Deoxycoformycin antagonizes ischemia-induced neuronal degeneration

Deoxycoformycin, a potent and specific adenosine deaminase antagonist, reduced ischemic hippocampal damage and the associated hypermotility in Mongolian gerbils. Cerebral ischemia was induced by a bilateral 5 min occlusion of the carotid arteries. Deoxycoformycin (500 micrograms/kg IP), administered 15 min prior to ischemia, prevented the increase in locomotor activity normally observed with this model and significantly reduced the ischemia-induced damage to CA1 hippocampal neurons. The results suggest that deoxycoformycin may be useful in the prevention of brain damage due to cerebral ischemia.     

Fluoxetine affords robust neuroprotection in the postischemic brain via its anti-inflammatory effect

Fluoxetine is a selective serotonin reuptake inhibitor that is widely used in the treatment of major depression including after stroke. In this study, we tested whether fluoxetine protects neuronal death in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO). The administration of fluoxetine intravenously (10 mg/kg) at 30 min, 3 hr, or 6 hr after MCAO reduced infarct volumes to 21.2+/-6.7%, 14.5+/-3.0%, and 22.8+/-2.9%, respectively, of that of the untreated control. Moreover, the neuroprotective effect of fluoxetine was evident when it was administered as late as 9 hr after MCAO/reperfusion. These neuroprotective effects were accompanied by improvement of motor impairment and neurological deficits. The fluoxetine-treated brain was found to show marked repressions of microglia activation, neutrophil infiltration, and proinflammatory marker expressions. Moreover, fluoxetine suppressed NF-kappaB activity dose-dependently in the postischemic brain and also in lipopolysaccharide-treated primary microglia and neutrophil cultures, suggesting that NF-kappaB activity inhibition explains in part its anti-inflammatory effect. These results demonstrate that curative treatment of fluoxetine affords strong protection against delayed cerebral ischemic injury, and that these neuroprotective effects might be associated with its anti-inflammatory effects.     

Rapid tolerance to focal cerebral ischemia in rats is attenuated by adenosine A1 receptor antagonist.

Two types of ischemic tolerance in the brain, rapid and delayed, have been reported in terms of the interval between the conditioning and test insults. Although many reports showed that delayed-phase neuroprotection evoked by preconditioning is evident after 1 week or longer, there have been a few investigations about rapidly induced tolerance, and the reported neuroprotective effects become ambiguous 7 days after the insults. The authors examined whether this rapid ischemic tolerance exists after 7 days of reperfusion in a rat focal ischemic model, and investigated modulating effects of the adenosine A 1 receptor antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine). Preconditioning with 30 minutes of middle cerebral artery occlusion reduced infarct volume 7 days after 180 minutes of subsequent focal ischemia given after 1-hour reperfusion. The rapid preconditioning also improved neurologic outcome. These beneficial effects were attenuated by pretreatment of 0.1 mg/kg DPCPX, which did not influence the infarct volume after conditioning (30 minutes) or test (180 minutes) ischemia when given alone. The results show that preconditioning with a brief focal ischemia induces rapid tolerance to a subsequent severe ischemic insult, the effect of which is still present after 7 days of reperfusion, and that the rapid ischemic tolerance is possibly mediated through an adenosine A 1 receptor-related mechanism.     

局灶性鼠脑缺血时一氧化氮及一氧化氮合酶抑制剂的作用机制

目的研究一氧化氮在鼠脑局灶性脑缺血再灌注损伤中的作用。方法用线栓法建立大鼠大脑中动脉区缺血再灌注模型，分别用选择性和非选择性诱导型一氧化氮合酶抑制剂对鼠脑局灶性缺血再灌注过程中脑组织一氧化氮的变化规律及可能作用进行探讨。结果非选择性一氧化氮合酶抑制剂（Ｌ－ＮＡＭＥ）可加重局灶性脑缺血性损害，而选择性诱导型一氧化氮合酶抑制剂（ａｍｉｎｏｇｕａｎｉｄｉｎｅ，ＡＧ）具有明确的脑保护作用。结论不同类型的一氧化氮合酶所产生的一氧化氮在脑局灶性缺血性损害中具有不同的作用。     

