Ostendorf Adam P, Wong Michael
Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
CNS Drugs. 2015 Feb;29(2):91-9. doi: 10.1007/s40263-014-0223-x.
Despite a large number of available medical options, many individuals with epilepsy are refractory to existing therapies that mainly target neurotransmitter or ion channel activity. A growing body of preclinical data has uncovered a molecular pathway that appears crucial in many genetic and acquired epilepsy syndromes. The mammalian target of rapamycin (mTOR) pathway regulates a number of cellular processes required in the growth, metabolism, structure, and cell-cell interactions of neurons and glia. Rapamycin and similar compounds inhibit mTOR complex 1 and decrease seizures, delay seizure development, or prevent epileptogenesis in many animal models of mTOR hyperactivation. However, the exact mechanisms by which mTOR inhibition drives decreased seizure activity have not been completely determined. Nonetheless, these preclinical data have led to limited use in humans with epilepsy due to tuberous sclerosis complex and polyhydramnios, megalencephaly, and symptomatic epilepsy with promising results. Currently, larger controlled studies are underway using mTOR inhibitors in individuals with tuberous sclerosis complex and intractable epilepsy.
尽管有大量可用的医学选择，但许多癫痫患者对主要针对神经递质或离子通道活性的现有疗法无效。越来越多的临床前数据揭示了一条在许多遗传性和获得性癫痫综合征中似乎至关重要的分子途径。雷帕霉素哺乳动物靶点（mTOR）途径调节神经元和神经胶质细胞生长、代谢、结构及细胞间相互作用所需的许多细胞过程。在许多mTOR过度激活的动物模型中，雷帕霉素及类似化合物可抑制mTOR复合物1，并减少癫痫发作、延缓癫痫发作发展或预防癫痫发生。然而，mTOR抑制导致癫痫活动减少的确切机制尚未完全确定。尽管如此，由于结节性硬化症合并羊水过多、巨头畸形及症状性癫痫，这些临床前数据在癫痫患者中的应用有限，但已取得了有希望的结果。目前，正在对结节性硬化症合并难治性癫痫患者使用mTOR抑制剂进行更大规模的对照研究。
