rhG—CSF增加实验性脑缺血周围区的nestin蛋白表达

目的研究重组人粒细胞集落刺激因子(recombinant human granulocyte colony-stimulatingfactor,rhG-CSF)对大鼠局灶性脑缺血的神经元保护作用.方法用线栓法建立大鼠大脑中动脉缺血再灌注模型,于再灌注不同时间点对治疗组和对照组进行神经缺损评分(NSS);并用免疫组织化学方法测定神经上皮干细胞蛋白(nestin)的表达.结果与对照组相比,rhG-CSF治疗组大鼠的神经缺损评分明显降低(P＜0.05);治疗组脑梗死区周围的nestin表达较对照组增多.结论脑缺血再灌注后,一定剂量rhG-CSF可能通过提高nestin的表达,增加神经细胞的修复,改善脑卒中的预后.     

兴奋性氨基酸在缺血性海马神经元损害中的作用的研究

采用大鼠全脑缺血模型,研究脑缺血再灌流海马氨基酸含量的动态变化及相应病理改变,观察NMDA(N-甲基-D-门冬氮酸)受体拮抗剂MK-801的疗效,提示兴奋性氨基酸(Glu,Asp)可能参与海马神经元损害,MK-801能有效防止海马CA_1区迟发性神经元坏死。兴奋性氨基酸受体拮抗剂的研究,将为临床缺血性中风治疗提供新的途径。     

通心络对大脑中动脉栓塞模型大鼠脑缺血后脑组织caspase-3、P53和HSP70的影响

目的探讨通心络胶囊在缺血脑保护方面的作用机制。方法采用线栓法制备大鼠大脑中动脉闭塞(MCAO)模型。将SD大鼠随机分为假手术组、MCAO模型组、MK-801组及通心络大、小剂量治疗组。MK-801组按体重0.5 mg/(kg.d)经腹腔注射MK-801,1次/d;通心络大、小剂量治疗组分别按体重1.0、0.5 g/(kg.d)给予通心络原粉灌胃,2次/d。采用流式细胞、Western blot及RT-PCR技术观察通心络对大鼠脑缺血后神经细胞凋亡率和caspase-3、P53、HSP70蛋白及其mRNA表达的影响。结果通心络和MK-801均可明显降低MCAO模型大鼠缺血后各时间点脑部神经细胞凋亡百分率(P<0.05,P<0.01),以通心络大剂量治疗组效果最显著;模型组caspase-3、P53蛋白及其mRNA表达较假手术组4明显增高,通心络和MK-801均可使其表达降低,其中通心络大剂量治疗组最显著(P<0.01);与模型组比较,各治疗组HSP70蛋白及其mRNA表达明显增高(P<0.05,P<0.01)。结论通心络可降低MCAO模型大鼠神经细胞凋亡百分率而发挥脑保护作用,其机制可能与抑制细胞凋亡相关因子caspase-3、P53表达及促进应激保护性HSP70表达有关。     

缺血后处理通过NMDA受体对全脑缺血大鼠的神经保护作用

目的观察缺血后处理对大鼠全脑缺血再灌注损伤的神经保护作用,并探讨NMDA受体在该过程中的作用。方法采用4-VO法制备全脑缺血模型,将30只SD大鼠完全随机分为假手术组(S组)、全脑缺血(15 min)再灌注组(I/R组)、缺血后处理组(15 s/15 s,3cycle)(IP组)、NMDA受体阻滞剂MK-801预处理组(IP+MK-801组)、NR2B选择性受体阻滞剂ifenprodil预处理组(IP+ifenprodil组),以水迷宫、旷场实验及神经功能缺损评分评价其对行为学的影响,以尼氏染色法观察大鼠海马CA1区存活细胞的变化。结果与全脑缺血组大鼠相比,缺血后处理组大鼠逃避潜伏期缩短,穿越平台增加,旷场试验评分及神经功能缺陷评分更低,病理形态学改变减轻,每250μm存活神经元数增多,差异均有统计学意义(P<0.05);上述改变均被MK-801阻断,与缺血后处理组有统计学差异(P<0.05),IP+ifenprodil组的表现与缺血后处理组未见差异。结论 NMDA受体可能参与缺血后处理对全脑缺血大鼠的神经保护作用。     

