Kokate T G, Cohen A L, Karp E, Rogawski M A
Neuronal Excitability Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Neuropharmacology. 1996;35(8):1049-56. doi: 10.1016/s0028-3908(96)00021-4.
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 (ED50 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 (ED50 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 ED50 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.
对孕酮（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3β - 差向异构体的几种结构相关代谢产物进行了评估，以考察其对毛果芸香碱、 kainic 酸和N - 甲基 - D - 天冬氨酸（NMDA）诱导的小鼠癫痫发作的保护活性。在α - 位具有3 - 羟基且α - 或β - 构型中具有5 - H的类固醇在预防毛果芸香碱（416 mg/kg，皮下注射）诱导的边缘性运动性癫痫发作和癫痫持续状态方面非常有效（半数有效剂量值，7.0 - 18.7 mg/kg，腹腔注射）。在β - 位具有3 - 羟基的相应差向异构体也有效，但效力较低（半数有效剂量值，33.8 - 63.5，腹腔注射）。尽管神经活性类固醇在预防毛果芸香碱癫痫发作方面的效力远低于苯二氮䓬类药物氯硝西泮，但具有5α,3α - 构型的类固醇具有与氯硝西泮相当或更高的保护指数值（运动功能损害的半数致死剂量除以癫痫发作保护的半数有效剂量），这表明一些神经活性类固醇可能具有较低的相对毒性。具有5α,3α - 或5β,3α - 构型的类固醇也会使由kainic 酸（32 mg/kg，皮下注射）诱导的边缘性癫痫发作的发作延迟呈现剂量依赖性，但不能完全预防癫痫发作。然而，当在第一剂后1小时给予第二剂类固醇时，可完全预防kainic 酸诱导的边缘性癫痫发作和癫痫持续状态。这些类固醇还会使NMDA（257 mg/kg，皮下注射）诱导的致死率出现剂量依赖性延迟，但不能完全预防NMDA癫痫发作或致死率。我们得出结论，神经活性类固醇在预防小鼠毛果芸香碱和kainic 酸诱导的癫痫发作及癫痫持续状态方面非常有效，可能对治疗人类某些形式的癫痫持续状态有用。
