Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano, Italy.
Neurotherapeutics. 2011 Apr;8(2):304-15. doi: 10.1007/s13311-011-0039-z.
Experimental evidence and clinical observations indicate that brain inflammation is an important factor in epilepsy. In particular, induction of interleukin-converting enzyme (ICE)/caspase-1 and activation of interleukin (IL)-1β/IL-1 receptor type 1 axis both occur in human epilepsy, and contribute to experimentally induced acute seizures. In this study, the anticonvulsant activity of VX-765 (a selective ICE/caspase-1 inhibitor) was examined in a mouse model of chronic epilepsy with spontaneous recurrent epileptic activity refractory to some common anticonvulsant drugs. Moreover, the effects of this drug were studied in one acute model of seizures in mice, previously shown to involve activation of ICE/caspase-1. Quantitative analysis of electroencephalogram activity was done in mice exposed to acute seizures or those developing chronic epileptic activity after status epilepticus to assess the anticonvulsant effects of systemic administration of VX-765. Histological and immunohistochemical analysis of brain tissue was carried out at the end of pharmacological experiments in epileptic mice to evaluate neuropathology, glia activation and IL-1β expression, and the effect of treatment. Repeated systemic administration of VX-765 significantly reduced chronic epileptic activity in mice in a dose-dependent fashion (12.5-200 mg/kg). This effect was observed at doses ≥ 50 mg/kg, and was reversible with discontinuation of the drug. Maximal drug effect was associated with inhibition of IL-1β synthesis in activated astrocytes. The same dose regimen of VX-765 also reduced acute seizures in mice and delayed their onset time. These results support a new target system for anticonvulsant pharmacological intervention to control epileptic activity that does not respond to some common anticonvulsant drugs.
实验证据和临床观察表明，脑炎症是癫痫的一个重要因素。特别是，白细胞介素转换酶（ICE）/半胱天冬酶-1的诱导和白细胞介素（IL）-1β/IL-1 受体 1 轴的激活都发生在人类癫痫中，并有助于实验诱导的急性癫痫发作。在这项研究中，VX-765（一种选择性 ICE/半胱天冬酶-1 抑制剂）在一种具有自发复发性癫痫活动的慢性癫痫小鼠模型中的抗惊厥活性进行了研究，该模型对一些常见的抗惊厥药物有抗性。此外，还研究了该药物在一种先前显示涉及 ICE/半胱天冬酶-1 激活的急性癫痫发作小鼠模型中的作用。对暴露于急性癫痫发作或癫痫持续状态后发展为慢性癫痫活动的小鼠进行脑电图活动的定量分析，以评估系统给予 VX-765 的抗惊厥作用。在癫痫小鼠的药理实验结束时进行脑组织的组织学和免疫组织化学分析，以评估神经病理学、神经胶质细胞激活和 IL-1β表达以及治疗效果。重复系统给予 VX-765 以剂量依赖性方式显著减少了小鼠的慢性癫痫活动（12.5-200mg/kg）。这种作用在≥50mg/kg 的剂量下观察到，并且随着药物的停用而可逆。最大药物作用与激活星形胶质细胞中 IL-1β 合成的抑制有关。相同剂量方案的 VX-765 还减少了小鼠的急性癫痫发作，并延迟了其发作时间。这些结果支持了一种新的抗惊厥药理干预目标系统，以控制对一些常见抗惊厥药物无反应的癫痫活动。
