Rg1 exerts protective effect in CPZ-induced demyelination mouse model via inhibiting CXCL10-mediated glial response

• Published in: Acta pharmacologica Sinica 2022-03, Vol.43 (3), p.563-576
• Main Authors: Dong, Yi-xiao, Chu, Shi-feng, Wang, Sha-sha, Tian, Ya-juan, He, Wen-bin, Du, Yu-sheng, Wang, Zhen-zhen, Yan, Xu, Zhang, Zhao, Chen, Nai-hong
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cell activation; Central nervous system; Chemokine CXCL10 - antagonists & inhibitors; Chinese medicine; Cuprizone; Cuprizone - pharmacology; CXCL10 protein; Demyelinating Diseases - pathology; Demyelination; Disease Models, Animal; Dose-Response Relationship, Drug; Experiments; Ginseng; Ginsenosides; Ginsenosides - pharmacology; Hypokinesia - pathology; Immunoglobulins; Immunology; Inflammation; Inflammation Mediators - metabolism; Internal Medicine; Laboratory animals; Male; Medical Microbiology; Medical research; Mice; Mice, Inbred C57BL; Microenvironments; Microglia; Microglia - drug effects; MPTP; Myelin; Myelination; Nervous system; Neuroprotection; NF-kappa B - drug effects; NF-κB protein; Nuclear transport; Panax - chemistry; Panax - metabolism; Phagocytosis; Phagocytosis - drug effects; Pharmacology/Toxicology; Phenotypes; RNA, Small Interfering - pharmacology; Vaccine; Ventricle (lateral)
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-021-00696-3

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.