Activation of FXR by ganoderic acid A promotes remyelination in multiple sclerosis via anti-inflammation and regeneration mechanism
Activation of FXR by ganoderic acid A promotes remyelination in multiple sclerosis via anti-inflammation and regeneration mechanism
复制标题
灵芝酸 A 激活 FXR，通过抗炎和再生机制促进多发性硬化症的髓鞘再生。
DOI：
10.1016/j.bcp.2021.114422
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发表时间：
2021-01-28
影响因子：
5.8
通讯作者：
Bao, Hongkun
中科院分区：
文献类型：
--
作者：
Jia, Yue;Zhang, Dandan;Bao, Hongkun
多发性硬化（MS）是一种中枢神经系统炎性脱髓鞘疾病，是青年人非创伤性神经功能障碍的主要原因。MS的发病机制尚不清楚，然而，胶质细胞-神经免疫信号的失调在疾病进展阶段起着关键作用。现有的大多数药物都是针对免疫系统的，但到目前为止还没有批准的药物通过促进脱髓鞘后的髓鞘再生。人们对通过靶向将免疫失衡从促炎症和凋亡转变为抗炎和髓鞘再生阶段期间的再生来鉴定用于治疗MS的新型药剂有很大的兴趣。在此，我们报道了灵芝酸A（GAA）显著增强了两种MS动物模型的髓鞘再生和挽救运动缺陷，包括铜唑酮诱导的脱髓鞘和髓鞘少突胶质细胞糖蛋白（MOG）35 - 55诱导的实验性自身免疫性脑脊髓炎模型。在这两个独立的MS动物模型中，GAA调节神经免疫以增强抗炎和再生标志物IL-4和BDNF，抑制炎症标志物IL-1 β和IL-6，随后下调小胶质细胞活化和星形胶质细胞增殖。药理学和遗传学的法尼酯X受体（FXR）消融废除了GA诱导的髓鞘再生和恢复MS小鼠的运动缺陷。因此，GAA是一种新的和潜在的治疗剂，可以通过FXR受体依赖性机制挽救MS神经免疫失衡和髓鞘再生。GAA改善MS患者髓鞘再生以挽救运动功能的临床研究是必要的。
Multiple sclerosis (MS), as an inflammatory demyelinating disorder of central nervous system, is the leading cause of non-traumatic neurologic disability in young adults. The pathogenesis of MS remains unknown, however, a dysregulation of glia-neuroimmune signaling plays a key role during progressive disease stage. Most of the existing drugs are aimed at the immune system, but there is no approved drug by promoting remyelination after demyelination so far. There is a great interest in identifying novel agents for treating MS by targeting to switch the immune imbalance from pro-inflammation and apoptosis to anti-inflammation and regeneration during remyelination phase. Here, we reported that ganoderic acid A (GAA) significantly enhanced the remyelination and rescued motor deficiency in two animal models of MS, including cuprizone-induced demyelination and myelin oligodendrocyte glycoprotein (MOG) 35-55-induced experimental autoimmune encephalomyelitis model. In these two independent MS animal models, GAA modulated neuroimmune to enhance the anti-inflammatory and regeneration markers IL-4 and BDNF, inhibited inflammatory markers IL-1 beta and IL-6, followed by down-regulation of microglia activation and astrocyte proliferation. Pharmacological and genetic ablation of farnesoid-X-receptor (FXR) abolished GAA-induced remyelination and restoration of motor deficiency in MS mice. Thus, GAA is a novel and potential therapeutic agent that can rescue MS neuroimmune imbalance and remyelination through an FXR receptor-dependent mechanism. Clinical investigation on the therapeutic effect of GAA in improving remyelination of the MS patients to rescue the motor function is warranted.