脑缺血再灌流时脑温的动态改变

目的了解脑缺血再灌流后脑温的变化,为脑缺血动物的实验研究、以及亚低温脑保护作用机制提供理论依据。方法将SD大鼠分为四动脉阻断、双颈总动脉阻断、单侧颈总动脉阻断以及四动脉阻断10min、20min、30min后再灌流组。用点式测温仪同时测量不同部位脑组织的温度。结果脑组织内存在温度梯度;脑缺血后同一时间点纹状体、海马和颞肌的温度不一致;不同程度脑缺血后脑温的变化不一致,双侧颈总动脉阻断的脑缺血中脑温的改变呈波浪状,单侧颈总动脉阻断的脑缺血中缺血侧脑温低于对照侧;四动脉阻断的全脑缺血中,缺血后不同时间开始再灌流脑温都有回升现象;脑缺血的严重程度和持续时间可影响动物的清醒和脑温的变化。结论本实验的结果说明了在脑缺血实验研究时采用连续监测、并将脑温控制在特定的范围内,避免脑缺血和再灌流期间脑温的波动影响实验结果的准确性。     

复方丹参片对慢性脑缺血大鼠脑内VEGF表达的影响

目的研究中药复方丹参对慢性脑缺血大鼠脑内VEGF表达的影响,探讨复方丹参治疗慢性脑缺血的作用机制。方法采用永久性双侧大鼠颈总动脉结扎术(2VO)制备大鼠慢性脑缺血模型。术后每日给予复方丹参0.75mg/kg灌胃,对照组给予同等量蒸馏水,1次/d,共8周。用免疫组化法观察2VO大鼠脑内VEGF表达。结果药物组大鼠脑内VEGF表达明显增强。结论复方丹参片可显著增加2VO大鼠脑内VEGF的表达,提示复方丹参片可促进VEGF在大鼠脑内表达,促进慢性脑缺血的代偿修复。     

茶多酚对脑缺血大鼠脑内少突胶质细胞的影响

目的 观察茶多酚对脑缺血大鼠脑内少突胶质细胞（OLG）的影响。方法 将雄性SD大鼠随机分为假手术组、对照组、茶多酚组。制备全脑缺血模型后，茶多酚组大鼠被分为3组分别按剂量25mg／kg、50mg／kg、100mg／kg茶多酚予以腹腔注射，每日1次，连续7d；免疫组化法检测各组大鼠皮质前体OLG、未成熟OLG及成熟OLG的变化。结果 与假手术组比较，对照组皮质前体OLG明显增多，未成熟OLG及成熟OLG明显减少（均P〈0．05）；与对照组比较，茶多酚干预后皮质前体OLG有不同程度的减少，未成熟OLG及成熟OLG则有不同程度的增加，差异有统计学意义（25mg／kg、100mg／kg，均P〈0．05；50mg／kg，P〈0.01）。结论 茶多酚对OLG缺血性反应有保护作用，并呈现剂量依赖性。     

不同剂量BPI-1095对大鼠局灶性脑缺血损伤后Bcl-2蛋白表达的影响

目的:观察不同剂量BPI-1095对大鼠脑缺血后梗死面积百分数和神经元Bcl-2蛋白表达的影响，探讨BPI-1095对大鼠局灶性脑缺血损伤的保护作用及可能机制。 方法:建立大鼠局灶性脑缺血模型，随机分成6组：（1）BPI-1095大剂量（240 mg/kg）组；（2）BPI-1095中剂量（80 mg/kg）组；（3）BPI-1095小剂量（27 mg/kg）组；（4）阿司匹林（80 mg/kg）组；（5）安慰剂组；（6）假手术组。于模型建立10min后灌胃给予不同剂量的药物，24 h后断头取脑，应用免疫组化方法观察各组Bcl-2蛋白表达，同时用氯化三苯四唑（TTC）染色，测定大鼠大脑半球梗死面积百分数。结果:（1）BPI-1095大、中剂量治疗组梗死面积百分数明显小于安慰剂组（P <0.05）；而中小剂量组与阿司匹林组间比较没有统计学差异。（2）各组脑组织缺血周边和皮层凋亡保护蛋白Bcl-2表达阳性细胞较非缺血侧明显增多（P <0.05），以大剂量组最为明显，其阳性细胞百分数与安慰剂组和阿司匹林组比较均有统计学差异（P <0.05）。（3）BPI-1095不同剂量组之间Bcl-2蛋白表达没有统计学差异，不具有剂量依赖性。结论:BPI-1095对局灶性脑缺血有神经保护作用，以大剂量治疗组及中剂量治疗组疗效显著。其作用机制与上调Bcl-2蛋白的表达有关。     

