(R)-ketamine ameliorates demyelination and facilitates remyelination in cuprizone-treated mice: A role of gut–microbiota–brain axis

• Published in: Neurobiology of disease 2022-04, Vol.165, p.105635-105635, Article 105635
• Main Authors: Wang, Xingming, Chang, Lijia, Wan, Xiayun, Tan, Yunfei, Qu, Youge, Shan, Jiajing, Yang, Yong, Ma, Li, Hashimoto, Kenji
• Format: Article
• Language: English
• Subjects: (R)-ketamine; Animals; Brain; Cuprizone - toxicity; Demyelination; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Gut–microbiota; Humans; Ketamine - pharmacology; Mice; Mice, Inbred C57BL; Microbiota; Microglia; Myelin Sheath; Oligodendroglia; Remyelination; RNA, Ribosomal, 16S
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2022.105635

Multiple sclerosis (MS) is the most common demyelinating disease that attacks the central nervous system. We recently reported that the new antidepressant (R)-ketamine could ameliorate the disease progression in experimental autoimmune encephalomyelitis model of MS. Cuprizone (CPZ) has been used to produce demyelination which resembles demyelination in MS patients. This study was undertaken to investigate whether (R)-ketamine could affect demyelination in CPZ-treated mice and remyelination after CPZ withdrawal. Repeated treatment with (R)-ketamine (10 mg/kg/day, twice weekly, for 6 weeks) significantly ameliorated demyelination and activated microglia in the brain compared with saline-treated mice. Furthermore, pretreatment with ANA-12 (TrkB antagonist) significantly blocked the beneficial effects of (R)-ketamine on the demyelination and activated microglia in the brain of CPZ-treated mice. The 16S rRNA analysis showed that (R)-ketamine significantly improved abnormal composition of gut–microbiota and decreased levels of lactic acid of CPZ-treated mice. In addition, there were significant correlations between demyelination (or microglial activation) in the brain and the relative abundance of several microbiome, suggesting a link between gut microbiota and brain. Interestingly, (R)-ketamine could facilitate remyelination in the brain after CPZ withdrawal. In conclusion, the study suggests that (R)-ketamine could ameliorate demyelination in the brain of CPZ-treated mice through TrkB activation, and that gut–microbiota–microglia crosstalk may play a role in the demyelination of CPZ-treated mice. Therefore, it is likely that (R)-ketamine could be a new therapeutic drug for MS. •(R)-ketamine ameliorated demyelination of cuprizone-treated mice through TrkB activation.•(R)-ketamine improved abnormal composition of gut microbiota and lactic acid of cuprizone-treated mice.•There were correlations between relative abundance of microbiome and microglial marker in the brain.•(R)-ketamine facilitated remyelination after cuprizone withdrawal.•(R)-ketamine could be a new therapeutic drug for multiple sclerosis.