Vartanian M G, Cordon J J, Kupina N C, Schielke G P, Posner A, Raser K J, Wang K K, Taylor C P
Department of Neurological and Neurodegenerative Diseases, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Brain Res Dev Brain Res. 1996 Sep 2;95(2):169-75. doi: 10.1016/0165-3806(96)00073-9.
This study was performed to investigate whether the anticonvulsant phenytoin has neuroprotective effect in a model of hypoxia-ischemia with neonatal rats. The left carotid artery of each rat was ligated, followed by 3 h of hypoxic exposure (8% O2) in a temperature-regulated environment (36 degrees C). Two weeks later, brain damage was assessed by measuring loss of brain hemisphere weight. Phenytoin had no effect on body temperature or plasma glucose, but attenuated brain damage in a dose-dependent manner (3, 10, and 30 mg/kg i.p.) when administered before the hypoxic episode. Phenytoin administered during or after hypoxia did not alter hypoxic brain damage significantly. A parallel experiment using histological examination of frozen brain sections demonstrated less brain infarction after phenytoin treatment (30 mg/kg i.p.). In an additional experiment measuring breakdown of an endogenous brain calpain substrate, spectrin, phenytoin treatment reduced this measure of early cellular damage. Our results indicate that pretreatment with phenytoin is neuroprotective at a plasma phenytoin concentration of approximately 12 micrograms/ml. These results are consistent with the hypothesis that blockade of voltage-dependent sodium channels reduces brain damage following ischemia.
本研究旨在探讨抗惊厥药物苯妥英钠在新生大鼠缺氧缺血模型中是否具有神经保护作用。结扎每只大鼠的左颈动脉，随后在温度调节环境（36℃）中进行3小时的低氧暴露（8%氧气）。两周后，通过测量脑半球重量损失来评估脑损伤。苯妥英钠对体温或血糖无影响，但在低氧发作前给药时，以剂量依赖方式（腹腔注射3、10和30mg/kg）减轻了脑损伤。在缺氧期间或之后给予苯妥英钠并未显著改变缺氧性脑损伤。一项使用冰冻脑切片组织学检查的平行实验表明，苯妥英钠治疗（腹腔注射30mg/kg）后脑梗死较少。在另一项测量内源性脑钙蛋白酶底物血影蛋白分解的实验中，苯妥英钠治疗降低了这种早期细胞损伤的指标。我们的结果表明，苯妥英钠预处理在血浆苯妥英钠浓度约为12μg/ml时具有神经保护作用。这些结果与电压依赖性钠通道阻滞可减少缺血后脑损伤的假说一致。