蛇床子素在缺血再灌注脑损伤模型中的脑保护作用

目的研究蛇床子素（osthole）在缺血再灌注脑损伤中的脑保护作用。方法实验用SD大鼠55只随机分为假手术组、模型组和三个不同剂量给药组（Ost）,其中模型组和给药组采用四血管阻塞法大鼠全脑缺血模型（4VO模型）。各给药组于缺血15min再灌注后1h给予5mg／kg、25mg／kg、125mg／kg蛇床子素腹腔注射治疗。各实验组动物在进行神经功能学评分后,分别用于分析海马CA1区细胞组织形态学变化和caspase3蛋白半定量分析,评价蛇床子素在缺血再灌注脑损伤后的脑保护作用。结果缺血15min再灌注后1h给药的各蛇床子素治疗组大鼠的行为学评分和组织形态学分析结果均明显优于模型组（P〈0．01）并在25mg／kg剂量时表现出最大保护效果,其caspase3表达水平显著降低。结论蛇床子素在脑缺血再灌注脑损伤后有一定的脑保护作用。     

麻醉剂对大鼠脑温变化规律的影响

目的探讨不同麻醉方式对大鼠脑温变化规律的影响。方法大鼠随机分为水合氟醛腹腔麻醉组和七氟烷吸入麻醉组。大鼠麻醉后，持续监测皮质、纹状体温度和肛温变化。结果腹腔麻醉组脑温波动明显；而吸入麻醉组温度相对稳定。结论七氟烷吸入麻醉对大鼠脑温影响较小。     

TMB—8对脑缺血大鼠脑血流量的作用

目的 研究8－（N，N－二乙胺）－n－辛基－3，4，5－三甲氧基苯甲酸酯（TMB－8）对局灶性脑缺血大鼠脑血流量（CBF）的作用。方法 用激光多谱勒血流仪测量大脑中动脉阻断（MCAO）大鼠脑血流量。分别于阻断前30分钟和阻断后20分钟给予TMB－8进行干预。结果 MCAO后，CBF迅速下降，维持恒定。阻断前30分钟给予TMB－8 0．5、1和2mg/kg，可剂量依赖性抑制CBF下降，阻断后20分钟给予TMB－8 1mg/kg，也能明显增加CBF。结论 TMB－8能预防和治疗MCAO局灶性脑缺血大鼠CBF减少，改善缺血区血供。     

脑温不同对缺血脑组织细胞坏死和凋亡的影响

低温用于治疗脑缺血和重型颅脑外伤已取得一定进展。但脑缺血后将脑温控制到何种程度 ,既能使其发挥最大的护脑作用 ,又不产生严重并发症 ,未见统一标准。本实验以大鼠全脑缺血再灌注模型 ,观察脑缺血后不同程度降温对脑细胞变性坏死和凋亡的影响。1　材料和方法1 .1　实验动物     

