Modulating miR-146a Expression by Hydrogen Sulfide Ameliorates Motor Dysfunction and Axonal Demyelination in Cuprizone-Induced Multiple Sclerosis.

Abstract

Multiple sclerosis (MS) is a progressive neuro-inflammatory and neuro-autoimmune disease. Although hydrogen sulfide has recently shown potential therapeutic impacts in different neurological diseases, its effects on MS are still obscure. MiR-146a is considered a vital target for different therapeutic approaches in treating MS. The present study is directed to explore the therapeutic effects of NaHS (hydrogen sulfide donor) on cuprizone-induced MS and to explore whether NaHS can mediate its effects via regulating miR-146a expression. A total of 28 male C57Bl/6 mice were divided into 4 groups; control, cuprizone-intoxicated, NaHS control (100 μmol/kg/day, i.p), and NaHS-treated groups. Intriguingly, NaHS treatment managed to improve locomotor coordination and curb neuronal inflammation and demyelination as evidenced by hematoxylin & eosin, and Luxol fast blue staining and the increased myelin basic protein (MBP) content. Additionally, NaHS reduced interleukin-1 receptor-associated kinase-1 (IRAK-1), nuclear transcription factor kappa B (NF-κB), interleukin (IL)-17, and IL-1β brain levels along with downregulation of miR-146a expression compared with the untreated cuprizone-intoxicated group. Furthermore, NaHS-treated animals revealed much less oxidative stress compared to the untreated animals as evidenced by elevated glutathione and reduced malondialdehyde contents. Altogether, the current work reported that NaHS could improve motor dysfunction and reduce axonal demyelination, oxidative stress, as well as neuro-inflammation in mice with MS. Thus, using H2S-releasing compounds could be a promising approach in MS treatment strategies. The mechanism of these beneficial effects may involve the regulation of miR-146a/NF-κB/IL-1β axis.