Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice
Neuroactive steroids protect against pilocarpine- and kainic acid-induced limbic seizures and status epilepticus in mice
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DOI：
10.1016/s0028-3908(96)00021-4
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发表时间：
1996-01-01
影响因子：
4.7
通讯作者：
Rogawski, MA
中科院分区：
文献类型：
--
作者：
Kokate, TG;Cohen, AL;Rogawski, MA
研究了孕酮(3α-羟基孕烷-20-酮)和脱氧皮质酮(3α-羟基孕烷-21-二醇-20酮)及其3个β-异构体的几种结构相关代谢产物对毛果芸香碱、海人酸和N-甲基-D-天冬氨酸(NMDA)诱导的小鼠癫痫发作的保护作用。α构型含3-羟基、α或β构型含5-H的类固醇对匹罗卡品(416 mg/kg，S.C.)诱导的边缘运动性惊厥和癫痫持续状态(ED(50)值7.0~18.7 mg/kg，i.p.)均有较好的保护作用。相应的β-位含3-羟基的同分异构体也是有效的，但效力较低(ED(50)值，33.8-63.5，I.P.)。尽管神经活性类固醇对匹罗卡品发作的保护作用明显低于苯二氮类，但5α，3α构型的类固醇的保护指数值(运动障碍的TD50除以癫痫保护的ED(50))与氯硝西潘相当或更高，表明某些神经活性类固醇的相对毒性可能较低。具有5α、3α或5β、3α构型的类固醇在红藻氨酸(32 mg/kg，S.C.)诱导的边缘癫痫发作中也产生了剂量依赖的延迟，但不能完全预防癫痫发作。然而，当在第一次给药后1小时再给第二次类固醇时，对红藻氨酸诱导的边缘癫痫和癫痫持续状态有完全的保护作用。类固醇还可剂量依赖性地延迟NMDA(257 mg/kg，S.C.)诱导的致死，但不能完全预防NMDA癫痫发作或致死。我们的结论是，神经活性类固醇对匹罗卡品和海人酸致小鼠癫痫发作和癫痫持续状态有很高的保护作用，可能对治疗人类某些形式的癫痫持续状态有用。爱思唯尔科学有限公司出版。
Several structurally related metabolites of progesterone (3 alpha-hydroxy pregnane-20-ones) and deoxycorticosterone (3 alpha-hydroxy pregnane-21-diol-20-ones) and their 3 beta-epimers were evaluated for protective activity against pilocarpine-, kainic acid- and N-methyl-D-aspartate (NMDA)-induced seizures in mice. Steroids with the 3-hydroxy group in the alpha-position and 5-H in the alpha- or beta-configurations were highly effective in protecting against pilocarpine (416 mg/kg, s.c.)-induced limbic motor seizures and status epilepticus (ED(50) values, 7.0-18.7 mg/kg, i.p.). The corresponding epimers with the 3-hydroxy group in the beta-position were also effective but less potent (ED(50) values, 33.8-63.5, i.p.). Although the neuroactive steroids were considerably less potent than the benzodiazepine clonazepam in protecting against pilocarpine seizures, steroids with the 5 alpha,3 alpha-configuration had comparable or higher protective index values (TD50 for motor impairment divided by ED(50) for seizure protection) than clonazepam, indicating that some neuroactive steroids may have lower relative toxicity. Steroids with the 5 alpha,3 alpha- or 5 beta,3 alpha-configurations also produced a dose-dependent delay in the onset of limbic seizures induced by kainic acid (32 mg/kg, s.c.), but did not completely protect against the seizures. However, when a second dose of the steroid was administered 1 hr after the first dose, complete protection from the kainic acid-induced limbic seizures and status epilepticus was obtained. The steroids also caused a dose-dependent delay in NMDA (257 mg/kg, s.c.)-induced lethality, but did not completely protect against NMDA seizures or lethality. We conclude that neuroactive steroids are highly effective in protecting against pilocarpine- and kainic acid-induced seizures and status epilepticus in mice, and may be of utility in the treatment of some forms of status epilepticus in humans. Published by Elsevier Science Ltd.