胡黄连苷Ⅱ对大鼠脑缺血性损害和基质金属蛋白酶-9表达的影响及治疗的最佳时间窗与剂量的选取

目的探讨胡黄连苷Ⅱ对大鼠脑缺血性损伤和基质金属蛋白酶-9(MMP-9)表达的影响,以及最佳治疗时间窗与剂量的选取。方法将174只Wistar大鼠随机分为脑缺血组、正常对照组和治疗组,按正交试验设计治疗组大鼠再分为缺血1.0 h、1.5 h、2.0 h、2.5 h,以及分别用胡黄连苷Ⅱ5 mg/kg、10 mg/kg、20mg/kg和40 mg/kg亚组。用双侧颈总动脉结扎法制作脑缺血大鼠模型,治疗组大鼠按相应时间点和剂量经腹腔注射胡黄连苷Ⅱ。用HE染色观察脑变性细胞指数(DCI)及形态;电镜观察脑组织超微结构。免疫组化染色和Western blot法检测脑组织MMP-9蛋白水平,逆转录(RT)-PCR检测MMP-9 mRNA水平。结果脑缺血组大鼠脑组织损害和MMP-9表达水平明显高于正常对照组(均P0.05)。与脑缺血组比较,治疗组的脑组织损害及DCI和MMP-9表达水平明显减轻和降低(均P0.05)。治疗组各亚组间两两比较,缺血1 h亚组与2 h、2.5 h亚组间脑DCI的差异有统计学意义(均P0.05);缺血2 h与2.5 h亚组间的脑MMP-9阳性细胞指数,缺血1 h与1.5 h、2 h亚组,1.5 h与2.5 h亚组,2 h与2.5 h亚组间的脑MMP-9蛋白水平的差异均有统计学意义(均P0.05);以及剂量5 mg/kg与20 mg/kg亚组间的脑MMP-9 mRNA水平的差异有统计学意义(均P0.05)。各剂量亚组间的脑DCI、MMP-9阳性细胞指数和蛋白水平的差异均无统计学意义(均P0.05)。结论胡黄连苷Ⅱ能抑制大鼠脑缺血后MMP-9的表达,并有显著的脑保护作用。按治疗时间窗最大化和用药剂量最小化的原则,其最佳的治疗时间窗为脑缺血后2 h内,剂量为(10~20)mg/kg。     

门冬氨酸钾对局灶性脑缺血再灌注大鼠的保护作用研究

目的 观察门冬氨酸钾对大鼠局灶性脑缺血再灌注后神经细胞凋亡的保护作用。 方法 采用雄性SD大鼠右侧大脑中动脉闭塞模型,缺血2 h,再灌注22 h。大鼠随机分为5组,每组10 只,在缺血后1 h经腹腔注射给予生理盐水（1 ml/kg）或不同剂量门冬氨酸钾（10 mg/kg、25 mg/kg、 62.5 mg/kg和125 mg/kg）,观察不同剂量门冬氨酸钾对大鼠脑缺血再灌注后神经功能缺损和梗死 体积的影响。另取32只大鼠随机分为溶剂对照组和门冬氨酸钾组,在缺血后1 h腹腔注射生理盐水 （1 ml/kg）或门冬氨酸钾（62.5 mg/kg）,同时设立假手术组16只,检测三组大鼠脑组织三磷酸腺苷 （adenosine triphosphate,ATP）和乳酸水平（每组10只）,以及凋亡性细胞情况（每组6只）。 结果 与溶剂对照组比较,62.5 mg/kg剂量的门冬氨酸钾能显著改善神经功能缺损（P <0.001）, 降低梗死体积（P =0.011）;与溶剂对照组比较,25 mg/kg剂量的门冬氨酸钾能减少梗死体积 （P =0.040）,但神经功能评分无差异;10 mg/kg和125 mg/kg剂量的门冬氨酸钾组神经功能评分和 梗死体积与溶剂对照组均无差异。与溶剂对照组比较,门冬氨酸钾（62.5 mg/kg）能减少ATP的下降 （P =0.036）和细胞凋亡（P <0.001）。 结论 门冬氨酸钾对大鼠局灶性脑缺血再灌注后的细胞凋亡有保护作用。     

