The University of Toronto, Department of Pharmacology and Toxicology, Toronto, Canada.
The University of Toronto, Department of Pharmacology and Toxicology, Toronto, Canada.
Seizure. 2018 Dec;63:26-36. doi: 10.1016/j.seizure.2018.10.012. Epub 2018 Oct 28.
The anti-seizure effects of progesterone family compounds have long been known. Over the years, however, most studies have focused on progesterone and on its secondary metabolite allopregnanolone (ALLO), with less attention being paid to its primary metabolite 5a-dihydroprogesterone (DHP). Here we review animal and clinical studies related to the anti-seizure effects of progesterone and its 5a neuroactive metabolites, including DHP and ALLO. Progesterone and its reduced metabolites all have demonstrated seizure-suppression effects in animal models - except in models of absence seizures - with the common side effects of sedation and ataxia. Progesterone and ALLO have also shown anti-seizure effects in clinical trials. A large Phase III trial has revealed that female patients with premenstrual exacerbations of seizures benefit most from progesterone therapy. A liquid suspension of ALLO has also been tested in patients with supra-refractory status epilepticus with some success in a small phase II trial. ALLO's C3 methyl analog ganaxolone is under development as an anti-seizure drug. Progesterone's anti-seizure effects are mostly independent of its genomic receptors and are, in large part, due to its active metabolites. ALLO is a potent allosteric modulator of GABA receptors. Other membrane receptors are thought to be involved in the DHP's anti-seizure actions, but their exact nature is not yet known. Potential drawbacks to the development of progesterone family compounds as anti-seizure drug are their endocrine effects. These compounds might form a basis for the future development of novel anti-seizure drugs, however, with hormonal side effects being mitigated through rational drug design.
孕激素家族化合物的抗惊厥作用早已为人所知。然而，多年来，大多数研究都集中在孕激素及其次级代谢物别孕烯醇酮（ALLO）上，而对其主要代谢物 5α-二氢孕酮（DHP）的关注较少。在这里，我们回顾了与孕激素及其 5α 神经活性代谢物（包括 DHP 和 ALLO）的抗惊厥作用相关的动物和临床研究。孕激素及其还原代谢物在动物模型中均表现出抑制癫痫发作的作用-除了失神性癫痫发作模型外-其常见的副作用为镇静和共济失调。孕激素和 ALLO 在临床试验中也显示出抗惊厥作用。一项大型 III 期试验表明，孕激素治疗对经前期癫痫发作加重的女性患者最有效。ALLO 的 C3 甲基类似物 ganaxolone 也在难治性癫痫持续状态患者中进行了测试，在一项小型 II 期试验中取得了一定的成功。孕激素的抗惊厥作用主要与其基因组受体无关，在很大程度上与其活性代谢物有关。ALLO 是 GABA 受体的有效变构调节剂。其他膜受体被认为参与了 DHP 的抗惊厥作用，但它们的确切性质尚不清楚。作为抗惊厥药物，孕激素家族化合物的开发存在潜在的缺陷，即它们的内分泌作用。然而，这些化合物可能为新型抗惊厥药物的未来发展奠定基础，通过合理的药物设计减轻激素副作用。