地卓西平马来酸盐对雄性大鼠自发活动和前脉冲抑制及再认记忆的影响

目的 观察急性腹腔注射N-甲基-D-天冬氨酸(NMDA)受体拮抗剂地卓西平马来酸盐(MK-801)刘大鼠自发活动、感觉运动门控和物体再认记忆的影响,探讨MK-801模拟精神分裂症不同内表现型的适宜剂量.方法 成年雄性SD大鼠共104只,按照体质量采用分层随机化方法进行分组.(1)取SD大鼠48只,分为MK-801小剂量组、MK-801中剂量组、MK-801高剂量组和对照组,每组12只,观察不同剂量MK-801 (0.1、0.2、0.4 mg/kg)对大鼠自发活动的影响;(2)取SD大鼠32只,分为MK-801小剂量组、MK-801中剂量组、MK-801高剂量组和对照组,每组8只,观察不同剂量MK-801(0.1、0.2、0.4 mg/kg)对大鼠前脉冲抑制(PPI)的影响;(3)取SD大鼠24只,分为MK-801小剂量组和对照组,每组12只,观察小剂量MK-801 (0.1 mg/kg)对大鼠物体辨别测试的影响.结果 (1)中高剂量MK-801 (0.2,0.4 mg/kg)呈剂量依赖性诱导大鼠自发活动的增加以及PPI的损害(P＜0.05或P＜0.01),小剂量(0.1 mg/kg)组在自发活动和PPI上与对照组差异无统计学意义(P＞0.05).(2)小剂量MK-801组在物体辨别测试中对新物体的偏爱指数显著低于对照组[(57.79±10.66)％比(73.34±18.52)％,P＜0.05].结论 中高剂量MK-801可引起自发活动和感觉运动门控功能异常,而小剂量在排除运动系统异常的前提下可特异性地破坏大鼠的再认记忆,提示MK-801模拟精神分裂症的不同内表现型时应根据研究目的选择适宜剂量.     

MK-801建立谷氨酸功能低下精神分裂症小鼠模型的研究

目的用谷氨酸N-甲基-D-天冬氨酸(NMDA)受体非竞争性拮抗剂地卓西平马来酸盐(MK-801)建立谷氨酸功能低下精神分裂症小鼠模型,评价MK-801不同剂量时对这种模型的行为学改变,探讨其适宜剂量。方法根据文献及预试验,确定MK-801的实验剂量,用DigBehv自发活动视频分析系统测定腹腔注射MK-801不同剂量组小鼠的自发活动,用评分量表评价小鼠的刻板行为,并与注射生理盐水组比较。结果MK-801(0．125～0．50 mg／kg)呈剂量依赖性增加小鼠的自发活动和刻板行为。MK-801剂量为0．25 mg／kg时能显著增加小鼠的自发活动和刻板行为,而且从行为学方面评定,没有明显的神经毒性作用。0．50 mg/kg剂量组出现了后肢肌力障碍和明显的共济失调等神经毒性表现。结论0．25 mg／kg的MK-801可作为谷氨酸功能低下小鼠模型的最适宜剂量,引起的行为学改变能够客观量化。     

NMDA受体拮抗剂MK-801对新生大鼠室管膜下区胶质纤维酸性蛋白表达的影响

目的研究N-甲基-D-天冬氨酸(NMDA)受体拮抗剂MK-801对新生7 d大鼠室管膜下区(SVZ)胶质纤维酸性蛋白(GFAP)表达的影响。方法将40只新生SD大鼠分成对照组和MK-801组,各组按出生后(P)时间点再随机分成4个亚组:P7 d、P14 d、P21 d、P28 d组。新生大鼠均于生后第3天给药,MK-801组腹腔注射MK-801 10 mg.kg-1;对照组腹腔注射同量生理盐水。通过免疫组化学方法观察大鼠SVZ区GFAP阳性细胞数。结果①对照组GFAP阳性细胞数于P14 d开始增加,至P21 d达最大值;但P28 d时阳性细胞迅速下降;②MK-801组GFAP阳性细胞数与对照组相比,P7 d和P28 d无明显差异,P14 d(65.40±6.11)和P21 d(239.60±12.92)细胞数明显减少;而对照组P14 d(79.20±5.26)、P21 d(265.20±7.40)GFAP阳性细胞数明显增多,差异有显著统计学意义(P<0.01)。结论 NMDA受体拮抗剂MK-801对正常新生大鼠SVZ区GFAP的表达有抑制作用,能够抑制SVZ区神经干细胞的增殖和分化。     

