MS, Beattie EC. TNFalpha-induced AMPA-receptor trafficking in CNS neurons; relevance toexcitotoxicity? Neuron Glia Biol,2004;1:263-73.
[70]Ridet Jl, Malhotra SK, Privat A, et al. Reactive astrocytes: cellulr andmolecular cues to biological funtion[J].Trends Neurosxi,2006,20:570-577.
[71]Shibata, M, Ohtani, R, Ihara,M, Tomimoto,H.White matter lesions andglial activation in a novel mouse model of chronic cerebral hypoperfusion.Stroke,2004,35,2598–2603.
[72]Maragakis NJ, Rothstein JD. Mechanisms of disease: astrocytes inneurodegenerative disease. Nat. Clin. Pract.Neurol,2006;2:679–689.
[73]Ridet JL, Malhotra SK, Privat A, Gage FH. Reactive astrocytes: cellularand molecular cues to biological function. Trends Neurosci,1997,20:570-577.
[74]Norris, CM, Kadish, I, Blalock, EM, Chen, KC, Thibault, V,Porter, NM,Landfield, PW, Kraner, SD. Calcineurin triggers reactive/inflammatoryprocesses in astrocytes and is upregulated in aging and Alzheimer's models.J. Neurosci.2005,25:4649-4658.
[75]O'Callaghan, JP, Sriram, K. Glial fibrillary acidic protein and related glialproteins as biomarkers of neurotoxicity. Expert Opin. Drug Saf.2005,4:433-442.
[76]Chen Yong, Hallenbeck, John M, et al. Overexpression of MonocyteChemoat t ractant Protein1in t he Brain Exacer bates Ischemic BrainInjury and Is Associated With Recruitment of Inflammatory Cells [J].Journal of Cerebral Blood Flow&Metabolism.2003,23(6):748-755.
[77]Hanisch U K. Microglia as a source and target of cytokines [J]. Glia.2002,40:140-155.
[78]Gdel Zoppo, I. Ginis, JM. Hallenbeck, C. Iadecola, X. Wang,GZ.Feuerstein, Inflammation and troke: putative role forcytokines,adhesion molecules and iNOS in brain response toischemia.Brain Pathol.2000,10:95-112.
[79]J Yrjanheikki, R Keinnen, M Pellikka, THfkfelt, J Koistinaho.Tetracyclines inhibit microglial ctivation and are neuroprotective inglobalbrain ischemia, Proc. Natl. Acad. Sci. U. S. A.1998,5:15769-15774.
[80]H. Akiyama, T. Arai, H. Kondo, E. Tanno, C. Haga, K. Ikeda, Cellmediators of inflammation in the Alzheimer disease brain, Alzheimer Dis.Assoc. Disord.2000;14:47-53.
[81]Gregersen R., Lambertsen K. and Finsen B. Microglia and macrophagesare the major source of tumor necrosis factor in permanent middle cerebralartery occlusion in mice. J. Cereb.Blood Flow Metab,2000,20:53-65.
[82]Rossi DJ，Oshima T，Attwell D.Glutamate release in severe brain ischaemiais mainly by reversed uptake[J].Nature.2000;403(6767):316-321.
[83]Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA. Peroxynitritegenerated by inducible nitric oxide synthase and NADPHoxidase mediatesmicroglial toxicity to oligodendrocytes. Proc Natl Acad Sci USA,2005,102:9936–9941.
[84]Iadecola C. Neurovascular regulation in the normal brain and inAlzheimer’s disease.Nat Rev Neurosci2004;5:347–360.
[85]Imai H, Masayasu H, Dewar D, Graham DI, Macrae IM. Ebselen protectsboth gray and white matter in a rodent model of focal cerebral ischemia.Stroke2001;32:2149–54.
[86]Farkas E, Luiten PG. Cerebral microvascular pathology in aging andAlzheimer'sdisease. Prog Neurobio,2001;64:575-611
[87]Fagan SC, Hess DC, Hohnadel EJ, Pollock DM, Ergul A. Targets forvascular protection after acute ischemic stroke. Stroke,2004,35:2220-5.
