绞股蓝总皂甙对慢性脑缺血性白质氧化性损伤的保护作用

目的 探讨绞股蓝总皂甙对慢性脑缺血大鼠脑白质氧化性损伤的保护作用以及对脑缺血大鼠认知功能的影响.方法 将57只成年雄性SD大鼠按随机数字表法分成假手术组(n=12)、模型组(n=15)、绞股蓝总皂甙200 mg组(n=15)、绞股蓝总皂甙400 mg组(n=15),后3组采用双侧颈总动脉结扎法制备慢性脑缺血模型,且在造模后3h分别将等量生理盐水,200 mg/kg、400mg/kg绞股蓝总皂甙溶液灌胃,1次/d,持续33 d.应用Morris水迷宫实验测试各组大鼠空间学习与记忆能力的改变,酶联免疫吸附法(ELISA)测定大鼠胼胝体、视束内超氧化物歧化酶(SOD)活性、丙二醛(MDA)含量,免疫组化染色用8-羟基脱氧鸟苷(8-OHdG)抗体测定中枢神经细胞的氧化损伤水平.结果 与模型组相比,绞股蓝总皂甙400 mg组大鼠的逃避潜伏期明显缩短及在原平台象限的游泳时间明显延长,差异有统计学意义(P＜0.05).与假手术组比较,模型组大鼠胼胝体及视束内MDA含量明显增加,SOD活性明显降低,差异有统计学意义(P＜0.05).与模型组相比,绞股蓝总皂甙400 mg组MDA含量明显降低,SOD活性明显升高,8-OHdG阳性细胞数明显减少,差异有统计学意义(P＜0.05).与模型组相比,绞股蓝总皂甙200 mg组SOD活性、MDA含量及8-OHdG阳性细胞数差异无统计学意义(P＞0.05).结论 绞股蓝总皂甙能有效改善慢性脑缺血大鼠脑白质氧化性损伤,提示其可能是一种有效的抗痴呆药物,但其作用的确切机制还有待进一步研究.     

局灶性脑缺血再灌注损伤大鼠脑、肝中IGF-1的动态表达及其意义

目的 探讨胰岛素样生长因子-1(IGF-1)在局灶性脑缺血再灌注损伤大鼠脑、肝中的表达变化及其意义.方法 采用线栓法制备大鼠局灶性脑缺血再灌注模型,应用免疫组化染色方法检测大鼠脑缺血再灌注后2h、1d、3d、7d时脑、肝标本中IGF-1蛋白的含量.结果 正常脑组织有低水平的IGF-1表达,脑缺血再灌注后2h后表达即有明显升高,1d时持续升高,至3d时达高峰,7d时又有所回落,其表达主要位于大脑皮质区.经方差分析,脑组织中IGF-1蛋白含量脑缺血再灌注组与对应各时间点假手术组比较差异均有统计学意义(P<0.05);假手术组各时间点比较差异无统计学意义(P>0.05);脑缺血再灌注组1d和7d间比较差异无统计学意义(P>0.05),其余脑缺血再灌注组各时间点间比较差异均有统计学意义(P<0.05).正常肝组织中有极低水平IGF-1表达,脑缺血再灌注2h、1d、3d后肝组织中IGF-1蛋白含量与假手术组各对应时间点比较差异无统计学意义(p>0.05),脑缺血再灌注7d时与脑缺血再灌注组其余各时间点及假手术组对应时间点比较差异均有统计学意义(P<0.05).结论 脑缺血再灌注损伤后大鼠脑、肝中内源性IGF-1水平有明显变化,提示IGF-1的变化与脑缺血再灌注损伤有关联.     