莱菔硫烷对大鼠局灶性脑缺血再灌注损伤的保护作用及机制研究

目的 探讨莱菔硫烷对大鼠局灶性脑缺血再灌注损伤的保护作用及机制.方法 采用线栓法制备大鼠大脑中动脉阻断局灶性脑缺血模型,分别于MCAO后1h腹腔注射莱菔硫烷2.5mg/kg、5mg/kg、10mg/kg.于缺血2h再灌注24h时进行神经行为缺损评分,TTC染色评价脑梗死体积,测定脑组织中超氧化物歧化酶(SOD)活力和丙二醛(MDA)含量.免疫荧光组织化学染色法检测黄核蛋白NQ01和脂质过氧化酶Prx6的表达.结果 莱菔硫烷给药组与对照组相比均能改善大鼠脑缺血再灌注后神经行为缺损评分,减少脑梗死体积.其中5mg/kg组能显著改善大鼠脑缺血再灌注后神经行为缺损评分,减少脑梗死体积,增强SOD活性,降低MDA含量.免疫荧光组织化学染色法提示NQ01和Prx6的表达明显增强.结论 莱菔硫烷对大鼠局灶性脑缺血再灌注损伤有神经保护作用,其机制可能与上调内源性抗氧化蛋白NQ01和Prx6的表达有关.     

N-Methyl-D-Aspartate受体拮抗剂对大鼠海马神经干细胞内源性激活的实验研究

目的研究N-Methyl-D-Aspartate(NMDA)受体拮抗剂MK-801对大鼠神经干细胞(NSC)内源性激活的作用.方法将不同年龄阶段(10 d、3月、10月)的SD大鼠分为实验组和对照组,实验组腹腔注射MK-801,对照组腹腔注射生理盐水,用免疫组织化学方法测定两组大鼠海马齿状回颗粒层(SGZ)的Brdu阳性细胞、Nestin阳性细胞表达数.结果2组的10 d幼鼠,Brdu阳性细胞、Nestin阳性细胞增殖均不明显,2组无显著差异(P＞0.05),而在3月成年鼠实验组Brdu阳性细胞7 d达高峰,Nestin阳性细胞11 d达高峰,较对照组增殖较明显(P＜0.05);实验组10月老龄鼠Brdu阳性细胞、Nestin阳性细胞表达更明显,并可持续到18 d,2组比较统计学有显著意义(P＜0.01).结论NMDA受体拮抗剂MK-801可明显促进3月成鼠、10月老年鼠脑中NSC的增殖、分化.     

代谢型谷氨酸受体1亚型选择性拮抗剂LY367385对抗大鼠缺血性脑水肿

目的研究代谢型谷氨酸受体1亚型（mGluR1）选择性拮抗剂LY367385对大鼠缺血性脑水肿的影响.方法Wistar雄性大鼠（280～320g）线栓法复制大脑中动脉闭塞（MCAO）脑缺血模型.动物随机分为生理盐水（NS）对照组、LY367385给药组及MK-801给药组,于MCAO后1min,侧脑室内注射NS或LY367385（500nmol）5μl,或腹腔注射MK-801（1mg/kg）.各组动物分别于MCAO 6、24h进行神经病学评分、脑含水量测定及脑梗死面积测定.结果LY367385明显改善大鼠脑缺血引起的神经症状,而MK-801在MCAO 6h增加神经病学评分.LY367385降低大鼠MCAO引起的脑含水量增加,MK-801无明显作用.LY367385及MK-801均降低脑梗死面积百分率,且LY367385作用优于MK-801.结论LY367385能对抗大鼠脑缺血性脑水肿,作用明显优于MK-801.     