LY393615, a novel neuronal Ca(2+) and Na(+) channel blocker with neuroprotective effects in models of in vitro and in vivo cerebral ischemia

In the present studies we have examined the effects of a new calcium channel blocker, LY393615 ((N-Butyl-[5,5-bis-(4-fluorophenyl)tetrahydrofuran-2-yl]methylamine hydrochloride, NCC1048) in a model of hypoxia-hypoglycaemia in vitro and in a gerbil model of global and in two rat models of focal cerebral ischaemia in vivo. Results indicated that LY393615 protected against hypoxia-hypoglycaemic insults in brain slices and also provided significant protection against ischaemia-induced hippocampal damage in gerbil global cerebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 30 min before and 2 h 30 min after occlusion. The compound penetrated the brain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In further studies LY393615 was protective 1 h post-occlusion when administered at 15 mg/kg i.p. followed by 2 doses of 5 mg/kg i.p. 2 and 3 h later. LY393615 dosed at 15 mg/kg i.p. followed by 2 further doses of 5 mg/kg i.p. (2 and 3 h later) also produced a significant reduction in the infarct volume following Endothelin-1 (Et-1) middle cerebral artery occlusion in the rat when administration was initiated immediately (P<0.01) or 1 h (P<0.05) after occlusion. The compound was also evaluated in the intraluminal monofilament model of focal ischaemia. The animals had the middle cerebral artery occluded for 2 h, and 15 min after reperfusion LY393615 was administered at 15 mg/kg i.p. followed by 2 mg/kg/h i.v. infusion for 6 h. There was no reduction in infarct volume using this dosing protocol. In conclusion, in the present studies we have reported that a novel calcium channel blocker, LY393615, with good bioavailability protects against neuronal damage caused by hypoxia-hypoglycaemia in vitro and both global and focal cerebral ischaemia in vivo. The compound is neuroprotective when administered post-occlusion and may therefore be a useful anti-ischaemic agent.     

急性鼠脑缺血时选择性酶抑制剂的脑保护作用

目的 研究７－硝基吲唑（７－ＮＩ）在大鼠脑缺血后的保护作用。方法 用线栓法建立大鼠大脑中动脉缺血模型。用７－ＮＩ（选择性ｎＮＯＳ抑制剂）研究了鼠脑缺血过程中脑组织ＮＯＳ活性梗死体积以及梗死外周区神经元变化。结果 ７－ＮＩ明显抑制了神经元型ＮＯＳ活性,减少了脑梗死体积并显著减轻了神经元缺血早期变性变化。结论 ７－ＮＩ对因急性期脑组织有明显保护使用。     

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.     

Oxypurinol attenuates ischemia-induced hippocampal damage in the gerbil

Oxypurinol, an inhibitor of the enzyme xanthine oxidase, reduced ischemic hippocampal damage and the associated hypermotility in Mongolian gerbils. Cerebral ischemia was induced in unanesthetized gerbils by a bilateral 5-min occlusion of the carotid arteries. Oxypurinol (40 mg/kg, IP), administered 20 min prior to carotid occlusion, prevented the increase in locomotor activity observed in saline-injected ischemic animals and significantly reduced the damage to, and loss of, CA1 hippocampal neurons observed 5 days postischemia. These findings suggest that oxypurinol may be useful for the prevention of cerebral ischemic damage.     

Focal cerebral ischemia in the cat: pretreatment with a competitive NMDA receptor antagonist, D-CPP-ene

The effects of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D-(E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D-CPP-ene; SDZ EAA 494) upon ischemic brain damage have been examined in anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of the middle cerebral artery (MCA) and the animals were killed 6 h later. The amount of early ischemic brain damage was assessed in coronal sections at 16 predetermined stereotaxic planes. Pretreatment with D-CPP-ene (15 mg/kg i.v. followed by continuous infusion at 0.17 mg/kg/min until death), 15 min prior to MCA occlusion, significantly reduced the volume of ischemic brain damage (from 20.6 +/- 9.9% of the cerebral hemisphere in vehicle-treated cats to 7.2 +/- 4.4% in drug-treated cats; p less than 0.01). The competitive NMDA receptor antagonist D-CPP-ene is as effective as noncompetitive NMDA antagonists in reducing the amount of ischemic brain damage in this model of focal cerebral ischemia in a gyrencephalic species.     