7—nitro—indazole减小大鼠暂时性局灶性脑梗塞灶范围

目的探讨神经元型一氧化氮合酶（ｎＮＯＳ）在暂时性局灶性脑缺血中的作用。方法用栓线法建立了大脑中动脉阻塞（ＭＣＡＯ）模型的大鼠上，观察特异性ｎＮＯＳ抑制剂７－ｎｉｔｒｏ－ｉｎｄａｚｏｌｅ（７－ＮＩ）对大鼠缺血３ｈ、再灌注３ｈ脑梗塞灶范围的影响。结果７－ＮＩ（２５ｍｇ／ｋｇ）可减小大鼠脑梗塞灶范围，且主要减小大脑皮质梗塞灶，其作用可被Ｌ－精氨酸（３００ｍｇ／ｋｇ）逆转，Ｄ－精氨酸（３００ｍｇ／ｋｇ）则否。结论ｎＮＯＳ产生的ＮＯ在暂时性局灶性脑缺血中起损害作用     

Reduction of infarct size by the NO donors sodium nitroprusside and spermine/NO after transient focal cerebral ischemia in rats

Nitric oxide (NO) plays a dual role (neuroprotection and neurotoxicity) in cerebral ischemia. NO promoting strategies may be beneficial shortly after ischemia. Therefore, we have studied the hemodynamic and possible neuroprotective effects of two NO donors, the classical nitrovasodilator sodium nitroprusside (SNP) and the NONOate spermine/NO, after transient focal cerebral ischemia in rats. Parietal cortical perfusion was measured by laser-Doppler flowmetry. The effects of increasing intravenous doses (10-300 microgram) of sodium nitroprusside and spermine/NO on cortical perfusion and arterial blood pressure were assessed. Transient (2 h) focal cerebral ischemia was carried out by the intraluminal thread method. The effects of intraischemic intravenous infusion of SNP (0.11, 1.1 mg/kg) and spermine/NO (0.36, 3.6 mg/kg) on hemodynamic parameters and infarct size developed after 1 week reperfusion were assessed. In control conditions, SNP and, to a lesser extent, spermine/NO induced dose-dependent hypotension and concomitant reduction in cortical perfusion. In focal cerebral ischemia, infusion of SNP (0.11 mg/kg) and spermine/NO (0.36, 3.6 mg/kg) reduced the infarct size. In the case of spermine/NO, cortical perfusion was maintained above the control levels during the ischemic insult. No significant hypotension was elicited by NO donors at the dose-ratios infused. In conclusion, brain damage induced by transient focal ischemia is reduced by intravenous NO donors. Neuroprotective effects of spermine/NO are due at least in part to improvement of brain perfusion, while sodium nitroprusside must provide direct cytoprotection. These results give further support to the protective effect of NO in the early stages of cerebral ischemia and point to the therapeutic potential of NONOates in the management of brain ischemic damage.     

Influence of various agents on the development of brain edema in the rat following microembolism. Protective effect of gamma-butyrolactone

Brain edema was induced in rats by injecting 50 mu microspheres, labelled with 85Sr, into the internal carotid artery. The use of radioactive microspheres as embolic agents enabled the number of microspheres to be determined in each cerebral hemisphere. Edema was assessed 12 or 24 h after embolization by measuring brain water content and, in some experiments, sodium and potassium. Pretreatments with dexamethasone, parachlorophenylalanine (an inhibitor of 5-hydroxytryptamine synthesis), mepyramine and metiamide (H1 and H2 histamine receptor antagonists) or aminophylline did not influence significantly the development of brain edema evaluated 24 h after embolization. Aminophylline treatment (100 mg/kg) markedly increased mortality following embolization. Gamma-butyrolactone (300 mg/kg, every 2 h) inhibited significantly the development of brain edema evaluated 12 hours after embolization. Increases in water and sodium in the embolized cerebral hemisphere were reduced by about 50%. This protective effect may be related to the known depressant action on brain metabolism.     