Caffeine-induced expression of c-fos mRNA and NGFI-A mRNA in caudate putamen and in nucleus accumbens are differentially affected by the N-methyl-d-aspartate receptor antagonist MK-801

Caffeine (100 mg/kg, i.p.) induces a rapid increase in the expression of mRNA for the immediate early genes (IEGs) c-fos and NGFI-A in rat striatum. We have examined how this response is affected by pretreatment with either the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (1 and 3 mg/kg, i.p.), the competitive NMDA receptor antagonist D-CPP (6 mg/kg, i.p.), or the non-selective excitatory amino acid receptor antagonist kynurenic acid (300 mg/kg, i.p.). The two NMDA receptor antagonists significantly reduced the caffeine-induced expression of both c-fos mRNA and NGFI-A mRNA in the medial part of the caudate putamen. The effect was less pronounced in the lateral part of the caudate putamen. MK-801 caused an enancement of c-fos and NGFI-A mRNA expression in nucleus accumbens. Pretreatment with kynurenic acid caused no marked alterations in the caffeine-induced expression of c-fos mRNA and NGFI-A mRNA in any brain region. These findings suggest that glutamatergic transmission via NMDA receptors contributes to the induction of c-fos mRNA and NGFI-A mRNA by caffeine in striatum. In addition we show that MK-801 can either increase or decrease the caffeine effect of IEGs depending on the region studied.     

Effects of MK-801 on DNA synthesis in neonatal rat brain regions under normoxic and hypoxic conditions

Global metabolic insults such as ischemia/hypoxia, damage neural cells through release of excitatory amino acids and their subsequent actions at the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are highly expressed in neonatal rat brain, and the current study examines the effects of receptor blockade with MK-801 on DNA synthesis under normoxic and hypoxic conditions. At one day of age, hypoxia alone caused a decrease in [3H]thymidine incorporation into DNA throughout the brain, whereas MK-801 alone decreased incorporation selectively in regions known to be enriched in NMDA receptors. MK-801 afforded no protection from hypoxia and instead exacerbated the effects of hypoxia in the cerebellum. At 8 days of age, hypoxia alone or MK-801 alone still produced the same patterns of inhibition of DNA synthesis, but MK-801 neither prevented nor exacerbated the effects of hypoxia; animals receiving MK-801 showed a significant incidence of hypoxia-induced mortality. These data suggest that excitatory actions exerted at the NMDA receptor serve to maintain cell replication in neonatal brain and, as distinct from the situation for excitatory amino acid-induced cell death, these receptors do not participate in adverse effects of hypoxia on DNA synthesis.     

Comparison of the neuroprotective effects of the N-methyl-D-aspartate antagonist MK-801 and the opiate-receptor antagonist nalmefene in experimental spinal cord ischemia

Both N-methyl-D-aspartate (NMDA)-receptor antagonists and opiate-receptor antagonists have been shown to limit tissue damage after ischemic central nervous system injury. We compared the neuroprotective effects of the noncompetitive NMDA-receptor antagonist MK-801 and the opiate-receptor antagonist nalmefene in a model of global spinal cord ischemia and reperfusion in unanesthetized rabbits. MK-801 (1 mg/kg) or nalmefene (0.1 mg/kg) was administered intravenously 5 minutes after reperfusion. MK-801 treatment and nalmefene treatment each significantly improved the neurologic and histologic outcome compared with saline controls. Differences in these outcome measures between MK-801 treatment and nalmefene treatment did not reach statistical significance. Our results are consistent with the hypothesis that multiple factors, including endogenous opioids and excitatory amino acids, contribute to the secondary tissue injury after central nervous system ischemia. These data also provide further evidence that therapeutic interventions with opiate-receptor antagonists or NMDA antagonists may be beneficial in limiting neurologic dysfunction after ischemic brain or spinal cord injury.     