[88]Ni JW, Matsumoto K, Li HB,et al. Neuronal damage and decrease ofCentral Acetylcholine level following permanent occlusion of bilateralcommon carotid arteries in rat[J]. Brain Res,1995,673(2):290-296.
[89]Otori T, Katsumata T, Katayama Y, Terashi A. Measurement of regionalcerebral blood flow and glucose utilization in rat brain under chronichypoperfusion conditions following bilateral carotid artery occlusion.Analyzed by autoradiographical methods. Nippon Ika DaigakuZasshi,1997,64:428-39.
[90]Morris RG. Developments of water-maze procedure for studying spatiallearning in the rat. J Neurosci Methods,1984;11:47–60.
[91]Tanaka K,Wada N, Hori K,et al. Chronic cerebral hypoperfusion disruptsdiscrininatine behavior in acquired-learning rats[J]. J Neurosci Methods,1998,84:63-68.
[92]Dela Torre JC, Cada A, Nelson N,et al. Reduced cytochrome oxidace andmemory dysfunction after chronic brain ischemia in aged rats[J]. NeurosciLett,1997,223(2):165-168.
[93]Jong GT, Farkas E, Stienstra CM,et al. Cerebral hypoperfusion yieldscapillary damage in the hypocampal CAl area that correlates with spatialmemory impairment [J]. Neuroscience,1999,91(1):203-210.
[94]Meguro K, LeMestric C Landeau B,et al. Relations betweenhypometabolism in the posterior association neocortex and hippocampalAtrophy in Alzheimer’ disease:PET/MRI correlative study[J].JNeurolNeurosurg Psychiatry,2001,71:315-32.
[95]Pantoni, L, Leys, D, Fazekas, F, Longs treth Jr, WT, Inzitari, D, Wallin, A,Filippi, M, Scheltens, P, Erkinjuntti, T, Hachinski, V. Role of whitematter lesions in cognitive impairment of vascular origin. Alzheimer Dis.Assoc. Disord.1999,13, S49–S54.
[96]孙莉,张昱,邹昕颖.慢性前脑缺血致痴呆大鼠皮质及皮质下白质区病理学变化的对比研究[J].中风与神经疾病杂志,2004,21(5):403-405.
[97]扈荣,钟晓明.血管性痴呆动物模型的研究概况[J].浙江中医药大学学报,2008,32(1):137-140.
[98]He Z, Liao Y, Zheng M, Zeng FD, Guo LJ. Piracetam improves cognitivedeficits caused by chronic cerebral hypoperfusion in rats. Cell MolNeurobiol2008,28:613-27.
[99]Ohtaki H, Fujimoto T, Sato T, Kishimoto K, Fujimoto M, Moriya M, et al.Progressive expression of vascular endothelial growth factor (VEGF) andangiogenesis after chronic ischemic hypoperfusion in rat. Acta NeurochirSuppl,2006,96:283-7.
[100]Gerlai R. Behavioral tests of hippocampal function: simple paradigmscomplex problems. Behav Brain Res,2001,125:269-77.
[101]Peng Y, Xu S, Chen G, Wang L, Feng Y, Wang X. l-3-n-Butylphthalideimproves cognitive impairment induced by chronic cerebralhypoperfusion in rats. J Pharmacol Exp Ther,2007;321:902–10.
[102]Watanabe T, Zhang N, Liu M, Tanaka R, Mizuno Y, Urabe T. Cilostazolprotects against brain white matter damage and cognitive impairment in arat model of chronic cerebral hypoperfusion. Stroke,2006,37:1539-45.
[103]Yenari MA, Xu L, Tang XN, Qiao Y, Giffard RG. Microglia potentiatedamage to blood-brain barrier constituents: improvement by minocyclinein vivo and in vitro. Stroke,2006,37:1087-1093.
