Mechanisms related to the pathogenesis of the optic neuritis and the development of new therapeutic avenues

本研究采用实验性自身免疫性脑脊髓炎(EAE)作为多发性硬化症(MS)的动物模型，探讨视神经炎的发病机制。首先，我们研究了细胞凋亡相关蛋白1(ASK1)缺乏对EAE严重程度的影响。我们的结果表明，ASK1缺乏减轻了EAE的神经炎症，而不影响T细胞的增殖能力。此外，口服一种特定的小分子ASK1抑制剂可抑制EAE引起的脊髓和视神经自身免疫性炎症。这些结果提示，ASK1可能是治疗包括MS在内的自身免疫性脱髓鞘疾病的有效靶点。其次，我们发现少突胶质细胞发育的重要基因--寡核苷酸的缺失延缓了EAE疾病的发生，提示寡核苷酸信号通路可能与MS的发病率和神经系统症状的严重程度有关。第三，我们发现口服亚精胺可以减轻视神经炎的严重程度，提示亚精胺可能适合于治疗MS和视神经炎。

Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), was used in our study to elucidate the possible mechanisms underlying the pathogenesis of the optic neuritis. Firstly, we investigated the effect of apoptosis-related kinase 1 (ASK1) deficiency on the severity of EAE. Our results show that ASK1 deficiency attenuates neuroinflammation in EAE, without affecting the proliferation capability of T cells. Moreover, oral treatment with a specific small molecular weight inhibitor of ASK1 suppressed EAE-induced autoimmune inflammation in both spinal cords and optic nerves. These results suggest that ASK1 may serve as a valid therapeutic target for autoimmune demyelinating disorders including MS. Secondly, we found that the deficiency of olig1, a gene important for the development of oligodendrocytes, delayed the onset of EAE disease, suggesting that the olig1 signaling pathways may be involved in the incidence rate and the severity of neurological symptoms in MS. Thirdly, we found that oral administration of spermidine, a natural component of our diet, reduced the severity of the optic neuritis, suggesting that spermidine might be suitable for the treatment of MS and optic neuritis.