Kaminski Rafal M, Marini Herbert, Kim Won-Joo, Rogawski Michael A
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3702, USA.
Epilepsia. 2005 Jun;46(6):819-27. doi: 10.1111/j.1528-1167.2005.00705.x.
Men with epilepsy often have sexual or reproductive abnormalities that are attributed to alterations in androgen levels, including subnormal free testosterone. Levels of the major metabolites of testosterone-androsterone (5alpha-androstan-3alpha-ol-17-one; 5alpha,3alpha-A), a neurosteroid that acts as a positive allosteric modulator of GABA(A) receptors, and its 5beta-epimer etiocholanolone (5beta-androstan-3alpha-ol-17-one; 5beta,3alpha-A)-also may be reduced in epilepsy. 5alpha,3alpha-A has been found in adult brain, and both metabolites, which also can be derived from androstenedione, are present in substantial quantities in serum along with their glucuronide and sulfate conjugates. This study sought to determine whether these endogenous steroid metabolites can protect against seizures.
The anticonvulsant activity of 5alpha,3alpha-A and 5beta,3alpha-A was investigated in electrical and chemoconvulsant seizure models in mice. The steroids also were examined for activity against extracellularly recorded epileptiform discharges in the CA3 region of the rat hippocampal slice induced by perfusion with 55 microM 4-aminopyridine (4-AP).
Intraperitoneal injection of 5alpha,3alpha-A-protected mice in a dose-dependent fashion from seizures in the following models (ED50, dose in mg/kg protecting 50% of animals): 6-Hz electrical stimulation (29.1), pentylenetetrazol (43.5), pilocarpine (105), 4-AP (215), and maximal electroshock (224). 5beta,3alpha-A also was active in the 6-Hz and pentylenetetrazol models, but was less potent (ED50 values, 76.9 and 139 mg/kg, respectively), whereas epiandrosterone (5alpha,3beta-A) was inactive (ED50, <or=300 mg/kg). 5alpha,3alpha-A (10-100 microM) also inhibited epileptiform discharges in a concentration-dependent fashion in the in vitro slice model, whereas 5beta,3alpha-A was active but of lower potency, and 5alpha,3beta-A was inactive.
5alpha,3alpha-A and 5beta,3alpha-A have anticonvulsant properties. Although of low potency, the steroids are present in high abundance and could represent endogenous modulators of seizure susceptibility.
癫痫男性常出现性或生殖方面的异常，这些异常被认为与雄激素水平改变有关，包括游离睾酮水平低于正常。睾酮的主要代谢产物——雄酮（5α-雄甾烷-3α-醇-17-酮；5α,3α-A），一种作为GABA(A)受体正性变构调节剂的神经甾体，以及其5β-差向异构体本胆烷醇酮（5β-雄甾烷-3α-醇-17-酮；5β,3α-A）——在癫痫患者体内水平也可能降低。5α,3α-A已在成人大脑中被发现，这两种代谢产物也可由雄烯二酮衍生而来，它们及其葡萄糖醛酸和硫酸酯结合物在血清中大量存在。本研究旨在确定这些内源性甾体代谢产物是否具有抗惊厥作用。
在小鼠电惊厥和化学惊厥模型中研究了5α,3α-A和5β,3α-A的抗惊厥活性。还检测了这些甾体对用55微摩尔4-氨基吡啶（4-AP）灌注诱导的大鼠海马切片CA3区细胞外记录的癫痫样放电的作用。
腹腔注射5α,3α-A可使小鼠在以下模型中以剂量依赖方式免受惊厥发作（半数有效剂量[ED50]，以mg/kg计，保护50%动物的剂量）：6赫兹电刺激（29.1）、戊四氮（43.5）、毛果芸香碱（105）、4-AP（215）和最大电休克（224）。5β,3α-A在6赫兹和戊四氮模型中也有活性，但效力较低（ED50值分别为76.9和139 mg/kg），而表雄酮（5α,3β-A）无活性（ED50，≤300 mg/kg）。在体外切片模型中，5α,3α-A（10 - 100微摩尔）也以浓度依赖方式抑制癫痫样放电，而5β,3α-A有活性但效力较低，5α,3β-A无活性。
5α,3α-A和5β,3α-A具有抗惊厥特性。尽管效力较低，但这些甾体大量存在，可能代表癫痫易感性的内源性调节剂。
