Perez-Cruz Claudia, Likhodii Sergei, Burnham W M
The University of Toronto Epilepsy Research Program and Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Exp Neurol. 2006 Aug;200(2):283-9. doi: 10.1016/j.expneurol.2006.02.012. Epub 2006 Apr 19.
Deoxycorticosterone (DOC) is a steroid hormone that suppresses seizures in both humans and animals. At higher doses, DOC's anticonvulsant actions are accompanied by sedation and ataxia. The mechanism of DOC's anticonvulsant actions is not known, although it has been suggested that they may relate to DOC's secondary metabolite 3-alpha-5-alpha-tetrahydrodeoxycorticosterone (THDOC). The present study was designed to study the relation of DOC's anticonvulsant actions to its primary and secondary metabolites in 15-day-old rats. It was found that DOC's anticonvulsant and ataxic effects were suppressed by finasteride, which blocks the formation of DOC's primary metabolite, 3-alpha-5-alpha-dehydrodeoxycorticosterone (DHDOC). They were not suppressed by indomethacin (INDO), which blocks the conversion of DHDOC into THDOC. The direct anticonvulsant effects of DHDOC and THDOC were also tested. DHDOC and THDOC were both potent anticonvulsants in 15-day old rats. Both also caused ataxia at high doses. DHDOC had a therapeutic index (TI) of 3.2, however, which was better than either DOC (TI = 1.2) or THDOC (TI = 1.5). It appears that DOC itself is not anticonvulsant, but that its anticonvulsant effects may relate to both its primary and secondary metabolites. DOC's primary metabolite, DHDOC--with its good TI--deserves a test in the treatment of childhood seizures.
脱氧皮质酮（DOC）是一种类固醇激素，可抑制人类和动物的癫痫发作。在较高剂量下，DOC的抗惊厥作用会伴有镇静和共济失调。尽管有人提出DOC的抗惊厥作用可能与其二级代谢产物3-α-5-α-四氢脱氧皮质酮（THDOC）有关，但其抗惊厥作用的机制尚不清楚。本研究旨在研究15日龄大鼠中DOC的抗惊厥作用与其一级和二级代谢产物之间的关系。研究发现，非那雄胺可抑制DOC的抗惊厥和共济失调作用，非那雄胺可阻断DOC一级代谢产物3-α-5-α-脱氢脱氧皮质酮（DHDOC）的形成。吲哚美辛（INDO）不能抑制其作用，吲哚美辛可阻断DHDOC向THDOC的转化。还测试了DHDOC和THDOC的直接抗惊厥作用。DHDOC和THDOC在15日龄大鼠中均为有效的抗惊厥剂。高剂量时两者也都会引起共济失调。然而，DHDOC的治疗指数（TI）为3.2，优于DOC（TI = 1.2）或THDOC（TI = 1.5）。似乎DOC本身并无抗惊厥作用，但其抗惊厥作用可能与其一级和二级代谢产物均有关。DOC的一级代谢产物DHDOC具有良好的治疗指数，值得在儿童癫痫治疗中进行测试。
