Rg1 exerts protective effect in CPZ-induced demyelination mouse model via inhibiting CXCL10-mediated glial response
Rg1 exerts protective effect in CPZ-induced demyelination mouse model via inhibiting CXCL10-mediated glial response
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Rg1 通过抑制 CXCL10 介导的神经胶质反应对 CPZ 诱导的脱髓鞘小鼠模型发挥保护作用
DOI：
10.1038/s41401-021-00696-3
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发表时间：
2021-06-08
影响因子：
8.2
通讯作者：
Chen, Nai-hong
中科院分区：
文献类型：
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作者：
Dong, Yi-xiao;Chu, Shi-feng;Chen, Nai-hong
髓鞘损伤和异常髓鞘再生过程导致中枢神经系统功能障碍。神经胶质激活引起的微环境改变是髓磷脂异常疾病的特征。我们之前的研究表明，人参的主要成分人参皂苷Rg1可以改善mptp介导的小鼠髓磷脂损伤，但其潜在机制尚不清楚。本研究探讨了Rg1在铜酮（CPZ）诱导的小鼠脱髓鞘模型中的作用及其机制。小鼠用CPZ溶液（300 mg·kg - 1·d - 1, ig）治疗5周；从第2周开始，小鼠接受Rg1(5、10和20 mg·kg−1·d−1，ig)，持续4周。我们发现，Rg1剂量依赖性地缓解了cpz治疗小鼠的运动迟缓，并改善了cpz破坏的运动协调能力。此外，Rg1在病理检查中显著减少脱髓鞘和轴索损伤。我们进一步发现，Rg1的神经保护作用与抑制CXCL10介导的神经胶质反应调节有关，该调节是由NF-κB核易位和CXCL10启动子激活介导的。在小胶质细胞系BV-2中，我们发现Rg1对小胶质细胞促炎和迁移表型的影响与CXCL10有关，而Rg1诱导的小胶质细胞吞噬与CXCL10无直接关系。在CPZ诱导脱髓鞘小鼠模型中，在CPZ治疗前3周向小鼠侧脑室注射AAV-CXCL10 shRNA，在行为和病理分析中阻断了Rg1给药的有益作用。综上所述，CXCL10介导Rg1对cpz诱导脱髓鞘小鼠模型的保护作用。这项研究为髓磷脂异常的潜在疾病改善疗法提供了新的见解。
Myelin damage and abnormal remyelination processes lead to central nervous system dysfunction. Glial activation-induced microenvironment changes are characteristic features of the diseases with myelin abnormalities. We previously showed that ginsenoside Rg1, a main component of ginseng, ameliorated MPTP-mediated myelin damage in mice, but the underlying mechanisms are unclear. In this study we investigated the effects of Rg1 and mechanisms in cuprizone (CPZ)-induced demyelination mouse model. Mice were treated with CPZ solution (300 mg· kg−1· d−1, ig) for 5 weeks; from week 2, the mice received Rg1 (5, 10, and 20 mg· kg−1· d−1, ig) for 4 weeks. We showed that Rg1 administration dose-dependently alleviated bradykinesia and improved CPZ-disrupted motor coordination ability in CPZ-treated mice. Furthermore, Rg1 administration significantly decreased demyelination and axonal injury in pathological assays. We further revealed that the neuroprotective effects of Rg1 were associated with inhibiting CXCL10-mediated modulation of glial response, which was mediated by NF-κB nuclear translocation and CXCL10 promoter activation. In microglial cell line BV-2, we demonstrated that the effects of Rg1 on pro-inflammatory and migratory phenotypes of microglia were related to CXCL10, while Rg1-induced phagocytosis of microglia was not directly related to CXCL10. In CPZ-induced demyelination mouse model, injection of AAV-CXCL10 shRNA into mouse lateral ventricles 3 weeks prior CPZ treatment occluded the beneficial effects of Rg1 administration in behavioral and pathological assays. In conclusion, CXCL10 mediates the protective role of Rg1 in CPZ-induced demyelination mouse model. This study provides new insight into potential disease-modifying therapies for myelin abnormalities.