一氧化氮及一氧化氮合酶抑制剂在大鼠局灶性脑缺血时作用研究

目的：观察一氧化氮及一氧化氮合酶抑制剂在大鼠局灶性脑缺血时的作用方法;民凝大鼠大脑中动脉制成脑缺血模型,选择脑缺血３０ｍｉｎ,６０ｍｉｎ,１２０ｍｉｎ,１８０ｍｉｎ为研究时点,观察各时点用选择性,非选择性一氧化氮合酶抑制剂亚硝酸盐含量测定,缺血脑组织坏死体积测定及损伤海马ＣＡ１电镜观察。     

Increase in endogenous brain superoxide dismutase as a potential mechanism of lipopolysaccharide-induced brain ischemic tolerance.

A low dose (0.5 mg/kg) of lipopolysaccharide (LPS), administered 72 hours before 60-minute middle cerebral artery occlusion, induced a delayed neuroprotection proven by the significant decrease (-35%) of brain infarct volume in comparison with control, whereas infarct volumes remained unchanged in rats treated 12, 24, or 168 hours before ischemia. This delayed neuroprotective effect of LPS was induced only with low doses (0.25 to 1 mg/kg), whereas this effect disappeared with a higher dose (2 mg/kg). The delayed neuroprotection of LPS was induced in the cortical part of the infarcted zone, not in the subcortical part. The beneficial effect of LPS on consequences of middle cerebral artery occlusion was suppressed by dexamethasone (3 mg/kg) and indomethacin (3 mg/ kg) administered 1 hour before LPS, whereas both drugs had no direct effect on infarct volume by themselves, suggesting that activation of inflammatory pathway is involved in the development of LPS-induced brain ischemic tolerance. Preadministration of cycloheximide, an inhibitor of protein synthesis, also blocked LPS-induced brain ischemic tolerance suggesting that a protein synthesis is also necessary as a mediating mechanism. Superoxide dismutase (SOD) could be one of the synthesized proteins because lipopolysaccharide increased SOD brain activity 72 hours, but not 12 hours, after its administration, which paralleled the development of brain ischemic tolerance. In contrast, catalase brain activity remained unchanged after LPS administration. The LPS-induced delayed increase in SOD brain content was suppressed by a previous administration of indomethacin. These data suggest that the delayed neuroprotective effect of low doses of LPS is mediated by an increased synthesis of brain SOD that could be triggered by activation of inflammatory pathway.     

Failure of levemopamil to improve histological outcome following temporary occlusion of the middle cerebral artery in cats

Levemopamil, a novel calcium channel blocker with antagonistic action on serotonin S₂-receptors has been reported to be a promising compound for therapy in cerebral ischemia. This data has been obtained in the rat only, and it is of interest to determine if these beneficial effects are present in other models of ischemia in other species. The present study was therefore designed to examine its effect on histological outcome and changes in EEG after focal cerebral ischemia and reperfusion in the cat. Focal cerebral ischemia was induced by a reversible 1 hour occlusion of the middle cerebral artery followed by reperfusion of the brain. Six hours after the induction of the insult, the brain was perfusion-fixed and evaluated for histological damage by light microscopy. In 8 animals an intravenous infusion of levemopamil was initiated 5 minutes after middle cerebral artery occlusion at a rate of 4 mg/kg/h for 15 min and then at 0.6 mg/kg/h until the end of the study. A control group (n = 7) received a similar infusion of saline. The EEG amplitude did not differ between the two groups at any point of the study. The area of ischemic damage in the sections obtained for histological examination at 1-mm intervals, as well as the total volume of ischemic damage for both groups (treated: 1.33 cm³; untreated: 0.97 cm³) also did not show any significant differences. These results indicate that postischemic treatment with levemopamil at this dose, and in this model of focal cerebral ischemia and reperfusion, does not attenuate the ischemic damage.     