Protective effect of the glutamate antagonist, MK-801 in focal cerebral ischemia in the cat

The effects of the glutamate N-methyl-D aspartate (NMDA) receptor antagonist, MK-801, upon ischemic brain damage has been examined in anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery and the animal were killed 6 h later. The amount of early ischemic damage was assessed in coronal sections at 16 predetermined stereotactic planes. Pretreatment with MK-801 (5 mg/kg, i.v.), 30 min before occlusion of the middle cerebral artery significantly reduced the volume of ischemic damage (from 32.7 +/- 4.0% of the cerebral hemisphere in vehicle-treated cats to 16.2 +/- 4.5% in MK-801-treated cats). NMDA receptor antagonists that penetrate the blood-brain barrier, such as MK-801, merit further study as protective agents against ischemic brain damage.     

The excitatory amino acid receptor antagonist MK-801 prevents the hypersensitivity induced by spinal cord ischemia in the rat.

Protection by the NMDA receptor antagonist MK-801 against transient spinal cord ischemia-induced hypersensitivity was studied in rats. The spinal ischemia was initiated by vascular occlusion resulting from the interaction between the photosensitizing dye Erythrosin B and an argon laser beam. The hypersensitivity, termed allodynia, where the animals reacted by vocalization to nonnoxious mechanical stimuli in the flank area, was consistently observed during several days after induction of the ischemia. Pretreatment with MK-801 (0.1-0.5 mg/kg, iv) 10 min before laser irradiation dose dependently prevented the occurrence of allodynia. The neuroprotective effect of MK-801 was not reduced by maintaining normal body temperature during and after irradiation. There was a significant negative correlation between the delay in the administration of MK-801 after irradiation and the protective effect of the drug. Histological examination revealed slight morphological damage in the spinal cord in 38% of control rats after 1 min of laser irradiation without pretreatment with MK-801. No morphological abnormalities were observed in rats after pretreatment with MK-801 (0.5 mg/kg). The present results provide further evidence for the involvement of excitatory amino acids, through activation of the NMDA receptor, in the development of dysfunction following ischemic trauma to the spinal cord.     

Tissue plasminogen activator-induced ischemic injury is reversed by NMDA antagonist MK-801 in vivo

In vitro studies suggested that tissue plasminogen activator (t-PA) may aggravate ischemic injury by enhancing N-methyl-D-aspartate (NMDA) receptor signalling. It remained unclear whether NMDA signalling is also relevant for t-PA toxicity in vivo. We herein examined effects of intravenous t-PA (10 mg/kg), administered alone or in combination with the NMDA antagonist MK-801 (0.2 mg/kg), following 90 min of middle cerebral artery occlusion in mice. In our study, MK-801 alone, administered intraperitoneally, neither affected infarct volume nor brain swelling at 24 h after reperfusion. t-PA significantly increased infarct size, in accordance with previous findings. t-PA-induced ischemic injury was completely abolished and brain swelling markedly reduced when t-PA-treated animals received additional MK-801 injections. To elucidate how t-PA influences brain damage, we examined actions of t-PA on the expression of NO synthases by immunohistochemistry, showing that t-PA does not influence neuronal NO synthase, but increases inducible NO synthase in ischemic areas. The effect of t-PA on inducible NO synthase levels was completely reversed after cotreatment with MK-801. Our study provides in vivo evidence in a model of focal cerebral ischemia that t-PA-induced brain injury involves an NMDA receptor-dependent mechanism.     

The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat

Excessive activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in the sequence of neurochemical events that results in irreversible neuronal damage in cerebral ischemia. The effects of the NMDA antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) upon the amount of ischemic brain damage has been assessed quantitatively in the lightly anesthetized rat. Focal cerebral ischemia was produced by the permanent occlusion of one middle cerebral artery (MCA), and the animals were killed 3 hours after the arterial occlusion. MK-801 (0.5 mg/kg) was administered intravenously either 30 minutes prior to MCA occlusion or 30 minutes after the induction of ischemia. Pretreatment with MK-801 reduced the volume of ischemic damage both in the cerebral cortex (by 38% compared with untreated rats with MCA occlusion; p less than 0.01) and in the caudate nucleus (by 18% compared with controls; p less than 0.05). Treatment with MK-801, initiated 30 minutes after MCA occlusion, reduced the volume of ischemic damage in the cerebral cortex (by 52% compared with controls; p less than 0.01). The volume of ischemic damage in the caudate nucleus was minimally influenced by MK-801 treatment initiated after MCA occlusion. The antiischemic effects of MK-801 were readily demonstrable despite the hypotension that MK-801 induced in rats anesthetized with halothane (0.5%), nitrous oxide (70%), and oxygen (30%). The potency of MK-801 in reducing ischemic brain damage, even when administered after the induction of ischemia, highlights the potential use of NMDA receptor antagonists for the treatment of focal cerebral ischemia in humans.     

