THE NEUROSTEROID 3-ALPHA,5-ALPHA-THP HAS ANTISEIZURE AND POSSIBLE NEUROPROTECTIVE EFFECTS IN AN ANIMAL-MODEL OF EPILEPSY
THE NEUROSTEROID 3-ALPHA,5-ALPHA-THP HAS ANTISEIZURE AND POSSIBLE NEUROPROTECTIVE EFFECTS IN AN ANIMAL-MODEL OF EPILEPSY
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DOI：
10.1016/0006-8993(95)00793-p
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发表时间：
1995-10-23
期刊：
影响因子：
2.9
通讯作者：
FRYE, CA
中科院分区：
文献类型：
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作者：
FRYE, CA
一些抗惊厥药物可能通过增强GABA能系统的活性来抑制癫痫发作。孕酮(P)S的抗惊厥和神经保护作用可能是由于类固醇作用于GABA(A)-苯二氮卓受体复合体(GBRs)而不是细胞内孕激素受体(PR)，因为许多P代谢物在体外对苯二氮卓结合和氯离子通量的影响比P大，但对PR的亲和力较差。如果P的作用是由于代谢到GBR上更有效的孕激素，那么系统地给药其中一种P代谢物也应该可以防止中枢神经系统的损伤。为了验证这一假设，在雄性大鼠的穿支通路上方植入了一个双极电极。实验动物皮下注射5α-还原型P代谢物5α-孕酮-3α-醇-2-酮(3α，5α-THP)2.5 mg/kg，刺激穿支通路前3h，对照组给予芝麻油载体。经3α，5αTHP预处理的动物在刺激穿支通路时，咀嚼和流口水的持续时间、湿狗抖动、部分和完全惊厥的发生率均比用药前减少。两周后，用3α，5α-THP预处理的动物在Morris水迷宫任务中找到隐藏平台的潜伏期和距离更短。3α，5α-THP预处理还可减轻海马区CA1、CA3层的损伤，保护肺门区神经元的数量。这些数据表明，神经类固醇代谢物DFP，3α，5α-THP在癫痫动物模型中具有抗惊厥和神经保护作用。此外，这些数据表明，P的保护和抗惊厥作用的机制可能是通过GBR而不是PR。
Some anticonvulsant drugs may suppress seizures by enhancing activity of GABAergic systems. Progesterone (P)'s anti-convulsant and neuroprotective effects may be due to the steroid's actions on GABA(A)-benzodiazepine receptor complexes (GBRs) rather than intracellular progestin receptors (PRs), as many P metabolites have a greater effect in vitro on benzodiazepine binding and Cl- flux than P, but poor affinity for PRs. If P's actions are due to metabolism to a progestin more potent at GBRs, then systemic administration of one of those P metabolites should also prevent CNS damage. To test this hypothesis male rats were implanted with a bipolar electrode, aimed above the perforant pathway. Experimental animals received the 5 alpha-reduced P metabolite most effective at GBRs, 5 alpha-pregnan-3 alpha-ol-2-one (3 alpha,5 alpha-THP) 2.5 mg/kg s.c., 3 h prior to perforant pathway stimulation, while control animals received sesame oil vehicle. The duration of chewing and drooling, and the incidence of wet dog shakes, partial and full seizures were reduced during perforant pathway stimulation in animals pre-treated with 3 alpha,5 alpha-THP compared to vehicle. Two weeks later, animals pre-treated with 3 alpha,5 alpha-THP had shorter latencies and distances to find a hidden platform in a Morris Water maze task. 3 alpha,5 alpha-THP pre-treatment also reduced damage to CA1 and CA3 layers of the hippocampus and preserved the number of neurons in the hilar region. These data indicate that the neurosteroid metabolite df P, 3 alpha,5 alpha-THP, can have anticonvulsant and may have neuroprotective effects in an animal model of epilepsy. Further, these data suggest that the mechanism of P's protective and anticonvulsant effects may be via GBRs rather than PRs.