Cycloheximide reduces infarct volume when administered up to 6 h after mild focal ischemia in rats

We have previously described a rodent model of brief (30 min) middle cerebral artery occlusion followed by reperfusion, in which infarction develops gradually, reaching completion more than 3 days after ischemia, accompanied by morphological, biochemical, and pharmacological evidence of apoptosis. In the present study, we tested the hypotheses that delayed administration of a protein synthesis inhibitor would be effective in reducing tissue injury in this slowly evolving ischemic infarction, and that efficacy of this treatment would wane with more prolonged ischemia. Focal cerebral ischemia was induced in Long-Evans rats by occlusion of the right middle cerebral artery. Infarction volume was analyzed using triphenyl tetrazolium chloride staining, and morphology was studied using hematoxylin and eosin stained sections. Following 30 min middle cerebral artery occlusion and reperfusion, the core ischemic region exhibited vacuolization in the neuropil by 36 h after ischemia, and infarction reached full size by 7 days after ischemia. Cycloheximide reduced infarct volume when given up to 6 h after ischemia. If the duration of ischemic insult was increased to 90 min, the therapeutic window for delayed cycloheximide was only 30 min. In permanent middle cerebral artery occlusion, cycloheximide was ineffective even when given prior to ischemia onset. After mild, but not severe, ischemic insults, cerebral infarction develops slowly and may be treatable with protein synthesis inhibitors, even when treatment is delayed for up to 6 h after the onset of ischemia.     

Intracerebral adenosine infusion improves neurological outcome after transient focal ischemia in rats

Second Institute of New Drug Research, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan In order to elucidate the role of adenosine in brain ischemia, the possible protective effects of adenosine on ischemic brain injury were investigated in a rat model of brain ischemia both in vitro and in vivo. Exogenous adenosine dose-dependently rescued cortical neuronal cells from injury after glucose deprivation in vitro. Adenosine (1 mM) also significantly reduced hypoglycemia/hypoxia-induced glutamate release from the hippocampal slice. In a rat model of transient middle cerebral artery occlusion (MCAO), extracellular adenosine concentration was increased immediately after occlusion, and then returned to the baseline by 30 min after reperfusion. Adenosine infusion through a microdialysis probe into the ipsilateral striatum (1 mM adenosine, 2 microl min(-1), total 4.5 h from the occlusion to 3 h after reperfusion) showed a significant improvement in the neurological outcome, and about 25% reduction of infarct volume, although the effect did not reach statistical significance, compared with the vehicle-treated group at 20 h after 90 min of MCAO. These results demonstrated the neuroprotective effect of adenosine against ischemic brain injury both in vitro and in vivo, suggesting the possible therapeutic application of adenosine regulating agents, which inhibit adenosine uptake or metabolism to enhance or maintain extracellular endogenous adenosine levels, for stroke treatment.     

Dose-response analysis of the effect of 21-aminosteroid tirilazad mesylate (U-74006F) upon neurological outcome and ischemic brain damage in permanent focal cerebral ischemia

The protective effects of the 21-aminosteroid tirilazad mesylate (U-74006F), one of the most efficacious inhibitors of free radical-initiated lipid peroxidation, against ischmic brain damage particularly in permanent focal cerebral ischemia still remain controversial. The present study was designed to determine the degree of neuroprotection produced by various doses of U-74006F in permanent middle cerebral artery occlusion. Focal cerebral ischemia was achieved mby permanent occlusion of the left middle cerebral artery in male Sprague-Dawley rats. Four groups of rats were studied: viz. vehicle-administered controls (n = 7), and U-74006F-treated animals at doses of 0.3 mg/kg (n = 7), 1.0 mg/kg (n = 7) and 3.0 mg/kg (n = 7) (i.v. 15 min, 2 h and 6 h post occlusion, and 3.3 times higher than the first 3 doses, i.p. 12 h post occlusion). Twenty-four hours after surgery, the animals were subjected to neurological examination using a grading scale of 0 to 3, and sacrificed to assess ischemic damage by means of tetrazolium chloride staining. A dose-related attenuation of neurological deficits and ischemic damage was observed. At the two highest doses, the volume of ischemic damage in the cerebral hemisphere was reduced by 25.3% (P < 0.05) and 32.9% (P < 0.005), compared to the controls. The neurological deficit score for animals treated with U-74006F (3.0 mg/kg) was also significantly lower than for the controls (1.7 ± 1.1 vs. 2.7 ± 0.8; P < 0.05). This study shows that U-74006F ameliorates postischemic neurologic deficits and provides dose-dependent neuroprotection against ischemic brain damage in focal cerebral infarction.     

