Developing Antiepileptogenic Drugs for Acquired Epilepsy: Targeting the Mammalian Target of Rapamycin (mTOR) Pathway.
Developing Antiepileptogenic Drugs for Acquired Epilepsy: Targeting the Mammalian Target of Rapamycin (mTOR) Pathway.
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DOI：
10.4255/mcpharmacol.09.16
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发表时间：
2009-01-01
期刊：
影响因子：
--
通讯作者：
Wong M
中科院分区：
文献类型：
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作者：
Zeng LH;Rensing NR;Wong M
虽然目前的癫痫药物主要是抑制癫痫发作的对症治疗，但未来癫痫药物开发的主要目标之一是确定可以完全预防癫痫或减缓其进展的抗癫痫或疾病修饰疗法。一个合理的抗癫痫策略是针对主要的细胞信号通路，最初触发下游机制，导致癫痫。最近的研究表明，哺乳动物雷帕霉素靶蛋白（mTOR）通路介导遗传性癫痫-多发性硬化症（TSC）的癫痫发生，并表明mTOR抑制剂（如雷帕霉素）可能具有抗TSC癫痫的特性。由于mTOR调节多种可能导致癫痫发生的细胞功能，包括离子通道表达，突触可塑性和程序性细胞死亡，mTOR抑制剂也可能代表其他更常见类型癫痫的有效抗癫痫治疗，例如由于脑损伤引起的获得性癫痫。在这里，我们描述了最近发表的一项研究的证据，mTOR介导癫痫发生在一个流行的动物模型获得性边缘癫痫由于脑损伤后红藻氨酸诱导癫痫持续状态，雷帕霉素在这个模型中具有抗癫痫作用。此外，假定的途径和机制上游和下游的mTOR参与癫痫发作的红藻氨酸模型被认为，确定可能的其他治疗靶点。最后，潜在的翻译应用，这和其他动物模型数据开发抗癫痫治疗的人获得性癫痫由于脑损伤进行了讨论。
While current medications for epilepsy are primarily symptomatic treatments that suppress seizures, one of the main goals of future drug development in epilepsy is the identification of antiepileptogenic or disease-modifying therapies that can completely prevent epilepsy or slow its progression. A rational antiepileptogenic strategy is to target primary cell signaling pathways that initially trigger the downstream mechanisms causing epileptogenesis. Recent work implicates the mammalian target of rapamycin (mTOR) pathway as mediating epileptogenesis in a genetic epilepsy, Tuberous Sclerosis Complex (TSC), and suggests that mTOR inhibitors, such as rapamycin, may have antiepileptogenic properties for epilepsy in TSC. As mTOR regulates multiple cellular functions that may contribute to epileptogenesis in general, including ion channel expression, synaptic plasticity, and programmed cell death, mTOR inhibitors might also represent an effective antiepileptogenic therapy for other, more common types of epilepsy, such as acquired epilepsies due to brain injuries. Here, we describe evidence from a recently-published study that mTOR mediates epileptogenesis in a popular animal model of acquired limbic epilepsy due to brain injury following kainate-induced status epilepticus, and that rapamycin has antiepileptogenic effects in this model. Furthermore, putative pathways and mechanisms upstream and downstream from mTOR involved in epileptogenesis in the kainite model are considered, identifying possible additional therapeutic targets. Finally, the potential translational applications of this and other animal model data for developing antiepileptogenic therapies for people with acquired epilepsy due to brain injury are discussed.