当归注射液抗慢性脑缺血大鼠认知功能损害的实验研究

目的 观察当归注射液对慢性脑缺血后认知功能改变及氧化应激损伤和胆碱能系统的影响,探讨当归注射液改善慢性脑缺血认知功能的作用及机制. 方法 50只Wistar大鼠采用随机数字表法分为假手术组(n=16)、生理盐水组(n=18)及当归治疗组(n=16),后两组大鼠制成双侧颈动脉结扎慢性脑缺血模型(即2VO模型),缺血4周、干预4周后水迷宫检测3组大鼠认知功能,并取脑皮质测定氧化产物及胆碱酯酶含量. 结果 慢性脑缺血后大鼠的空间记忆能力受损,定位航行实验中第4、5天当归治疗组的隐匿平台逃避潜伏期较假手术组有所增加,但较生理盐水组明显缩短(分别为22.53±1.27、27.67±1.34),3组之间差异有统计学意义(P<0.05);当归治疗组在空间探索试验中穿越平台的次数较生理盐水组增多(分别为1.25±0.78、0.56±0.63),在平台区的停留时间延长(分别为21.99±4.97、12.80±2.88),3组之间差异有统计学意义(P<0.05);当归治疗组AchE含量有所下降,但与假手术组比较差异仍有统计学意义(P<0.05),同时,MDA含量增高,SOD活力、抑制羟自由基能力及总抗氧化能力降低,与假手术组比较差异没有统计学意义(P>0.05). 结论 当归注射液能改善慢性脑缺血的认知功能损害,其作用可能与抑制氧化应激反应有关.     

左归丸对大鼠慢性脑缺血线粒体呼吸链酶复合物活性的影响

目的探讨左归丸对慢性脑缺血线粒体呼吸链酶复合物活性的影响及其机制。方法将实验大鼠随机分为对照组、假手术组、慢性脑缺血组和左归丸治疗组,各8例。后两组大鼠采用双侧颈总动脉结扎法建立慢性脑缺血大鼠模型。左归丸治疗组于术后3周开始每天予以左归丸液灌胃,剂量为4.0 g/kg/d。术后6周,测试各组大鼠脑皮质线粒体活性氧(ROS)水平及线粒体呼吸链酶复合物活性测定。结果与对照组及假手术组比较,慢性脑缺血组大鼠的脑的线粒体ROS水平明显增高(P0.01),呼吸链酶复合物Ⅰ-Ⅳ活性均有不同程度的明显降低(P0.01);接受左归丸治疗组的大鼠的脑的线粒体ROS水平明显降低(P0.05),呼吸链酶复合物Ⅳ(COX)活性得到明显改善(P0.05)。结论左归丸可能通过修复线粒体COX的活性水平,改善线粒体功能,减少ROS的生成,从而起到对慢性缺血的保护作用。     

PKA-CREB信号转导通路在大鼠慢性脑缺血所致认知功能障碍中的作用

目的:观察PKA-CREB信号转导通路在慢性脑缺血所致大鼠认知功能损害中的作用。方法:结扎大鼠双侧颈总动脉,制成慢性脑缺血模型,分缺血8周组和假手术对照组,术后第8周时用Morris水迷宫测定大鼠学习记忆能力。用Westernbloting检测大鼠海马胞核内PKAca及pCREB的表达。结果:缺血组与假手术组相比学习记忆能力明显下降(P<0.05),缺血组大鼠海马中PKAca及pCREB的表达与假手术组相比也下降(P<0.05),且两者之间的下降存在正相关关系。结论:PKA-CREB信号转导通路可能参与了慢性脑缺血所致大鼠认知功能的损害。     

脑红蛋白在脑梗死大鼠表达及丁苯酞干预效应

目的探讨脑红蛋白在脑梗死大鼠中的表达和丁苯酞干预在氧化应激损伤中作用。方法将90只雄性SD大鼠随机分为假手术组、模型组、治疗组。每组再分为3个亚组:1 d组、3 d组和7 d组,每亚组10只。模型组和治疗组采用线栓法制作大鼠大脑中动脉闭塞模型(MCAO),假手术组只分离不结扎。治疗组在动物苏醒后以丁苯酞植物油灌胃,假手术组和模型组同法给予等量植物油灌胃。每只大鼠在术后3h和处死前行神经功能评分,应用RT-PCR和免疫组化检测脑组织脑红蛋白(NGB)表达,化学比色法检测超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量。结果 (1)神经功能评分,模型组和治疗组术后3 h评分差异无统计学意义(P>0.05),各时间点处死前评分差异均有统计学意义(P<0.05)。(2)NGB mRNA和免疫组化表达随时间延长逐渐降低,各时间点模型组较假手术组、治疗组较模型组高,差异均有统计学意义(P<0.05)。(3)SOD活性和MDA含量随时间延长逐渐减少。SOD活性假手术组较治疗组、治疗组较模型组高,差异均有统计学意义(P<0.05);MDA含量假手术组较治疗组、治疗组较模型组低,差异均有统计学意义(P<0.05)。结论丁苯酞促进脑缺血大鼠脑红蛋白表达,减少氧化应激损伤。     