Do sodium channel blockers have neuroprotective effect after onset of ischemic insult?

OBJECTIVE: Cerebral ischemia causes a series of pathophysiologic events that may result in cerebral infarct. Some neurons are more vulnerable to ischemia, particularly pyramidal neurons in the hippocampal CA1 region. Pharmacologic intervention for treatment of cerebral ischemia aims to counteract secondary neurotoxic events or to interrupt the progression of this process. In the present study, we compare the neuroprotective effects of sodium channel blockers (mexiletine, riluzole and phenytoin) and investigate whether they have neuroprotective effect when given after ischemic insult. METHODS: A transient global cerebral ischemia model was performed in this study by clipping bilateral common carotid arteries during 45 minutes. Riluzole (8 mg/kg), mexiletine (80 mg/kg) and phenytoin (200 mg/kg) were injected into the rats intraperitoneally 30 minutes before or after reperfusion. Lipid peroxidation levels and cerebral water contents were evaluated 24 hours after ischemia. Histopathologic assessment of hippocampal region was determined 7 days after ischemia. RESULTS: Riluzole, mexiletine and phenytoin treatment after global ischemia significantly decreased water content of the ischemic brain (p<0.05 for each). No significant difference was observed in cerebral edema among the drug treatment groups (p>0.05). When pre-treatment and post-treatment groups were compared with each other, only riluzole pre-treatment group revealed better result for cerebral edema (p<0.05). Pre-treatment with these drugs revealed significantly better results for the malonyldialdehyde (MDA) level and the number of survival neuron on the hippocampal region than the post-treatment groups. CONCLUSION: It is demonstrated that riluzole, mexiletine and phenytoin are potent neuroprotective agents in the rat model of transient global cerebral ischemia, but they are more effective when given before onset of the ischemia.     

银杏叶提取物对大鼠缺血再灌注皮质内氨基酸动态平衡的影响

目的 :研究不同浓度银杏叶提取物 (GBE)对大鼠缺血再灌注损伤皮质内氨基酸动态平衡的影响。方法 :将119只 Wistar大鼠随机分为 17组 ,假手术组 7只 ,缺血组 -缺血 3h组 ,缺血 3h分别再灌注 1h、2 h、 3h组各 7只 ;治疗组 (即在缺血前 30分钟给予 GBE5 mg/kg、 10 mg/kg、 15 mg/kg,腹腔给药 ) -缺血 3h、缺血 3h分别再灌注 1h、 2 h、 3h组各 7只。动物模型参照 Zivin JV的大脑中动脉线栓模型并加以改进。结果 :比较缺血组和治疗组 ,可见给予 GBE后能明显减少谷氨酸 (Glu)、天门冬安酸 (Asp)的产生 ,增加了γ-氨基丁酸 (GABA )的生成和释放 ,5 mg/kg组与 10 mg/kg、 15 mg/kg组间有显著差别 ,而后二者间无显著差别。结论 :血小板活化因子拮抗剂 GBE可通过增强抑制性氨基酸的合成、释放 ,降低兴奋性氨基酸的合成、释放来保护缺血的神经元的 ,且与用药剂量有关。     

Effect of indomethacin on edema following single and repetitive cerebral ischemia in the gerbil

