Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba 260-8670, Japan.
Neurobiol Dis. 2022 Apr;165:105635. doi: 10.1016/j.nbd.2022.105635. Epub 2022 Jan 25.
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.
多发性硬化症（MS）是最常见的攻击中枢神经系统的脱髓鞘疾病。我们最近报道，新型抗抑郁药（R）-氯胺酮可以改善实验性自身免疫性脑脊髓炎模型中的疾病进展。铜吡啶（CPZ）已被用于产生类似于 MS 患者脱髓鞘的脱髓鞘。本研究旨在探讨（R）-氯胺酮是否可以影响 CPZ 处理的小鼠中的脱髓鞘和 CPZ 停药后的髓鞘再生。与盐水处理的小鼠相比，重复（R）-氯胺酮（10 mg/kg/天，每周两次，持续 6 周）治疗可显著改善大脑中的脱髓鞘和激活的小胶质细胞。此外，预先用 ANA-12（TrkB 拮抗剂）处理可显著阻断（R）-氯胺酮对 CPZ 处理的小鼠大脑中脱髓鞘和激活的小胶质细胞的有益作用。16S rRNA 分析表明，（R）-氯胺酮可显著改善 CPZ 处理的小鼠异常的肠道微生物群组成并降低乳酸水平。此外，大脑中的脱髓鞘（或小胶质细胞激活）与几种微生物群的相对丰度之间存在显著相关性，这表明肠道微生物群与大脑之间存在联系。有趣的是，（R）-氯胺酮可促进 CPZ 停药后大脑中的髓鞘再生。总之，该研究表明，（R）-氯胺酮可以通过激活 TrkB 来改善 CPZ 处理的小鼠大脑中的脱髓鞘，并且肠道微生物群-小胶质细胞串扰可能在 CPZ 处理的小鼠脱髓鞘中起作用。因此，（R）-氯胺酮可能成为治疗多发性硬化症的新药物。
