Institute of Biomedical Studies, Baylor University, Waco, TX 76798, USA.
Institute of Biomedical Studies, Baylor University, Waco, TX 76798, USA; Department of Psychology and Neuroscience, Baylor University, Waco, TX 76798, USA; Department of Biology, Baylor University, Waco, TX 76798, USA.
Epilepsy Res. 2020 Mar;161:106282. doi: 10.1016/j.eplepsyres.2020.106282. Epub 2020 Jan 30.
Existing therapies for epilepsy are primarily symptomatic and target mechanisms of neuronal transmission in order to restore the excitatory/inhibitory imbalance in the brain after seizures. However, approximately one third of individuals with epilepsy have medically refractory epilepsy and do not respond to available treatments. There is a critical need for the development of therapeutics that extend beyond manipulation of excitatory neurotransmission and target pathological changes underlying the cause of the disease. Epilepsy is a multifaceted condition, and it could be that effective treatment involves the targeting of several mechanisms. There is evidence for both dysregulated PI3K/Akt/mTOR (mTOR) signaling and heightened neuroinflammatory processes following seizures in the brain. Signaling via mTOR has been implicated in several epileptogenic processes, including synaptic plasticity mechanisms and changes in ion channel expression following seizures. Inflammatory signaling, such as increased synthesis of cytokines and other immune molecules, has also shown to play a significant role in the development of chronic epilepsy. mTOR pathway activation and immune signaling are known to interact in normal physiological states, as well as influence one another following seizures. Simultaneous inhibition of both processes could be a promising therapeutic avenue to prevent the development of chronic epilepsy by targeting two key pathological mechanisms implicated in epileptogenesis.
现有的癫痫治疗方法主要是针对神经元传递机制的症状治疗，以在癫痫发作后恢复大脑中的兴奋/抑制失衡。然而，大约三分之一的癫痫患者患有医学难治性癫痫，对现有治疗方法没有反应。因此，非常需要开发超越兴奋性神经递质传递操纵的治疗方法，并针对疾病原因的病理性变化。癫痫是一种多方面的疾病，有效的治疗可能需要针对多种机制。有证据表明，在大脑中癫痫发作后，PI3K/Akt/mTOR（mTOR）信号通路和神经炎症过程失调。mTOR 信号通路已被涉及几种致痫过程，包括突触可塑性机制和癫痫发作后离子通道表达的变化。炎症信号，如细胞因子和其他免疫分子的合成增加，也显示在慢性癫痫的发展中起重要作用。mTOR 途径的激活和免疫信号在正常生理状态下相互作用，并在癫痫发作后相互影响。同时抑制这两个过程可能是一种很有前途的治疗途径，可以通过针对癫痫发生中涉及的两个关键病理机制来预防慢性癫痫的发展。