Interaction between free radicals and excitatory amino acids in the formation of ischemic brain edema in rats

Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle, low-dose (375 mg/kg) dimethylthiourea, high-dose (750 mg/kg) dimethylthiourea, low-dose (0.5 mg/kg) MK-801, high-dose (2.0 mg/kg) MK-801, or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia, brain water content was determined. In eight vehicle-treated controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 83.29 +/- 0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example, 50.2% (p less than 0.001) in the high-dose dimethylthiourea group, 53.7% (p less than 0.001) in the low-dose MK-801 group, and 66.4% (p less than 0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

NMDA receptor antagonism does not inhibit induction of ischemic tolerance in gerbil brainin vivo

Effects of high and moderate affinity uncompetitive NMDA receptor antagonists (+)MK-801 and memantine on ischemic tolerance were compared in relation to telemetrically controlled brain temperature. The tolerance to an injurious 3 min test of global forebrain ischemia in Mongolian gerbils was induced 48 h earlier by 2 min preconditioning ischemia. Normothermic preconditioning was virtually harmless, and greatly reduced neurodegeneration evoked by test ischemia. In hyperthermic animals it was injurious and failed to induce tolerance. Memantine (5 mg/kg) and (+)MK-801 (3 mg/kg) injected i.p. 1 h before preconditioning did not inhibit ischemic tolerance in the normothermic gerbils, while in hyperthermic animals treated with (+)MK-801 ischemic tolerance was partially restored. Subchronic 3 day infusion of memantine (30 mg/kg/day) significantly decreased neurodegeneration, and preconditioning in the normothermic gerbils further reduced neuronal damage. Hyperthermia exacerbated preconditioning ischemia and in this way reduced expression of tolerance, while (+)MK-801 partially reversed this effect. Our results do not confirm previous reports on the role of NMDA receptors in the induction of ischemic tolerance in gerbils.     

The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats

The neuroprotective effects of dizocilipine maleate (MK-801), a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor/channel, were tested in the 4-vessel occlusion rat model of forebrain ischemia. Adult Wistar rats, treated intraperitoneally with MK-801 or saline using several different treatment paradigms were subjected to 5 (n = 208) or 15 (n = 62) min of severe, transient forebrain ischemia. In saline-treated animals, 15 min of ischemia (n = 13) produced extensive and consistent loss of pyramidal neurons in the CA1 zone of hippocampus. The degree and distribution of cell loss were not reduced by single dose preischemic administration of MK-801 at 1 (n = 7), 2.5 (n = 4), or 5 mg/kg (n = 8). In other animals subjected to 15 min of forebrain ischemia, multiple doses of MK-801 (5, 2.5, and 2.5 mg/kg) given immediately and at approximately 8 and 20 hr after cerebral reperfusion (n = 5) did not alter CA1 injury compared to saline-treated controls (n = 5). Five minutes of forebrain ischemia in saline-treated animals, (n = 82) resulted in significantly fewer (p less than 0.001) dead CA1 pyramidal cells and a greater variance compared to animals subjected to 15 min of ischemia. Power analysis of the preliminary saline-treated animals subjected to 5 min of ischemia (n = 22) indicated that 60 animals per group were necessary to detect a 15% difference between MK-801 and vehicle-treated groups. Multidose treatment with MK-801 (1 mg/kg) given 1 hr prior to 5 min of ischemia (n = 60) and again at approximately 8 and 16 hr after recirculation failed to attenuate hippocampal injury.(ABSTRACT TRUNCATED AT 250 WORDS)