[104]Matsui T, Mori T, Tateishi N, Kagamiishi Y, Satoh S, Katsube N, et al.Astrocytic activation and delayed infarct expansion after permanent focalischemia in rats. Part I: enhanced astrocytic synthesis of s-100beta in theperi infarct area precedes delayed infarct expansion. J Cereb Blood FlowMetab,2002,22:711-22.
[105]Liu X, Sullivan KA, Madl JE, Legare M, Tjalkens RB.Manganese-induced neurotoxicity: the role of astroglial-derived nitricoxide in striatal interneuron degeneration. Toxicol Sci,2006,91:521-31.
[106]Abraham H, Lazar G. Early microglial reaction following mild forebrainischemia induced by common carotid artery occlusion in rats. Brain Res,2000,862:63-73.
[107]Cai ZY, Yan Y, Chen R. Minocycline reduces astrocytic reactivation andneuroinflammation in the hippocampus of a vascular cognitiveimpairment rat model. Neurosci Bull,2010,26:28-36.
[108]Clarke WE, Berry M, Smith C, Kent A, Logan A. Coordination offibroblast growth factor receptor1(FGFR1) and fibroblast growthfactor-2(FGF-2) trafficking to nuclei of reactive astrocytes aroundcerebral lesions in adult rats. Mol Cell Neurosci,2001,17:17-30.
[109]Buskila Y, Farkash S, Hershfinkel M, Amitai Y. Rapid and reactive nitricoxide production by astrocytes in mouse neocortical slices. Glia,2005;52:169-176.
[110]Pappas BA, de la Torre JC, Davidson CM, Keyes MT, Fortin T. Chronicreduction of cerebral blood flow in the adult rat: late-emerging CA1cellloss and memory dysfunction. Brain Res,1996,708:50-8.
[111]龙大宏，杨丹迪，李佳拥，许孟杰，汪华侨。弯隆海马伞损伤对大鼠学习记忆和海马GFAP阳性神经胶质细胞的影响。神经解剖学杂志，2002，18(1):63-66.
[112]Farkas E, Luiten PG, Bari F. Permanent, bilateral common carotid arteryocclusion in the rat: a model for chronic cerebral hypoperfusion-relatedneurodegenerative diseases. Brain Res Rev,2007,54:162-80.
[113]Pappas BA, delaTorre JC, Davidson CM,et al. Chronic reduction ofcerebral blood flow in the adult rat: Late-emergatg CAl cell loss andmemory dysfunction[J]. Brain Res,1996,708(1):50-58.
[114]Ueno Y, Zhang N, Miyamoto N, Tanaka R, Hattori N, Urabe T.Edaravone attenuates white matter lesions through endothellal protectionin a rat chronic hypoperfusion model. Neuroscience,2009;16:2317-327.
[115]Wakita H, Tomimoto H, Akiguchi I, Matsuo A, Lin JX, Ihara M, et al.Axonal damage and demyelination in the white matter after chroniccerebral hypoperfusion in the rat. Brain Res,2002;924:63-70.
[116]Kim JE, Lee BR, Chun JE. Cognitive Dysfunction in16patients withcarotid stenosis: detailed neuropsychological Findings. J Clin Neurol,2007;3:9-17.
[117]Takamatsu J, Hirano A, Levy D, Henkind P. Experimental bilateralcarotid artery occlusion: a study of the optic nerve in the rat. NeuropatholAppl Neurol,1984;10:423-428.
[118]Goldberg MP, Ransom BR. New light on white matter. Stroke,2003;34:330–2.
[119]Kayoko Nakaji, Masafumi Ihara, Chiaki Takahashi. Matrix Metalloproteinase-2Plays a Critical Role in the Pathogenesis of White Matter LesionsAfter Chronic Cerebral Hypoperfusion in Rodents. Stroke,2006;37:2816–2823.
[120]Sarti C, Pantoni L, Bartolini L, Inzitari D. Persistent impairment of gaitperformances and working memory after bilateral common carotid arteryocclusion in the adult Wistar rat. Behav Brain Re,2002;136:13–20.
