Gilgun-Sherki Yossi, Panet Hana, Melamed Eldad, Offen Daniel
Laboratory of Neurosciences, Felsenstein Medical Research Center and Department of Neurology, Rabin Medical Center-Beilinson Campus, The Sackler School of Medicine, Tel Aviv University, Petah Tikva 49100, Israel.
Brain Res. 2003 Nov 7;989(2):196-204. doi: 10.1016/s0006-8993(03)03343-2.
Recent studies suggest that glutamate neurotoxicity is involved in the pathogenesis of multiple sclerosis (MS), and that treatment with glutamate receptor (AMPA/kainate) antagonists inhibits experimental autoimmune encephalomyelitis (EAE), the conventional model of MS. Therefore, we examined whether riluzole, an inhibitor of glutamate transmission, affects the pathogenesis and clinical features of MS-like disease in myelin oligodendrocyte glycoprotein (MOG)-induced EAE in mice. Here we report that riluzole (10 mg/kgx2/day, i.p.), administered before and even after the appearance of clinical symptoms, dramatically reduced the clinical severity of MOG-induced EAE, while all the MOG-immunized control mice developed significant clinical manifestations. Moreover, the riluzole-treated mice demonstrated only mild focal inflammation, and less demyelination, compared to MOG-treated mice, using histological methods. Furthermore, riluzole markedly reduced axonal disruption, as assessed by Bielshowesky's silver staining and by antibodies against non-phosphorylated neurofilaments (SMI-32). No difference was detected in the immune system potency, as T-cell proliferative responses to MOG were similar in both groups. In conclusion, our study demonstrates, for the first time, that riluzole can reduce inflammation, demyelination and axonal damage in the CNS and attenuate the clinical severity of MOG-induced EAE. These results suggest that riluzole, a drug used in amyotrophic lateral sclerosis (ALS), might be beneficial for the treatment of MS.
最近的研究表明，谷氨酸神经毒性参与了多发性硬化症（MS）的发病机制，并且用谷氨酸受体（AMPA/海人酸）拮抗剂进行治疗可抑制实验性自身免疫性脑脊髓炎（EAE），即MS的传统模型。因此，我们研究了谷氨酸传递抑制剂利鲁唑是否会影响小鼠中髓鞘少突胶质细胞糖蛋白（MOG）诱导的EAE中MS样疾病的发病机制和临床特征。在此我们报告，在出现临床症状之前甚至之后给予利鲁唑（10mg/kg×2/天，腹腔注射），可显著降低MOG诱导的EAE的临床严重程度，而所有接受MOG免疫的对照小鼠均出现了明显的临床表现。此外，与MOG处理的小鼠相比，使用组织学方法，利鲁唑处理的小鼠仅表现出轻度局灶性炎症和较少的脱髓鞘。此外，通过 Bielshowesky 银染色和针对非磷酸化神经丝的抗体（SMI-32）评估，利鲁唑显著减少了轴突破坏。两组中对MOG的T细胞增殖反应相似，因此在免疫系统效能方面未检测到差异。总之，我们的研究首次表明，利鲁唑可减轻中枢神经系统中的炎症、脱髓鞘和轴突损伤，并减轻MOG诱导的EAE的临床严重程度。这些结果表明，用于治疗肌萎缩侧索硬化症（ALS）的药物利鲁唑可能对MS的治疗有益。
