青蒿琥酯通过PINK1/Parkin通路激活线粒体自噬在抗NMDAR脑炎中的神经保护性研究

抗NMDAR脑炎是一种新型自身免疫性脑炎，急性期病情十分严重，且治疗方法有限，其发病机制亦不十分明确。申请人团队在前期研究中发现：在抗NMDAR脑炎患者脑脊液中，不仅代表线粒体损伤的mtDNA水平升高，而且代表神经元凋亡的Fas/FasL水平也升高。因此我们推测线粒体损伤所诱导的神经元凋亡参与了抗NMDAR脑炎的发病。有研究发现，受损线粒体可以通过PINK1/Parkin通路激活线粒体自噬而负性调节神经元凋亡，而青蒿琥酯正是作用于该途径的线粒体自噬诱导剂。因此我们推测青蒿素可以通过上调线粒体自噬、抑制神经元凋亡，达到保护神经组织甚至治疗抗NMDAR脑炎的作用。本研究拟采用野生型和Parkin-/-基因敲除鼠制作被动转运模型，予青蒿琥酯进行干预，探讨线粒体损伤和自噬在抗NMDAR脑炎发病中的作用，探索青蒿琥酯治疗抗NMDAR脑炎的疗效和作用机制，为阐明本病的发病机制、药物开发提供理论依据。

Anti-NMDAR encephalitis is a newly recognized autoimmune encephalitis, which is very serious in the acute stage with limited treatment and unclear pathogenesis. In our previous studies, we found elevated cell-free mtDNA and soluble Fas/FasL in the CSF of patients with anti-NMDAR encephalitis, which represent the levels of mitochondrial damage and neuronal apoptosis respectly. It sugguested that the mitochondrial injury and neuronal apoptosis participated in the pathogenesis of anti-NMDAR. Other studies have found that mitochondrial autophagy can be activated by mitochondrial injury via PINK1/Parkin pathway and negatively regulate neuronal apoptosis, and artesunate is just an inducer of mitochondrial autophagy via this pathway. Therefore, we speculated that artesunate could protect the neural tissue and even treat anti-NMDAR encephalitis by up-regulating mitochondrial autophagy and reducing neuronal apoptosis. In our this study, wild-type and Parkin(-/-) knockout mice will be used to make passive transport models. We will give artesunate in vivo for exploring the role of mitochondrial injury and mitochondrial autophagy in the pathogenesis of anti-NMDAR encephalitis, and also exploring the efficacy and mechanism of artesunate in the treatment of anti-NMDAR encephalitis. We hope to provide some development for the pathogenesis and drug therapies of anti-NMDAR encephalitis.