Reactive aldehydes are generated as a toxic end-product of lipid peroxidation under inflammatory oxidative stress condition which is a well-established phenomenon in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Alda-1, a selective agonist of mitochondrial aldehyde dehydrogenase 2 (ALDH2), is known to detoxify the reactive aldehydes. In this study, we investigated the effect of Alda-1 on CNS myelin pathology associated with reactive aldehydes and mitochondrial/peroxisomal dysfunctions in a mouse model of EAE. Daily treatment of EAE mice with Alda-1, starting at the peak of disease, ameliorated the clinical manifestation of disease along with the improvement of motor functions. Accordingly, Alda-1 treatment improved demyelination and neuroaxonal degeneration in EAE mice. EAE mice had increased levels of reactive aldehyde species, such as 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and acrolein (ACL) in the spinal cords and these levels were significantly reduced in Alda-1-treated EAE mice. Furthermore, Alda-1 treatment improved the loss of mitochondrial (OXPHOS) and peroxisomal (PMP70 and catalase) proteins as well as mitochondrial/peroxisomal proliferation factors (PGC-1α and PPARs) in the spinal cords of EAE mice. Taken together, this study demonstrates the therapeutic efficacy of ALDH2-agonist Alda-1 in the abatement of EAE disease through the detoxification of reactive aldehydes, thus suggesting Alda-1 as a potential therapeutic intervention for MS.

在炎性氧化应激条件下，反应性醛作为脂质过氧化作用的有毒终产物生成，这是多发性硬化症（MS）及其动物模型，实验性自身免疫性脑脊髓炎（EAE）发病机理中公认的现象。已知Alda-1是线粒体醛脱氢酶2（ALDH2）的选择性激动剂，可对活性醛进行解毒。在这项研究中，我们调查了Alda-1对EAE小鼠模型中与反应性醛和线粒体/过氧化物酶体功能障碍相关的中枢神经系统髓磷脂病理的影响。从疾病高峰开始，每天用Alda-1处理EAE小鼠可改善疾病的临床表现，并改善运动功能。因此，Alda-1处理改善了EAE小鼠的脱髓鞘和神经轴突变性。EAE小鼠的脊髓中反应性醛物质的水平升高，例如4-羟基壬烯醛（4-HNE），丙二醛（MDA）和丙烯醛（ACL），而在Alda-1处理的EAE小鼠中，这些醛水平显着降低。此外，Alda-1处理改善了EAE小鼠脊髓中线粒体（OXPHOS）和过氧化物酶体（PMP70和过氧化氢酶）蛋白以及线粒体/过氧化物酶体增殖因子（PGC-1α和PPAR）的损失。综上所述，该研究证明了ALDH2-激动剂Alda-1通过对活性醛的解毒来减轻EAE疾病的治疗功效，因此表明Alda-1作为MS的潜在治疗手段。和脊髓中的丙烯醛（ACL），并且这些水平在Alda-1处理的EAE小鼠中显着降低。此外，Alda-1处理改善了EAE小鼠脊髓中线粒体（OXPHOS）和过氧化物酶体（PMP70和过氧化氢酶）蛋白以及线粒体/过氧化物酶体增殖因子（PGC-1α和PPAR）的损失。综上所述，该研究证明了ALDH2-激动剂Alda-1通过对活性醛的解毒来减轻EAE疾病的治疗功效，因此表明Alda-1作为MS的潜在治疗手段。和脊髓中的丙烯醛（ACL），并且这些水平在Alda-1处理的EAE小鼠中显着降低。此外，Alda-1处理改善了EAE小鼠脊髓中线粒体（OXPHOS）和过氧化物酶体（PMP70和过氧化氢酶）蛋白以及线粒体/过氧化物酶体增殖因子（PGC-1α和PPAR）的损失。综上所述，该研究证明了ALDH2-激动剂Alda-1通过对活性醛的解毒来减轻EAE疾病的治疗功效，因此表明Alda-1作为MS的潜在治疗手段。Alda-1处理可改善EAE小鼠脊髓中线粒体（OXPHOS）和过氧化物酶体（PMP70和过氧化氢酶）蛋白以及线粒体/过氧化物酶体增殖因子（PGC-1α和PPAR）的损失。综上所述，该研究证明了ALDH2-激动剂Alda-1通过对活性醛的解毒来减轻EAE疾病的治疗功效，因此表明Alda-1作为MS的潜在治疗手段。Alda-1处理可改善EAE小鼠脊髓中线粒体（OXPHOS）和过氧化物酶体（PMP70和过氧化氢酶）蛋白以及线粒体/过氧化物酶体增殖因子（PGC-1α和PPAR）的损失。综上所述，该研究证明了ALDH2-激动剂Alda-1通过对活性醛的解毒来减轻EAE疾病的治疗功效，因此表明Alda-1作为MS的潜在治疗手段。