Edwards Heather E, Vimal Sutha, Burnham W McIntyre
University of Toronto Epilepsy Research Program and the Department of Pharmacology, University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada.
Epilepsia. 2005 Dec;46(12):1888-97. doi: 10.1111/j.1528-1167.2005.00295.x.
The mechanisms that mediate the acute anticonvulsant effects of deoxycorticosterone (DOC) were investigated in young rats.
Fifteen-day-old rats were pretreated with a variety of compounds, including (a) agonists of the receptors that bind DOC (mineralocorticoid receptors); (b) the DOC 5alpha- and 5alpha-3alpha-reduced metabolites, plus agonists that bind the receptors of the 5alpha-reduced metabolite of DOC (progesterone receptors); and (c) DOC itself in the presence and absence of metabolism and receptor blockers. Fifteen minutes later, pentylenetetrazol (PTZ) was administered, and maximal pentylenetetrazol (MMT) seizure responses were scored.
Agonists of mineralocorticoid receptors increased the latency to forelimb flexion in PTZ seizures and sometimes suppressed the seizures completely. At low, nonconvulsant doses, spironolactone (a mineralocorticoid-receptor antagonist) blocked the anticonvulsant effects of a nonsedating, but not a sedating, dose of DOC. These data suggest the possible direct involvement of mineralocorticoid receptors in the anticonvulsant effects of DOC. At low, nonconvulsant doses, finasteride (which blocks the metabolism of DOC) partially blocked the protective effects of DOC, suggesting the contribution of metabolites to the anticonvulsant actions of DOC. Dihydrodeoxycorticosterone (DHDOC)-the first metabolite of DOC, an agonist at progesterone receptors, and an allosteric modulator of the gamma-aminobutyric acid (GABA)(A) receptor-and tetrahydrodeoxycorticosterone, a secondary metabolite of DOC and an allosteric modulator of the GABA(A) receptor, both blocked MMT seizures.
These findings suggest that both DOC and its metabolites may contribute to the anticonvulsant effects seen in young rats, perhaps acting via interactions with several different receptors.
研究介导脱氧皮质酮（DOC）急性抗惊厥作用的机制。
对15日龄大鼠预先给予多种化合物，包括（a）与DOC结合的受体（盐皮质激素受体）的激动剂；（b）DOC的5α-和5α-3α-还原代谢产物，以及与DOC的5α-还原代谢产物（孕酮受体）的受体结合的激动剂；（c）存在和不存在代谢及受体阻滞剂时的DOC本身。15分钟后，给予戊四氮（PTZ），并对最大戊四氮（MMT）惊厥反应进行评分。
盐皮质激素受体激动剂增加了PTZ惊厥中前肢屈曲的潜伏期，有时可完全抑制惊厥。在低的、非惊厥剂量下，螺内酯（一种盐皮质激素受体拮抗剂）阻断了非镇静剂量（而非镇静剂量）的DOC的抗惊厥作用。这些数据表明盐皮质激素受体可能直接参与了DOC的抗惊厥作用。在低的、非惊厥剂量下，非那雄胺（阻断DOC的代谢）部分阻断了DOC的保护作用，表明代谢产物对DOC的抗惊厥作用有贡献。二氢脱氧皮质酮（DHDOC）——DOC的第一种代谢产物，一种孕酮受体激动剂，也是γ-氨基丁酸（GABA）（A）受体的变构调节剂——和四氢脱氧皮质酮，DOC的第二种代谢产物，也是GABA（A）受体的变构调节剂，均阻断了MMT惊厥。
这些发现表明，DOC及其代谢产物可能都对幼鼠的抗惊厥作用有贡献，可能通过与几种不同受体的相互作用发挥作用。
