Ravizza Teresa, Noé Francesco, Zardoni Daniela, Vaghi Valentina, Sifringer Marco, Vezzani Annamaria
Department of Neuroscience, Laboratory of Experimental Neurology, Mario Negri Institute for Pharmacological Research, Milano, Italy.
Neurobiol Dis. 2008 Sep;31(3):327-33. doi: 10.1016/j.nbd.2008.05.007. Epub 2008 May 29.
An enhanced production of IL-1beta in glia is a typical feature of epileptogenic tissue in experimental models and in human drug-refractory epilepsy. We show here that the selective inhibition of Interleukin Converting Enzyme (ICE), which cleaves the biologically active form of IL-1beta using VX-765, blocks kindling development in rats by preventing IL-1beta increase in forebrain astrocytes, without interfering with glia activation. The average afterdischarge duration was not altered significantly by VX-765. Up to 24 h after kindling completion and drug washout, kindled seizures could not be evoked in treated rats. VX-765 did not affect seizures or afterdischarge duration in fully kindled rats. These data indicate an antiepileptogenic effect mediated by ICE inhibition and suggest that specific anti-IL-1beta pharmacological strategies can be envisaged to interfere with epileptogenic mechanisms.
在实验模型和人类药物难治性癫痫中，神经胶质细胞中白细胞介素-1β（IL-1β）的产生增强是致痫组织的典型特征。我们在此表明，使用VX-765选择性抑制切割生物活性形式IL-1β的白细胞介素转换酶（ICE），可通过防止前脑星形胶质细胞中IL-1β增加来阻断大鼠的点燃发展，而不会干扰神经胶质细胞的激活。VX-765对平均放电后持续时间没有显著改变。在点燃完成和药物洗脱后长达24小时内，治疗组大鼠无法诱发点燃性癫痫发作。VX-765对完全点燃的大鼠的癫痫发作或放电后持续时间没有影响。这些数据表明ICE抑制介导了抗癫痫作用，并提示可以设想特定的抗IL-1β药理学策略来干扰致痫机制。
