Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA.
Neuropharmacology. 2010 Dec;59(7-8):573-81. doi: 10.1016/j.neuropharm.2010.08.017. Epub 2010 Sep 8.
Progesterone (P) is an endogenous anticonvulsant hormone. P is being evaluated as a treatment for epilepsy, traumatic brain injury, and other complex neurological conditions. Preclinical and clinical studies suggest that P appears to interrupt epileptogenic events. However, the potential disease-modifying effect of P in epileptogenic models is not widely investigated. In this study, we examined the effects of P on the development of hippocampus kindling in female mice. In addition, we determined the role of progesterone receptors (PR) in the P's effect on the kindling epileptogenesis utilizing PR knockout (PRKO) mice. P, at 25 mg/kg, did not affect seizures and did not exert sedative/motor effects in fully-kindled mice. P treatment (25 mg/kg, twice daily for 2 weeks) significantly suppressed the rate of development of behavioral kindled seizure activity evoked by daily hippocampus stimulation in wild-type (WT) mice, indicating a disease-modifying effect of P on limbic epileptogenesis. There was a significant increase in the rate of 'rebound or withdrawal' kindling during drug-free stimulation sessions following abrupt discontinuation of P treatment. A washout period after termination of P treatment prevented such acceleration in kindling. PRKO mice were kindled significantly slower than WT mice, indicating a modulatory role of PRs in seizure susceptibility. P's effects on early kindling progression was partially decreased in PRKO mice, but the overall (˜2-fold) delay in the rate of kindling for the induction of stage 5 seizures was unchanged in PRKO mice. Moreover, the acute anticonvulsant effect of P was undiminished in fully-kindled PRKO mice. These studies suggest that P exerts disease-modifying effects in the hippocampus kindling model at doses that do not significantly affect seizure expression and motor performance, and the kindling-retarding effects of P may occur partly through a complex PR-dependent and PR-independent mechanism.
孕酮（P）是一种内源性抗惊厥激素。P 正在被评估为治疗癫痫、创伤性脑损伤和其他复杂神经疾病的方法。临床前和临床研究表明，P 似乎可以中断致痫事件。然而，P 在致痫模型中的潜在疾病修饰作用尚未得到广泛研究。在这项研究中，我们研究了 P 对雌性小鼠海马点燃的发展的影响。此外，我们利用孕激素受体（PR）敲除（PRKO）小鼠确定了 PR 在 P 对点燃癫痫发生的影响中的作用。在完全点燃的小鼠中，P（25mg/kg）既不影响癫痫发作，也没有镇静/运动作用。P 治疗（25mg/kg，每日两次，持续 2 周）显著抑制了 WT 小鼠每日海马刺激诱发的行为点燃发作活动的发展速度，表明 P 对边缘性癫痫发生具有疾病修饰作用。在突然停止 P 治疗后的无药刺激期间，出现了“反弹或撤退”点燃的明显增加。在 P 治疗结束后的冲洗期后，防止了点燃的这种加速。PRKO 小鼠比 WT 小鼠点燃得明显慢，表明 PR 对癫痫易感性有调节作用。PRKO 小鼠中 P 对早期点燃进展的影响部分减少，但 PRKO 小鼠中诱导 5 期癫痫发作的点燃总（˜2 倍）延迟不变。此外，在完全点燃的 PRKO 小鼠中，P 的急性抗惊厥作用并未减弱。这些研究表明，P 在不显著影响癫痫发作表达和运动性能的剂量下，在海马点燃模型中发挥疾病修饰作用，P 对点燃的延缓作用可能部分通过复杂的 PR 依赖和 PR 独立机制发生。