血管生成对慢性低灌注状态下血脑屏障及脑白质损害的影响

目的 了解脑血管生成是否参与脑白质区域慢性低灌注状态下血脑屏障的破坏机制。方法 将72只雄性Wistar大鼠随机分为3组:假手术组、脑缺血组、干预组,脑缺血组及干预组大鼠结扎双侧颈总动脉构建慢性低灌注模型,干预组给予血管生成抑制剂灌胃以抑制血管生成; 对各组大鼠在相同时间点检测脑深部白质区域微血管密度、白质纤维密度以及伊文思蓝静脉注射6 h后脑白质区域组织内伊文思蓝水平。结果 脑缺血组及干预组大鼠脑白质区域血管密度和伊文思蓝浓度均显著高于假手术组,白质纤维密度显著低于假手术组,干预组微血管密度、白质纤维密度及脑组织内伊文思蓝水平显著低于脑缺血组。结论 慢性低灌注诱导的血管生成可能导致血脑屏障通透性增加,但血管生成有助于减轻白质损伤,但这种保护作用大于血脑屏障通透性改变带来的不利影响。     

α-硫辛酸对大鼠脑缺血再灌注损伤炎性机制的影响

目的探讨α-硫辛酸对大鼠脑缺血再灌注损伤炎性反应机制的影响。方法将SD大鼠随机分为假手术组(A)、脑缺血再灌注组(B)和硫辛酸预干预组(C),应用线栓法制备大脑中动脉闭塞2 h后再灌注模型,分别于再灌注6 h、24 h、3 d、7 d采用2,3,5-氯化三苯基四氮唑(TTC)染色法检测脑梗死灶大小,采用免疫组织化学和原位杂交的方法检测大鼠核转录因子(nuclear factor kappa B,NF-κB)、肿瘤坏死因子α(tumor necrosis factorα,TNF-α)的表达。结果与假手术组比较,模型组NF-κB的表达于再灌注6 h即增高(P<0.05),TNF-α的表达于24 h增高(P<0.05),3 d时均达高峰(均P<0.05),7 d时仍高于假手术组(均P<0.05);与模型组比较,硫辛酸预干预组于脑缺血再灌注24 h、3 d、7 d时NF-κB和TNF-α表达降低;α-硫辛酸预干预组NF-κB各时点组内比较未见统计学差异(F=2.245,P>0.05)。与模型组比较,α-硫辛酸预干预组梗死体积明显减小,神经功能缺损评分降低(P<0.05)。结论α-硫辛酸对大鼠脑缺血再灌注损伤具有一定的保护作用,其机制可能是α-硫辛酸抑制NF-κB、TNF-α的表达,从而抑制大鼠脑缺血再灌注损伤后的炎症反应有关。     

短暂陛全脑缺血/再灌注损伤致大鼠海马组织BNIP3表达水平的改变

目的 观察全脑缺血/再灌注损伤后大鼠海马组织Bc12/腺病毒E1819kD相互作用蛋白3(BNIP3)表达水平的改变. 方法 取10只成年雄性Wistar大鼠,采用随机数字表法分为假手术组和全脑缺血/再灌注72h组,每组5只.通过尼氏染色检测缺血模型是否引起海马神经元死亡.另取14只成年雄性Wistar大鼠采用随机数字表法分为假手术组(4只)、全脑缺血/再灌注1h组(5只)、全脑缺血/再灌注6h组(5只).在全脑缺血/再灌注后,于对应时间点取三组大鼠海马组织制备蛋白样品.western blot检测各时间点BNIP3表达水平的改变. 结果 (1)与假手术组比较,全脑缺血/再灌注72 h组中海马CAI区神经元形态不规则.细胞皱缩.胞核碎裂消失,表明海马神经元死亡.(2)大鼠海马组织BNIP3单体表达水平在全脑缺血/再灌注后上调,与假手术组相比.全脑缺血/再灌注1 h组(2.543±0.473)与全脑缺血/再灌注6 h组(2.942±0.777)的海马组织BNIP3单体蛋白表达水平都升高,差异有统计学意义(P<0.05).但全脑缺血/再灌注1 h组与全脑缺血/再灌注6 h组间比较差异无统计学意义(P>0.05).BNIP3双聚体在各时间点表达水平差异无统计学意义(P>0.05). 结论 全脑缺血/再灌注损伤可以引起大鼠海马组织BNIP3单体表达水平上调.     