Rat focal cerebral ischemia induced astrocyte proliferation and delayed neuronal death are attenuated by cyclin-dependent kinase inhibition.

Astroglial proliferation and delayed neuronal death are two common pathological processes in the ischemic brain. However, it is not clear if astrogliosis causes delayed neuronal death. In this study, we addressed this potential linkage by examining the relationship between attenuated astrocyte proliferation, induced by cyclin-dependent kinase (CDK) inhibition, and delayed neuronal death in rat ischemic hippocampus. Our results show that following middle cerebral artery occlusion (MCAO), astrocyte hypertrophy and proliferation were closely associated with delayed neuronal death. Importantly, administration of olomoucine, a selective CDK inhibitor, not only suppressed astroglial proliferation and glial scar formation, but also decreased neuronal cell death in the ischemic boundary zone and hippocampal CA1 region at days 1 and 30 after MCAO. These results indicate that reactive astrogliosis and delayed neuronal death, at least in rat hippocampus, are sequential pathological events following MCAO. Therefore, suppressing astroglial cell cycle progression in acute focal cerebral ischemia may be beneficial to neuronal survival. Our study also implies that cell cycle regulation should be considered as a promising future therapeutic intervention in treating those neurological diseases characterized by an excessive astrocyte proliferation.     

LY393615, a novel neuronal Ca and Na channel blocker with neuroprotective effects in models of in vitro and in vivo cerebral ischemia

In the present studies we have examined the effects of a new calcium channel blocker, LY393615 ((N-Butyl-[5,5-bis-(4-fluorophenyl)tetrahydrofuran-2-yl]methylamine hydrochloride, NCC1048) in a model of hypoxia–hypoglycaemia in vitro and in a gerbil model of global and in two rat models of focal cerebral ischaemia in vivo. Results indicated that LY393615 protected against hypoxia–hypoglycaemic insults in brain slices and also provided significant protection against ischaemia-induced hippocampal damage in gerbil global cerebral ischaemia when dosed at 10, 12.5 (P<0.05) or 15 mg/kg i.p. (P<0.01) 30 min before and 2 h 30 min after occlusion. The compound penetrated the brain well after a 15 mg/kg i.p. dose and had a half-life of 2.5 h. In further studies LY393615 was protective 1 h post-occlusion when administered at 15 mg/kg i.p. followed by 2 doses of 5 mg/kg i.p. 2 and 3 h later. LY393615 dosed at 15 mg/kg i.p. followed by 2 further doses of 5 mg/kg i.p. (2 and 3 h later) also produced a significant reduction in the infarct volume following Endothelin-1 (Et-1) middle cerebral artery occlusion in the rat when administration was initiated immediately (P<0.01) or 1 h (P<0.05) after occlusion. The compound was also evaluated in the intraluminal monofilament model of focal ischaemia. The animals had the middle cerebral artery occluded for 2 h, and 15 min after reperfusion LY393615 was administered at 15 mg/kg i.p. followed by 2 mg/kg/h i.v. infusion for 6 h. There was no reduction in infarct volume using this dosing protocol. In conclusion, in the present studies we have reported that a novel calcium channel blocker, LY393615, with good bioavailability protects against neuronal damage caused by hypoxia–hypoglycaemia in vitro and both global and focal cerebral ischaemia in vivo. The compound is neuroprotective when administered post-occlusion and may therefore be a useful anti-ischaemic agent.     

