Kokate T G, Yamaguchi S, Pannell L K, Rajamani U, Carroll D M, Grossman A B, Rogawski M A
Neuronal Excitability Section, Epilepsy Research Branch, National Institute of Neurological Disorders and Stroke, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
J Pharmacol Exp Ther. 1998 Nov;287(2):553-8.
GABA-potentiating neuroactive steroids such as pregnanolone have potent protective effects in the pentylenetetrazol seizure test. We sought to determine if tolerance develops to the anticonvulsant activity of pregnanolone with chronic administration. Mice were treated with two daily injections of a 2 x ED50 dose of pregnanolone (25 mg/kg, i.p.) for 7 days. On the day after the chronic treatment protocol, the dose-response relationship for protection in the pentylenetetrazol seizure test was obtained. The ED50 value after the chronic treatment protocol was not significantly different from that in naive mice (12 mg/kg), indicating that tolerance does not develop to the anticonvulsant activity of pregnanolone. In subsequent experiments, we extended the chronic treatment protocol to 14 days with three daily injections of pregnanolone (25 mg/kg, i.p.). Again, no tolerance was observed (ED50, 13 mg/kg). The anticonvulsant activity of pregnanolone was well correlated with plasma levels in both the naive and chronically (14 day) treated mice. The estimated plasma concentrations of pregnanolone representing threshold (10%) protection (125-150 ng/ml) and 50% protection (575-700 ng/ml) were similar in naive and chronically treated animals. In both chronically treated and naive animals, plasma levels of pregnanolone declined rapidly (t1/2, 16-19 min) and there was a corresponding reduction in the anticonvulsant activity. Our results with pregnanolone suggest that tolerance does not develop to the anticonvulsant activity of neuroactive steroids as it does with other GABA potentiating drugs such as benzodiazepines, supporting the potential clinical utility of neuroactive steroids in chronic seizure therapy.
γ-氨基丁酸（GABA）增强型神经活性甾体，如孕烷醇酮，在戊四氮惊厥试验中具有强大的保护作用。我们试图确定长期给药后是否会对孕烷醇酮的抗惊厥活性产生耐受性。小鼠每天接受两次2倍半数有效剂量（ED50）的孕烷醇酮（25mg/kg，腹腔注射），持续7天。在慢性治疗方案结束后的第二天，获得了戊四氮惊厥试验中保护作用的剂量-反应关系。慢性治疗方案后的ED50值与未处理小鼠（12mg/kg）的ED50值无显著差异，表明对孕烷醇酮的抗惊厥活性不会产生耐受性。在随后的实验中，我们将慢性治疗方案延长至14天，每天注射三次孕烷醇酮（25mg/kg，腹腔注射）。同样，未观察到耐受性（ED50，13mg/kg）。在未处理小鼠和慢性（14天）处理小鼠中，孕烷醇酮的抗惊厥活性与血浆水平密切相关。在未处理和慢性处理的动物中，代表阈值（10%）保护（125-150ng/ml）和50%保护（575-700ng/ml）的孕烷醇酮估计血浆浓度相似。在慢性处理和未处理的动物中，孕烷醇酮的血浆水平均迅速下降（半衰期，16-19分钟），抗惊厥活性也相应降低。我们关于孕烷醇酮的研究结果表明，与其他GABA增强型药物如苯二氮䓬类药物不同，对神经活性甾体的抗惊厥活性不会产生耐受性，这支持了神经活性甾体在慢性癫痫治疗中的潜在临床应用价值。
