Beekman M, Ungard J T, Gasior M, Carter R B, Dijkstra D, Goldberg S R, Witkin J M
Drug Development Group, National Institute on Drug Abuse, National Institute of Health, Baltimore, Maryland, USA.
J Pharmacol Exp Ther. 1998 Mar;284(3):868-77.
Neuroactive steroids are naturally occurring or synthetically derived compounds many of which have anticonvulsant, anesthetic, anxiolytic, analgesic or hypnotic properties. The major site of neuronal activity appears to be with a specific steroid-sensitive site on the gamma-aminobutyric acidA receptor/chloride ionophore complex. Ganaxolone (3 alpha-hydroxy-3 beta-methyl-5 alpha-pregnan-20-one) is a synthetic neuroactive steroid protected from metabolic attack of the 3 alpha position. Ganaxolone is an efficacious anticonvulsant agent in a variety of acute seizure models, as well as in electrical and chemical kindling models, and is currently under Phase II clinical investigation for epilepsy. A prior observation that ganaxolone appeared to reverse the marked behavioral changes induced by the convulsant pentylenetetrazol (PTZ) was systematically examined in the present study. A model to quantify PTZ-induced behaviors is described and used to evaluate ganaxolone in comparison with the anticonvulsants valproate, ethosuximide, clonazepam, diazepam and phenobarbital. All compounds were compared using dose equivalents based on their respective ED50 values in preventing convulsions induced by 70 mg/kg PTZ. The ED50 and lower doses of ganaxolone prevented the observed behavioral effects of PTZ as well as its depressant effects on locomotor activity and rearing of mice. In contrast, the other anticonvulsants, if effective, were much less potent. Strikingly, most of the other anticonvulsants were incapable of preventing all the behavioral effects of PTZ. Only phenobarbital prevented all the behavioral effects of PTZ and only at doses 4 to 8 times the anticonvulsant ED50. Rather than normalizing behavior as ganaxolone did, however, phenobarbital resulted in supranormal behavioral responses (e.g., increases in activity). Repeated administration of PTZ did not decrease the protective efficacy of ganaxolone. The results document the unique pharmacological profile of ganaxolone and suggest additional potential benefits from its use as an antiepileptic. Furthermore, because behavioral effects of PTZ have been used to model anxiety and anxiety associated with withdrawal from drugs of abuse, ganaxolone may find additional therapeutic application in those areas.
神经活性甾体是天然存在或人工合成的化合物，其中许多具有抗惊厥、麻醉、抗焦虑、镇痛或催眠特性。神经元活动的主要部位似乎是γ-氨基丁酸A受体/氯离子通道复合物上的一个特定的甾体敏感位点。加奈索酮（3α-羟基-3β-甲基-5α-孕烷-20-酮）是一种合成的神经活性甾体，其3α位可免受代谢攻击。加奈索酮在多种急性癫痫模型以及电点燃和化学点燃模型中是一种有效的抗惊厥药物，目前正处于癫痫的II期临床研究阶段。在本研究中，对先前观察到的加奈索酮似乎能逆转惊厥剂戊四氮（PTZ）引起的明显行为变化进行了系统研究。描述了一种量化PTZ诱导行为的模型，并将其用于评估加奈索酮，与抗惊厥药物丙戊酸、乙琥胺、氯硝西泮、地西泮和苯巴比妥进行比较。根据它们各自在预防70mg/kg PTZ诱导的惊厥中的ED50值，使用等效剂量对所有化合物进行比较。加奈索酮的ED50及更低剂量可预防PTZ观察到的行为效应及其对小鼠运动活动和竖毛的抑制作用。相比之下，其他抗惊厥药物即使有效，效力也低得多。令人惊讶的是，大多数其他抗惊厥药物无法预防PTZ的所有行为效应。只有苯巴比妥能预防PTZ的所有行为效应，且仅在抗惊厥ED50的4至8倍剂量时有效。然而，苯巴比妥并没有像加奈索酮那样使行为恢复正常，而是导致行为反应超常（例如，活动增加）。重复给予PTZ并没有降低加奈索酮的保护效力。这些结果证明了加奈索酮独特的药理学特性，并表明其作为抗癫痫药物使用可能带来额外的潜在益处。此外，由于PTZ的行为效应已被用于模拟焦虑以及与滥用药物戒断相关的焦虑，加奈索酮可能在这些领域找到更多的治疗应用。