局灶性脑缺血耐受和星形胶质细胞反应

目的　研究短暂性局灶性脑缺血预处理对永久性局灶性脑缺血的保护作用 ,及最佳预处理时间剂量 ,并探讨星形胶质细胞在脑缺血耐受中的反应。方法　采用开颅方法阻断大鼠大脑中动脉 ,通过观察大鼠脑梗死后神经功能损伤状况、脑梗死体积分析及病理形态学变化 ,评价不同的缺血预处理时间剂量 (10分钟、2 0分钟、30分钟 )对永久性局灶性脑缺血的保护作用。采用胶质纤维酸性蛋白 (GFAP)免疫组化法观察星形胶质细胞在脑缺血耐受中的反应。结果　与对照组相比 ,缺血预处理 2 0分钟未引起明显的神经元损伤 ,但使永久性局灶性脑缺血后神经功能损伤减轻 ,梗死体积明显减小 (P <0 .0 1)。免疫组化显示 ,2 0分钟缺血预处理组及重复缺血组星形胶质细胞在损伤预处理侧广泛激活。结论　 2 0分钟局灶性脑缺血预处理能够有效诱导脑缺血耐受。星形胶质细胞的激活可能与脑缺血耐受中神经元的存活相关。     

Exo-focal postischemic neuronal death in the rat brain

We describe delayed neuronal damage in ipsilateral areas remote from the ischemic area of rat brain after transient focal ischemia induced by embolization of the right middle cerebral artery (MCA). After 15, 30, 60 and 90 min of MCA occlusion, recirculation was achieved by removal of the embolus. Chronological changes in the distribution of the neuronal damage were determined by using the 45Ca autoradiographic technique and the histological method, and the mechanism involved was investigated by measuring local cerebral glucose metabolism. Depending on the duration of ischemia, 45Ca accumulation extended to the lateral segment of the caudate putamen and to the cerebral cortex, both supplied by the occluded MCA. Moreover, 3 days after ischemic insult, 45Ca had accumulated in the ipsilateral substantia nigra and ventral posterior nucleus of the thalamus. Histological examination revealed that the neurons in both areas suffered damage and were selectively reduced in number. Cerebral glucose utilization decreased in the thalamus, but increased approximately 30% (P less than 0.01) in the substantia nigra compared with the value in the corresponding contralateral area. Both areas lie outside the ischemic area, but have transsynaptic connections with the ischemic focus. Based on the present study, we suggest that the mechanisms of delayed neuronal death in these two remote areas may not be identical, but that this phenomenon may be caused by a transsynaptic process associated with the ischemic focus.     

Protective Effect of Zonisamide, an Antiepileptic Drug, Against Transient Focal Cerebral Ischemia with Middle Cerebral Artery Occlusion-Reperfusion in Rats

Summary: Purpose: The antiepileptic effects of zonisamide (ZNS) have been well documented experimentally and clinically. The purpose of this study was to examine whether ZNS reduces cerebral damage after transient focal ischemia in rats.
Methods : Ischemia was induced by a transient occlusion of the left middle cerebral artery (MCA) with a 3-0 nylon monofilament for 90 min. Neurological evaluation was performed by measuring the event of neurological deficit of the contralateral forepaw and hindpaw at 10 min and 1 day after MCA occlusion (MCAo). Brain infarct size was determined by measuring triphenyltetrazonium chloridenegative stained area of the serial brain sections 1 day after MCAo.
Results : The pre- or postischemic treatment with ZNS [(10–100 mgkg P.o.), 30 min before and 4 h after or 15 min and 4 h after the occlusion] markedly reduced cerebral damage in the ipsilateral hemisphere and the neurological deficit induced by transient ischemia. The reducing effect on the damage was observed in the cortical and subcortical regions. Preischemic treatment with carbamazepine (CBZ 60 mgkg p.0. twice 30 min before and 4 h after MCAo) tended to reduce the cerebral damage and neurological deficit, but the lower dose (20 mg/kg p.o. twice) did not. Valproate (VPA 1,000 mgkg p.o. twice) also had no effect.
Conclusions : ZNS at the anticonvulsant dose, unlike CBZ and VPA, ameliorated the brain infarction and the event of neurological deficit after transient focal cerebral ischemia. These data suggest that ZNS has therapeutic potential in protecting against ischemic cerebral damage, such as stroke.