[121] Almkvist O, Tallberg IM. Cognitive decline from estimated premorbidstatus predicts neurodegeneration in Alzheimer disease. Neuropsychology,2009;23:117–124.
[122]Itoo BA, Al-Hawsawi ZM, Khan AH. Hypoxic ischemic encephalopathy:incidence and risk factors in North Western Saudi Arabia [J]. Saudi MedJ,2003,24(2):147-153.
[123]Karman J, Ling C, Sandor M, Fabry Z. Dendritic cells in the initiation ofimmune responses against central nervous system-derived antigens.Immunol Lett2004;92:107–15.
[124]Miyake T，okada M，Kitamura T. Reactive Proliferation of astrocytesstudied by immunohistoehemistry for proliferating cell nuclear antigen.Brain Res.1992, Sep11;590(1-2):300-2.
[125]Roman, GC. Brain hypoperfusion: a critical factor in vascular dementia.Neurol. Res.2004,26,454–458.
[126]Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, vanSwieten JC, Stijnen T, Hofman A., Witteman JC, Breteler, MM.Inflammatory proteins in plasma and the risk of dementia: the RotterdamStudy. Arch. Neurol.2004,61,668–672
[127]de Groot JC, de Leeuw, FEOudkerk M,Hofman A, Jolles J, Breteler MM.Cerebral white matter lesions and subjective cognitive dysfunction: theRotterdam Scan Study. Neurology,2001,56,1539–1545.
[128]Chamorro A, Hallenbeck J. The harms and benefits of inflammatory andimmune responses in vascular disease. Stroke,2006,37,291–293
[129]Plaschke K, Grant M, Weigand MA, Zuchner J, Martin E, BardenheuerHJ. Neuromodulatory effect of propentofylline on rat brain under acuteand long-term hypoperfusion. Br J Pharmacol.2001;133:107–116.
[130]Wakita, H, Tomimoto,H,Akiguchi, I,Kimura, J. Glial activation and whitematter changes in the rat brain induced by chronic cerebral hypoperfusion:an immunohistochemical study. Acta Neuropathol (Berl).1994,87,484–492.
[131]Leite MC, Galland F, Brolese G, Guerra MC, Bortolotto JW, Freitas,R,Almeida LM, Gottfried C, Goncalves CA. A simple, sensitive and widelyapplicable ELISA for S100B:methodological features of the measurementof this glial protein. J. Neurosci. Methods,2008,169,93–99.
[132]Wardlaw JM, Farrall A, Armitage PA, Carpenter T, Chappell F, Doubal F,Chowdhury D, Cvoro V, Dennis MS. Changes in background blood–brainbarrier integrity between lacunar and cortical ischemic stroke subtypes.Stroke,2008,39:1327–1332.
[133]Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of theblood–brain barrier responsible for lacunar stroke, leukoaraiosis, anddementia? Stroke,2003,34:806–812.
[134]Wei DM, Rao GQ, Yang WH. Effection of Gypenosides on braindamage induced by ischemic. Pharm and Clin Materia Medica,2005,21:20-2.
[135]Yao BC, Yuan H, Huang X, Zhang JJ. Gypenosides on the effect of COXand mitochondrial ultrastructure in the hippocampal in rats after theinjection of Aβ1-40. J Chin Gerontology,2005,10:1193-4.
[136]Wang XP, Zhao L, Feng YX, Shang LS, Liu JC, Cao WP, et al. Protectionof Gypenosides on glutamate-induced oxidation in the cultured corticalneurons of embryonic rats. J Shan Dong Med Univ,2006,44:564-7.
[137]Attawish A, Chivapat S, Phadungpat S, Bansiddhi J, Techadmrongsin Y,Mitrijit O, Chaorai B, Chavalittumrong P. Chronic toxicity ofGynostemma pentaphy llum. Fitoterapia,2004;75:539–551.
[138]Dong XH. Gypenosides and acetylsalicylic acid on the effect of theformation of platelet aggregation and blood clots. J Jining Med Univ,2006;29:47–48.