BACKGROUND AND PURPOSE: Repetitive periods of cerebral ischemia result in more severe injury than a single period of ischemia of similar total duration. We investigated the possibility of prostaglandin mediation of this increased injury by attempting to modify brain edema formation with indomethacin pretreatment. METHODS: Under halothane/N2O anesthesia, groups of gerbils underwent bilateral carotid occlusion to induce forebrain ischemia. Group I underwent a single 15-minute period of carotid occlusion. Group II underwent three 5-minute periods of occlusion at hourly intervals. Groups III and IV were similar to groups I and II, respectively, but received 0.2 mg/kg indomethacin before carotid occlusion. Cortical and cerebellar water and sodium contents were determined in control animals (n = 6) at time zero and in experimental animals 24, 48, and 72 hours after ischemia (n = 6-10 gerbils/group at each time point). RESULTS: Cortical water and sodium contents in group II peaked 48 hours after insult (82.15 +/- 0.31% and 420 +/- 14 meq/kg dry wt, respectively) and were significantly higher than control and group I values at both 24 and 48 hours. Cortical water did not change from control in group I animals. Indomethacin pretreatment significantly attenuated increases in water and sodium content seen at 48 hours in gerbils undergoing repetitive ischemia (peak 80.02 +/- 0.45% and 300 +/- 39 meq/kg dry wt), but did not affect mortality. CONCLUSIONS: Indomethacin lessens edema after repetitive cerebral ischemia, suggesting that elevations of cyclooxygenase products are responsible, at least in part, for severe brain edema following repetitive ischemia.     

An optimal dose of tea polyphenols protects against global cerebral ischemia/reperfusion injury

Previous studies addressing the protection of tea polyphenols against cerebral ischemia/ reperfusion injury often use focal cerebral ischemia models, and the optimal dose is not unified. In this experiment, a cerebral ischemia/reperfusion injury rat model was established using a modified four-vessel occlusion method. Rats were treated with different doses of tea polyphenols (25, 50, 100, 150, 200 mg/kg) via intraperitoneal injection. Results showed that after 2, 6, 12, 24, 48 and 72 hours of reperfusion, peroxide dismutase activity and total antioxidant capacity in brain tissue gradually increased, while malondialdehyde content gradually decreased after tea polyphenol intervention. Tea polyphenols at 200 mg/kg resulted in the most apparent changes. Terminal deoxynucleotidyl transferase-mediated nick end labeling and flow cytometry showed that 200 mg/kg tea polyphenols significantly reduced the number and percentage of apoptotic cells in the hippocampal CA1 region of rats after cerebral ischemia/reperfusion injury. The open field test and elevated plus maze experiments showed that tea polyphenols at 200 mg/kg strengthened exploratory behavior and reduced anxiety of cerebral ischemia/reperfusion injured rats. Experimental findings indicate that tea polyphenols protected rats against cerebral ischemia/ reperfusion injury and 200 mg/kg is regarded as the optimal dose.     

Protective effect of phenytoin and its enhanced action by combined administration of mannitol and vitamin E in cerebral ischemia

Phenytoin is well known as the anticonvulsant agent and also said to protect the brain against ischemic damage. The purpose of the present experiment is to study the therapeutic effect of phenytoin on cerebral ischemia and confirm whether the effectiveness of phenytoin could be enhanced by combination of free radical scavengers such as mannitol and vitamin E. In this experiment, twenty-five dogs were subjected to ischemia, using the "canine model of complete ischemic brain regulated with a perfusion method" in which it is possible to control the degree of blood flow to a cerebral hemisphere via a perfusion pump at will. Five animals served as untreated control, fifteen received treatment with phenytoin (7 mg/kg in five dogs, 10 mg/kg in five dogs and 30 mg/kg in five dogs) and five treated with 10 mg/kg phenytoin, 2 g/kg of mannitol and 30 mg/kg of vitamin E. These drugs were administered intravenously 20 minutes prior to the production of ischemia, when cerebral blood flow was reduced to one-tenth its normal volume. After one hour, cerebral blood flow was restored and the recovery of electrical activity of the brain and the degree of brain swelling were observed for three hours. With regard to the recovery of EEG, no recovery of EEG was seen subsequent to recirculation except one dog in the control group. Whereas in the group treated with phenytoin, gradual emergence of slow wave ws observed soon after recirculation. The higher the administered dosage is, the better the degree of recovery of EEG was seen. Thus, the dose-related recovery of EEG was observed within the dose ranges tested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of adenosine agonists and an antagonist on excitatory transmitter release from the ischemic rabbit hippocampus

