Webster Kyria M, Sun Mujun, Crack Peter, O'Brien Terence J, Shultz Sandy R, Semple Bridgette D
Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Kenneth Myer Building, Melbourne Brain Centre, Royal Parade, Parkville, VIC, 3050, Australia.
Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, VIC, 3050, Australia.
J Neuroinflammation. 2017 Jan 13;14(1):10. doi: 10.1186/s12974-016-0786-1.
Epilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration and poor functional and psychosocial outcomes for TBI survivors, and epilepsy after TBI is often resistant to existing anti-epileptic drugs. The development of post-traumatic epilepsy (PTE) occurs in a complex neurobiological environment characterized by ongoing TBI-induced secondary injury processes. Neuroinflammation is an important secondary injury process, though how it contributes to epileptogenesis, and the development of chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding of how inflammation contributes to the development of epilepsy (epileptogenesis) after TBI is important to facilitate the identification of novel therapeutic strategies to reduce or prevent seizures. BODY: We reviewed previous clinical and pre-clinical data to evaluate the hypothesis that inflammation contributes to seizures and epilepsy after TBI. Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation. Three key signaling factors implicated in both seizure activity and TBI-induced secondary pathogenesis are highlighted in this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1β interacting with its receptors, and transforming growth factor-β signaling from extravascular albumin. Lastly, we consider age-dependent differences in seizure susceptibility and neuroinflammation as mechanisms which may contribute to a heightened vulnerability to epileptogenesis in young brain-injured patients.
Several inflammatory mediators exhibit epileptogenic and ictogenic properties, acting on glia and neurons both directly and indirectly influence neuronal excitability. Further research is required to establish causality between inflammatory signaling cascades and the development of epilepsy post-TBI, and to evaluate the therapeutic potential of pharmaceuticals targeting inflammatory pathways to prevent or mitigate the development of PTE.
癫痫是创伤性脑损伤（TBI）常见且使人衰弱的后果。癫痫发作会导致TBI幸存者出现进行性神经退行性变以及不良的功能和心理社会结局，并且TBI后的癫痫通常对现有的抗癫痫药物耐药。创伤后癫痫（PTE）的发生处于一个复杂的神经生物学环境中，其特征是持续存在TBI诱导的继发性损伤过程。神经炎症是一个重要的继发性损伤过程，然而其如何促成癫痫发生以及慢性自发性癫痫活动的发展仍知之甚少。对炎症如何促成TBI后癫痫（癫痫发生）发展的机制性理解，对于促进识别减少或预防癫痫发作的新治疗策略很重要。
我们回顾了之前的临床和临床前数据，以评估炎症促成TBI后癫痫发作和癫痫的假说。越来越多的证据表明，神经炎症是癫痫发作活动的常见后果，并且也促成癫痫发生以及癫痫发作起始（发作形成）和持续。本综述强调了在癫痫发作活动和TBI诱导的继发性发病机制中均涉及的三个关键信号因子：与Toll样受体相互作用的高迁移率族蛋白B1、与其受体相互作用的白细胞介素-1β以及来自血管外白蛋白的转化生长因子-β信号传导。最后，我们认为癫痫易感性和神经炎症中与年龄相关的差异是可能导致年轻脑损伤患者癫痫发生易感性增加的机制。
几种炎症介质具有致痫和促痫特性，直接和间接作用于神经胶质细胞和神经元，影响神经元兴奋性。需要进一步研究以确定炎症信号级联反应与TBI后癫痫发展之间的因果关系，并评估靶向炎症途径的药物预防或减轻PTE发展的治疗潜力。