盐酸美金刚对血管性痴呆大鼠疗效观察

目的 观察盐酸美金刚对血管性痴呆大鼠的疗效及作用机制.方法 80只健康Wistar大鼠(月龄12～14个月),体质量300～400 g,随机分为对照组、模型组、美金刚对照组及美金刚治疗组,每组20只.采用持久双侧颈总动脉结扎术造成血管性痴呆大鼠模型,美金刚对照组及美金刚治疗组于术后8周开始以美金刚(5 mg·kg-1)每天灌胃,对照组和模型组以同等量的0.5 g/L羧甲基纤维素钠灌胃,连续4周.采用Morris水迷宫衡量大鼠学习记忆水平;测定大鼠脑皮层、海马组织乙酰胆碱酯酶(AChE)、胆碱乙酰转移酶(ChAT)、丙二醛(MDA)、谷胱甘肽(GSH)活性的变化.结果 术后12周,与对照组相比,模型组大鼠的学习记忆能力明显下降(P<0.05);脑皮层、海马组织内AChE活性明显升高(P<0.05),ChAT活性明显降低(P<0.05),MDA活性明显升高(P<0.05),GSH活性明显降低(P<0.05);与模型组相比,美金刚治疗组大鼠的学习记忆能力明显提高(P<0.05);脑皮层、海马组织内AChE活性及ChAT活性差异无统计学意义(P>0.05)、MDA活性明显降低(P<0.05)、GSH活性明显升高(P<0.05).结论 盐酸美金刚对血管性痴呆大鼠的学习记忆能力有明显提高,作用机制是通过调节脑组织内MDA及GSH的活性来实现的,该实验研究为临床上血管性痴呆的治疗提供实验基础及理论依据.     

Relationship between cholinergic dysfunction and discrimination learning disabilities in Wistar rats following chronic cerebral hypoperfusion

The effects of chronic hypoperfusion of cerebral blood flow (CBF) on central cholinergic indices and intellectual functions were investigated in rats. Male Wistar rats, aged 9 weeks, were anesthetized with pentobarbital, and the bilateral common carotid arteries were permanently ligated. Cortical CBF in the hypoperfused rats was markedly decreased at 6 weeks after the operation. In the hypoperfused group, cholinergic indices were changed to consist two phases after the operation, before (acute) and after (chronic) 6 weeks after the operation. At 6 weeks, choline acetyltransferase activity was restored to the sham-operated level compared with the changes in the frontal cortex and thalamus + midbrain at 3 weeks. On the other hand, the maximum number of muscarinic acetylcholine receptors was reduced in the frontal cortex, hippocampus and striatum at 6 weeks and thereafter remained at this low level. In discrimination learning task, the percentage of correct responses in the hypoperfused rats was generally reduced in contrast with that of the sham-operated rats, although the number of total responses were not changed. As a consequence, cholinergic dysfunctions correlate with discrimination learning disabilities in the hypoperfused rats. These findings suggest that the hypoperfused rat may be useful for the cerebrovascular type dementia model to clarify pathophysiology.     

Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain

Though cerebral white matter injury is a frequently described phenomenon in aging and dementia, the cause of white matter lesions has not been conclusively determined. Since the lesions are often associated with cerebrovascular risk factors, ischemia emerges as a potential condition for the development of white matter injury. In the present study, we induced experimental cerebral hypoperfusion by permanent, bilateral occlusion of the common carotid arteries of rats (n=6). A sham-operated group served as control (n=6). Thirteen weeks after the onset of occlusion, markers for astrocytes, microglia, and myelin were found to be labeled by means of immunocytochemistry in the corpus callosum, the internal capsule, and the optic tract. The ultrastructural integrity and oligodendrocyte density in the optic tract were investigated by electron microscopy. Quantitative analysis revealed that chronic cerebral hypoperfusion caused mild astrogliosis in the corpus callosum and the internal capsule, while astrocytic disintegration in the optic tract increased by 50%. Further, a ten-fold increase in microglial activation and a nearly doubled oligodendrocyte density were measured in the optic tract of the hypoperfused rats as compared with the controls. Finally, vacuolization and irregular myelin sheaths were observed at the ultrastructural level in the optic tract. In summary, the rat optic tract appears to be particularly vulnerable to ischemia, probably because of the rat brains angioarchitecture. Since the detected glial changes correspond with those reported in vascular and Alzheimer dementia, this model of cerebral hypoperfusion may serve to characterize the causal relationship between ischemia and white matter damage.     

