Frye C A
Psychology Department, Bates College, Lewiston, ME 04240, USA.
Brain Res. 1995 Oct 23;696(1-2):113-20. doi: 10.1016/0006-8993(95)00793-p.
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 GABAA-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-20-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 of 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.
一些抗惊厥药物可通过增强γ-氨基丁酸（GABA）能系统的活性来抑制癫痫发作。孕酮（P）的抗惊厥和神经保护作用可能归因于该类固醇对GABAA-苯二氮䓬受体复合物（GBRs）的作用，而非细胞内孕激素受体（PRs），因为许多P代谢产物在体外对苯二氮䓬结合和氯离子通量的影响比P更大，但对PRs的亲和力较差。如果P的作用是由于代谢为在GBRs上更有效的孕激素，那么全身给予这些P代谢产物之一也应能预防中枢神经系统损伤。为了验证这一假设，将雄性大鼠植入双极电极，电极位于穿通通路上方。实验动物在穿通通路刺激前3小时皮下注射2.5mg/kg对GBRs最有效的5α-还原P代谢产物5α-孕烷-3α-醇-20-酮（3α,5α-四氢孕酮），而对照动物注射芝麻油载体。与载体相比，用3α,5α-四氢孕酮预处理的动物在穿通通路刺激期间咀嚼和流涎的持续时间以及湿狗样抖动、部分和全身性癫痫发作的发生率降低。两周后，用3α,5α-四氢孕酮预处理的动物在莫里斯水迷宫任务中找到隐藏平台的潜伏期和距离更短。3α,5α-四氢孕酮预处理还减少了海马CA1和CA3层的损伤，并保留了海马门区的神经元数量。这些数据表明，P的神经甾体代谢产物3α,5α-四氢孕酮在癫痫动物模型中具有抗惊厥作用，可能还具有神经保护作用。此外，这些数据表明P的保护和抗惊厥作用机制可能是通过GBRs而非PRs。
