Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis.
Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis.
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DOI：
10.1016/j.neulet.2011.02.037
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发表时间：
2011-06-27
影响因子：
2.5
通讯作者：
Wong M
中科院分区：
文献类型：
--
作者：
McDaniel SS;Wong M
传统上，癫痫的药物治疗旨在抑制癫痫发作活动，但无法改变基础疾病的进展。我们对癫痫发生机制的理解的最新进展为开发新的治疗方法打开了大门，这些治疗方法可以预防易患自发性癫痫发作的大脑病理变化。特别是，雷帕霉素（mTOR）信号通路的哺乳动物目标最近已获得的利益作为一个重要的调节剂参与癫痫发生的细胞变化，和mTOR抑制剂产生兴奋作为潜在的抗癫痫药物。mTOR超活化发生在结节性硬化症（TSC）中，这是癫痫的常见遗传原因，是上游调控分子基因突变的结果。在TSC动物模型中，mTOR抑制可预防癫痫和脑病理学。mTOR失调也已在多种其他遗传性和获得性癫痫中得到证实，包括脑肿瘤、局灶性皮质发育不良和由于癫痫持续状态或创伤引起的脑损伤的动物模型。事实上，mTOR抑制剂似乎在获得性癫痫的动物模型中也具有抗癫痫特性。因此，mTOR失调可能代表各种原因癫痫的最终共同途径。因此，mTOR抑制是一种令人兴奋的潜在抗癫痫策略，具有广泛的癫痫应用，并可能涉及许多治疗方式，包括生酮饮食。进一步的研究是必要的，以确定雷帕霉素和其他mTOR抑制剂的抗癫痫的临床效用，并通过进一步阐明参与癫痫发生的信号分子来设计新的治疗靶点。
Traditionally, medical therapy for epilepsy has aimed to suppress seizure activity, but has been unable to alter the progression of the underlying disease. Recent advances in our understanding of mechanisms of epileptogenesis open the door for the development of new therapies which prevent the pathogenic changes in the brain that predispose to spontaneous seizures. In particular, the mammalian target of rapamycin (mTOR) signaling pathway has recently garnered interest as an important regulator of cellular changes involved in epileptogenesis, and mTOR inhibitors have generated excitement as potential antiepileptogenic agents. mTOR hyperactivation occurs in tuberous sclerosis complex (TSC), a common genetic cause of epilepsy, as a result of genetic mutations in upstream regulatory molecules. mTOR inhibition prevents epilepsy and brain pathology in animal models of TSC. mTOR dysregulation has also been demonstrated in a variety of other genetic and acquired epilepsies, including brain tumors, focal cortical dysplasias, and animal models of brain injury due to status epilepticus or trauma. Indeed, mTOR inhibitors appear to possess antiepileptogenic properties in animal models of acquired epilepsy as well. Thus, mTOR dysregulation may represent a final common pathway in epilepsies of various causes. Therefore, mTOR inhibition is an exciting potential antiepileptogenic strategy with broad applications for epilepsy and could be involved in a number of treatment modalities, including the ketogenic diet. Further research is necessary to determine the clinical utility of rapamycin and other mTOR inhibitors for antiepileptogenesis, and to devise new therapeutic targets by further elucidating the signaling molecules involved in epileptogenesis.
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