JNK及ERK信号通路在颞叶癫痫所致海马神经元Parthanatos中的作用及机制研究

Temporal lobe epilepsy is the most common type of epilepsy, which is easy to develop into intractable epilepsy. The selective death of hippocampal neurons is the main pathological feature of temporal lobe epilepsy. However, the specific type of neuronal death is still lack of comprehensive understanding. Parthanatos characterized by over-activation of Poly-ADP-Ribose Polymerase 1 (PARP-1) is a newly discovered type of neuronal death. We have previously found that parthanatos exist in hippocampal neurons after epilepsy, although the underlying mechanism is not clear. In this study, we will use both magnesium deprivation induced neuronal epilepsy model and kainic acid induced epileptic rats model, use Western blot, enzyme activity detection and RNA interference method, to analyze the following questions:① The role of ROS in over-activation of PARP-1 after epilepsy; ② The role of ERK signaling pathway in the occurrence and development of Parthanatos after epilepsy;③ The role of JNK signaling pathway in the occurrence and development of Parthanatos after epilepsy. We aim to elucidate the mechanism of Parthanatos in neurons after epilepsy, and to explore new methods for the prevention and treatment of neuronal damage after temporal lobe epilepsy.

颞叶癫痫是最常见的癫痫类型，易发展成难治性癫痫。海马神经元选择性死亡是其主要病理特征，但涉及的具体神经元死亡方式仍缺乏全面认识。以PARP-1过度激活为特征的Parthanatos死亡现象是新近发现的神经元死亡方式，我们前期研究发现颞叶癫痫后海马神经元存在这种Parthanatos死亡现象，但其发生及调控机制不清。本项目拟采用神经元无镁培养癫痫模型、海人酸诱导大鼠颞叶癫痫模型，应用蛋白印迹分析、酶活性检测、RNA干扰等方法，从体外及体内两方面进一步研究：① ROS在癫痫后PARP-1过度激活中的始动作用及机制；② ERK信号通路在癫痫后Parthanatos发生及发展中的调控作用；③ JNK信号通路在癫痫后Parthanatos发生及发展中的调控作用。本研究通过阐明癫痫后神经元Parthanatos死亡机制，为防治颞叶癫痫后神经元损伤提供新的靶点和方法。

癫痫是一种常见的神经系统疾病，全球有超过6500万患者，致残率高。目前抗发作药物是癫痫治疗的主要方法，但只是对症治疗，不能从根本上解决癫痫发生。神经元死亡是癫痫发生发展的重要病理过程。Parthanatos死亡是近期公认的一种新的细胞程序性死亡方式，具有独特的生化特征。本项目率先从体内及体外两个方面证实了癫痫发生中海马神经元存在Parthanatos死亡方式，并发现其与氧化应激密切相关，干预Parthanatos死亡能够发挥显著的神经保护作用，为癫痫发生机制提供新的依据。此外，本研究发现在癫痫中JNK信号通路能通过增加细胞内及线粒体氧化应激水平，介导海马神经元Parthanatos死亡，为癫痫治疗提供新的靶点。