慢性脑缺血大鼠海马PARP、MDA的表达及阿魏酸钠的抗氧化作用

目的研究慢性脑缺血大鼠海马聚腺苷二磷酸核糖聚合酶(PARP)的表达,并探讨阿魏酸钠在慢性脑缺血所致的氧化应激性损伤中的作用。方法28只成年大鼠用于实验,10只采用双侧颈总动脉结扎制备大鼠慢性脑缺血模型,10只在颈总动脉结扎后给立即予阿魏酸钠腹腔注射,另8只为假手术组。2月后取大鼠海马,采用硫代巴比妥酸法检测丙二醛(MDA)含量,用免疫印迹的方法检测PARP蛋白的表达量。结果慢性脑缺血大鼠海马MDA及PARP蛋白含量明显增多,而经阿魏酸钠治疗后,MDA含量下降,PARP表达下调。结论慢性脑缺血可诱导内源性氧化应激使自由基增多,产生脂质过氧化损伤作用,并导致DNA链的断裂,激活PARP的表达;阿魏酸钠可减少MDA和PARP的生成,在慢性脑缺血氧化应激中起保护作用。     

EGb761对大鼠局灶性脑缺血再灌注损伤的保护作用

目的 :观察 EGb76 1对大鼠局灶性脑缺血再灌注损伤的保护作用。方法 :45只大鼠随机分为假手术组 (A组 ) ,脑缺血再灌注损伤组 (B组 ) ,EGb76 1治疗组 (C组 ) ,每组 15只。以线栓法制作大鼠脑缺血再灌注损伤模型。每组 10只缺血 6 0 min再灌注 6 0 min后断头处死 ,取脑测定 NO、NOS、MDA和 SOD变化 ,其余 5只缺血 3h再灌注 2 4h后断头处死 ,观察常规病理、Niss小体及凋亡细胞变化。C组于实验前 3天开始灌胃给 EGb76 1(15 0 mg/ kg,每日 2次 ,术前 1h、术后 12 h灌 EGb76 115 0 mg/ kg)。结果 :脑缺血再灌注后 ,B组 NO、MDA含量 ,NOS活性较 A组升高 ,SOD活性降低 (P<0 .0 5 ) ,病理变化明显 ,凋亡细胞增多。C组 NO、MDA含量及 NOS活性降低 ,SOD活性升高 (P<0 .0 5 ) ,C组病理变化减轻 ,凋亡细胞减少 (P<0 .0 5 )。结论 :EGb76 1对大鼠局灶性脑缺血再灌注损伤具有保护作用。     

新型脑白质病变动物模型及其脑小血管的病理学研究

目的建立一个新型的具有高血压及脑小血管病理改变的脑白质病变(white matter lesions,WMLs)动物模型。方法 13只雄性Sprague-Dawley大鼠,随机分为假手术组(n=6)与易卒中型肾血管性高血压-改良的2VO组(stroke-prone renovascular hypertensive rat-modified 2 vessel occlusion RHRSP/Modified 2VO)(n=7),RHRSP/Modified 2VO组先行双肾双夹术制作RHRSP模型,12周后间隔1周先后夹闭双侧颈总动脉。双肾双夹术后20周对大鼠进行水迷宫试验观察大鼠是否存在空间记忆功能的受损,组织病理学检测观察是否存在脑白质病变及相应的脑小血管病理学改变。结果双肾双夹术后12周,RHRSP/Modified 2VO组7只大鼠收缩压均大于180 mm Hg;水迷宫实验:RHRSP/Modified 2VO组的逃避潜伏期较假手术组明显升高(P0.05),穿越平台次数及原平台象限停留时间比较假手术组明显降低[(2.5±1.05 vs.5±1.67);(28.04%±14.13%vs.49.69%±13.12%)],差异具有统计学意义(P0.05);RHRSP/Modified 2VO组脑白质病变的分级明显高于假手术组(2.17±0.75 vs.0.33±0.52),差异具有统计学意义(P0.05),且RHRSP/Modified 2VO大鼠存在脑小血管的病理改变(小动脉管壁增厚、血脑屏障破坏及静脉胶原沉积)。结论 RHRSP/Modified 2VO是适用的WMLs动物模型,可用于探究WMLs的发病机制及治疗靶点。     

