吡仑帕奈调控神经元程序性坏死在创伤性脑损伤中的作用及机制研究

Traumatic brain injury (TBI) has high mortality and morbidity, and death of neurons might be one of the most important reasons. To date, there is no effective drugs has been proved to inhibit neuronal death in clinic. In recent clinical practice, we find that a new antiepileptic drug perampanel could improve the recovery of neurological dysfunction, and the results from animal models show that perampanel could reduce neuronal death after TBI. Necroptosis is a new type of cell death, which is also contribute to neuronal death after TBI. Our previous studies showed that perampanel significantly inhibited the expression and activity of RIPK3 and MLKL, two necroptosis-associated proteins. In summary, these results suggest that perampanel might protect against TBI through regulating necroptosis. On the basis of previous studies, the potential protective effects of perampanel against brain damage and neurological dysfunction after TBI will be studied. We will also elucidate the molecular mechanisms underlying perampanel-induced regulation of neuronal necroptosis with focus on RIPK1/RIPK3-MLKL pathway. This project may afford the fundamental theory basis in drug research for the treatment of TBI.

创伤性脑损伤（TBI）具有较高的致残率和死亡率，伤后大量神经元死亡是其重要原因之一，但目前尚无有效的药物可以减轻TBI后神经元死亡。我们在临床工作中发现，一种新型抗癫痫药物吡仑帕奈对TBI患者神经功能康复有促进作用，动物实验也证实它可以减轻TBI后神经元死亡。程序性坏死是一种新的细胞死亡方式，最新研究发现，TBI后神经元可发生程序性坏死，我们在预实验中证实吡仑帕奈可抑制程序性坏死相关分子RIPK3和MLKL的表达和活化。因此，我们推测吡仑帕奈可能通过调控程序性坏死减少TBI后神经元死亡，进而发挥神经保护作用。本课题拟在以往研究基础上，研究吡仑帕奈对TBI后脑损伤和神经功能障碍的保护作用，以RIPK1/3-MLKL信号通路为靶点阐明吡仑帕奈调控TBI后神经元程序性坏死的分子机制，为TBI的药物治疗研究提供新理论依据。

创伤性脑损伤（TBI）具有较高的致残率和死亡率，伤后大量神经元死亡是其重要原因之一，但目前尚无有效的药物可以减轻TBI后神经元死亡。我们在临床工作中发现，一种新型抗癫痫药物吡仑帕奈对TBI患者神经功能康复有促进作用，动物实验也证实它可以减轻TBI后神经元死亡。程序性坏死是一种新的细胞死亡方式，最新研究发现，TBI后神经元可发生程序性坏死，我们在预实验中证实吡仑帕奈可抑制程序性坏死相关分子RIPK3和MLKL的表达和活化。本项目在以往研究基础上，系统研究了吡仑帕奈对TBI后脑损伤和神经功能障碍的保护作用，并以RIPK1/3-MLKL信号通路为靶点初步阐明了吡仑帕奈调控TBI后神经元程序性坏死的分子机制。同时，我们的研究发现，吡仑帕奈通过调控Akt /GSK3β通路和线粒体Sirt3途径，影响了血脑屏障的通透性，达到脑保护作用。本研究对深入了解TBI后继发性脑损伤机制、扩展吡仑帕奈的临床应用价值均具有重要意义。