The purpose of this study was to determine the effects of adenosine agonists and an antagonist on ischemia-induced extracellular glutamate concentrations in an animal model of transient cerebral ischemia using in vivo cerebral microdialysis. Fifty New Zealand white rabbits were randomly assigned to one of five groups (normothermia, hypothermia, cyclopentyladenosine (CPA), theophylline, or propentofylline). Microdialysis probes were stereotactically placed in the dorsal hippocampus. Twenty minutes before the onset of ischemia, either 1 mg/kg CPA, 5 mg/kg propentofylline, or 20 mg/kg theophylline were administered intravenously. Esophageal temperature was maintained at 38 degrees C, except in the hypothermic animals, which were cooled to 30 degrees C throughout the entire experiment. Two 12-min periods of cerebral ischemia, separated by a 105-min interval of reperfusion, were produced by inflating a neck tourniquet. High-performance liquid chromatography was used to determine the glutamate concentration in the microdialysate. There were no significant increases in glutamate concentrations during the first ischemic period in any of the five groups. During the second ischemic episode, glutamate concentrations in the normothermic group peaked at levels approximately three times higher than the initial values. A similar pattern of changes in glutamate concentrations was observed in the CPA, propentofylline, and theophylline groups. In the hypothermic group, the concentrations of glutamate remained at baseline levels during the entire experiment. Contrary to expectations, neither the adenosine agonists (CPA, propentofylline) nor the antagonist (theophylline) had any effect on extracellular glutamate concentrations in the peri-ischemic period. Although adenosine and its analogs may be cerebroprotective agents, their mechanism of action is not fully understood. The data derived from this study indicates that the acute administration of such agents had no effect on ischemia-induced glutamate release within the hippocampus under these experimental conditions. Based on these results, further work is needed to compare in vivo versus in vitro experimental results in acute and long-term treatment studies with adenosine receptor agonists and antagonists.     

Effects of retrograde perfusion of the brain with combined drug therapy after focal ischemia in rat brain.

BACKGROUND AND PURPOSE: The ischemic edema associated with blood-brain barrier permeability changes and the excess production of free radicals are serious complications in prolonged cerebral ischemia. We examined the efficacy of transvenous perfusion of the brain, starting treatment 5 hours after occlusion of the middle cerebral artery for a period of 2 hours in rats with the combined agents mannitol (10 ml/2 hr) and dexamethasone (1 mg/2 hr) to counter edema and verapamil (0.05 mg/kg/2 hr) for vasodilation. METHODS: In experiment 1, blood-brain barrier permeability changes were examined in five groups with six rats each: group C rats underwent 7 hours of middle cerebral artery occlusion with no treatment; group V, treatment with verapamil alone; group VD, treatment with verapamil and dexamethasone; group VM, treatment with verapamil and mannitol; and group VDM, treatment with verapamil, dexamethasone, and mannitol. In experiment 2, we examined local cerebral blood flow, ischemic tissue damage volume, and water content of cerebral hemispheres in two groups of 16 rats each subjected to the same treatment as groups C and VDM rats in experiment 1. RESULTS: There was a significant reduction of blood-brain barrier permeability changes in the ischemic cortex of rats in group VDM compared with rats in the other groups. In the group undergoing transvenous perfusion of the brain with the three combined agents, there was a significant improvement of cerebral blood flow (39-58%, p < 0.05) in the ischemic cortex and reduction of ischemic cerebral damage volume (22%, p < 0.01) and water content of the ischemic hemisphere (p < 0.05) compared with the control group. CONCLUSIONS: The therapeutic approach using combined agents is effective treatment when initiated within 5 hours of focal cerebral ischemia in rats.