Morini Monica, Roccatagliata Luca, Dell'Eva Raffaella, Pedemonte Enrico, Furlan Roberto, Minghelli Simona, Giunti Debora, Pfeffer Ulrich, Marchese Monica, Noonan Douglas, Mancardi Gianluigi, Albini Adriana, Uccelli Antonio
Molecular Oncology Laboratory, National Cancer Research Institute, Genoa, Italy.
J Neuroimmunol. 2004 Mar;148(1-2):146-53. doi: 10.1016/j.jneuroim.2003.11.021.
Alpha-lipoic acid (alpha-LA) is a neuroprotective metabolic antioxidant that has been shown to cross the blood brain barrier. We tested whether alpha-LA is capable to prevent MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). Daily oral administration of alpha-LA, starting at the time of immunization, significantly prevented EAE progression as compared to control mice. This was associated with a reduction of CNS infiltrating T cells and macrophages as well as decreased demyelination. We then tested alpha-LA in a therapeutic protocol aimed at suppressing EAE after its onset. Intraperitoneal (i.p.), but not oral, administration of alpha-LA significantly prevented disease progression when compared to vehicle-treated controls. Similarly, we observed significant reduction of demyelination and inflammatory infiltration. This clinical effect was not due to an impairment of MOG35-55 recognition by encephalitogenic T cells. In contrast, MOG-specific T cells showed a decreased production of IFNgamma and IL-4, suggesting an immunosuppressive activity on both Th1 and Th2 cytokines. In addition, alpha-LA inhibited the proteolytic activity of MMP2 and MMP9 only at very high doses. Our data indicate that alpha-LA can effectively interfere with the autoimmune reaction associated with EAE through mechanisms other than its antioxidant activity and supports further studies on the use of alpha-LA as a potential therapy for MS.
α-硫辛酸（α-LA）是一种具有神经保护作用的代谢性抗氧化剂，已被证明能够穿过血脑屏障。我们测试了α-LA是否能够预防MOG35-55诱导的实验性自身免疫性脑脊髓炎（EAE），这是一种已确立的多发性硬化症（MS）模型。从免疫接种时开始每日口服α-LA，与对照小鼠相比，显著预防了EAE的进展。这与中枢神经系统浸润性T细胞和巨噬细胞数量减少以及脱髓鞘减少有关。然后，我们在旨在抑制EAE发病后进展的治疗方案中测试了α-LA。与载体处理的对照组相比，腹腔内（i.p.）而非口服给予α-LA显著预防了疾病进展。同样，我们观察到脱髓鞘和炎症浸润显著减少。这种临床效果并非由于致脑炎性T细胞对MOG35-55的识别受损。相反，MOG特异性T细胞显示IFNγ和IL-4的产生减少，表明对Th1和Th2细胞因子均具有免疫抑制活性。此外，α-LA仅在非常高的剂量下才抑制MMP2和MMP9的蛋白水解活性。我们的数据表明，α-LA可以通过其抗氧化活性以外的机制有效干扰与EAE相关的自身免疫反应，并支持进一步研究将α-LA用作MS的潜在治疗方法。
