Rhodes Madeline E, Frye Cheryl A
Department of Psychology, The University at Albany-SUNY, 1400 Washington Avenue, Albany, NY 12222, USA.
Epilepsy Behav. 2005 Mar;6(2):140-6. doi: 10.1016/j.yebeh.2004.11.019.
Progesterone has antiseizure effects, which may be due to the actions of its 5alpha-reduced metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP). Whether metabolism of progesterone to 3alpha,5alpha-THP in the hippocampus is essential for its antiseizure effects was investigated. In Experiment 1, ovariectomized rats were administered subcutaneous progesterone (500 microg) or vehicle (sesame oil), followed 1 hour later by subcutaneous administration of an inhibitor of the 5alpha-reductase enzyme, finasteride (50 mg/kg), or vehicle (90% sesame oil, 10% ethanol). Administration of progesterone increased the latency to, and decreased the number of, tonic seizures and increased hippocampal 3alpha,5alpha-THP levels, compared with vehicle. Administration of finasteride with progesterone attenuated progesterone's antiseizure effects and decreased levels of 3alpha,5alpha-THP in the hippocampus. Finasteride administration alone did not alter ictal behavior or 3alpha,5alpha-THP levels compared with vehicle. In Experiment 2, ovariectomized rats were administered subcutaneous progesterone (500 microg) or vehicle (sesame oil), followed 1 hour later by bilateral infusions of finasteride (10 microg) or vehicle (beta-cyclodextran) into the hippocampus. Administration of finasteride to the hippocampus of progesterone-primed rats significantly increased ictal activity and decreased hippocampal 3alpha,5alpha-THP levels, compared with progesterone administration alone. These data suggest that formation of 3alpha,5alpha-THP in the hippocampus is important for progesterone's antiseizure effects.
孕酮具有抗癫痫作用，这可能归因于其5α-还原代谢产物5α-孕烷-3α-醇-20-酮（3α,5α-四氢孕酮）的作用。研究了孕酮在海马体中代谢为3α,5α-四氢孕酮对其抗癫痫作用是否至关重要。在实验1中，对去卵巢大鼠皮下注射孕酮（500微克）或赋形剂（芝麻油），1小时后皮下注射5α-还原酶抑制剂非那雄胺（50毫克/千克）或赋形剂（90%芝麻油，10%乙醇）。与赋形剂相比，注射孕酮可增加强直发作的潜伏期并减少发作次数，同时增加海马体中3α,5α-四氢孕酮的水平。非那雄胺与孕酮联合使用可减弱孕酮的抗癫痫作用，并降低海马体中3α,5α-四氢孕酮的水平。与赋形剂相比，单独注射非那雄胺不会改变发作行为或3α,5α-四氢孕酮水平。在实验2中，对去卵巢大鼠皮下注射孕酮（500微克）或赋形剂（芝麻油），1小时后双侧海马体注射非那雄胺（10微克）或赋形剂（β-环糊精）。与单独注射孕酮相比，对预先注射孕酮的大鼠海马体注射非那雄胺可显著增加发作活动并降低海马体中3α,5α-四氢孕酮的水平。这些数据表明，海马体中3α,5α-四氢孕酮的形成对孕酮的抗癫痫作用很重要。