首乌延寿丹对大鼠局灶性脑缺血的保护作用

目的研究首乌延寿丹对大鼠局灶性脑缺血的保护机制。方法采用改良的线栓法制作大鼠大脑中动脉栓塞模型(MCAO)。将健康成年大鼠随机分为5组:假手术组、缺血模型组、缺血前首乌延寿丹低、中、高处理组。测定丙二醛(MDA)含量、超氧化物歧化酶(SOD)、过氧化氢酶(CAT),并进行病理组织学检查。结果首乌延寿丹能明显提高缺血脑组织中SOD、CAT活性,降低MDA含量,减轻脑水肿,首乌延寿丹能改善脑缺血造成的大鼠脑组织损伤。结论首乌延寿丹对大鼠局灶性脑缺血有明显的保护作用,其机制可能是通过有效的拮抗自由基损伤,提高脑组织抗氧化能力来实现的。     

Cumulative white matter changes in the gerbil brain under chronic cerebral hypoperfusion

Summary An animal model of chronic brain hypoperfusion has been developed by applying coiled clips to the bilateral carotid artery of Mongorian gerbils. The brain tissue damage was neuropathologically studied after 1, 4, 8, and 12 weeks of hypoperfusion. The hippocampus, basal ganglia, and cerebral cortex of the chronically hypoperfused gerbil showed lesions with various severity which are probably due to ischemic episodes. In the cerebral white matter, however, two types of lesions were observed; one similar to those in the gray matter, and the other observed only in the white matter after more than an 8-week duration of brain hypoperfusion. The lesion specific to the white matter showed rarefaction and gliosis without locally associated ischemic changes. This type of the white matter lesion was never found in the gerbil brain before 8 weeks and, significantly, increased in number and size by 12 weeks post operation. The accumulation of the white matter lesions is characteristic in the gerbil with chronic hypoperfusion. The observed white matter-specific lesion resembles the histological changes in aged brain with cerebrovascular diseases.     

甲基维生素B12对拟血管性痴呆大鼠记忆功能及脑白质病理变化的影响

目的 观察甲基维生素B12对拟血管性痴呆大鼠记忆功能及脑白质病理变化的影响。方法 反复前脑缺血制备大鼠拟血管性痴呆模型，造模后甲基维生素B12治疗1周、2周、4周时Morris水迷宫检测大鼠学习记忆功能、LFB染色观察白质髓鞘变化、电镜下观察少突胶质细胞、髓鞘超微结构，并与假手术组及对照组对比。结果 治疗4周大鼠游迷宫时间明显短于对照组，造模2周、4周时LFB染色均可见白质髓鞘脱失，但治疗组明显较对照组轻。造模4周电镜下少突胶质细胞、髓鞘改变治疗组轻于对照组。结论 甲基维生素B12能改善拟血管性痴呆大鼠记忆功能，并能减轻脑白质病理变化。     

Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat

Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52–64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter. Using the TUNEL method, the number of cells showing DNA fragmentation increased three- to eightfold between 3 and 30 days post-surgery compared to sham-operated animals. Double labeling with TUNEL and immunohistochemistry for markers of either astroglia or oligodendroglia showed that DNA fragmentation occurred in both of these glia. Messenger RNA for caspase-3 increased approximately twofold versus the sham-operated rats between 1 and 30 days post-surgery. Immunohistochemistry revealed up-regulation of caspase-3 in the oligodendroglia of the white matter, and also in the astroglia and neurons of the gray matter. Molecules involved in apoptotic signaling such as TNF- and Bax were also up-regulated in glial cells. These results indicate that chronic cerebral hypoperfusion induces white matter degeneration in association with DNA fragmentation in oligodendroglia.