Ginsenoside-Re inhibits experimental autoimmune encephalomyelitis as a mouse model of multiple sclerosis by downregulating TLR4/MyD88/NF-κB signaling pathways

• Published in: Phytomedicine (Stuttgart) 2024-01, Vol.122, p.155065-155065, Article 155065
• Main Authors: Oh, Jinhee, Kwon, Tae Woo, Choi, Jong Hee, Kim, Yunna, Moon, Sang-Kwan, Nah, Seung-Yeol, Cho, Ik-Hyun
• Format: Article
• Language: English
• Subjects: Alzheimer disease; animal models; astrocytes; autoimmune diseases; bEND.3 cells; blood-brain barrier; cell adhesion; cell adhesion molecules; chemokine CCL5; encephalitis; endothelial cells; Experimental autoimmune encephalomyelitis; gene expression; Ginsenoside-Re; ginsenosides; glycoproteins; inflammation; interleukin-6; lipopolysaccharides; macrophages; mice; Multiple sclerosis; myelin sheath; occludins; oligodendroglia; Panax ginseng; sclerosis; spinal cord; therapeutics
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2023.155065

Ginsenosides are main active compounds of Panax ginseng with pharmacological effects on immunological/neurological diseases. Recently, ginsenoside-Re (G-Re) has been shown to exert neuroprotective effects on neurodegenerative diseases such as Alzheimer's disease. However, whether G-Re has an effect on multiple sclerosis (MS), a representative autoimmune disease of the central nervous system (CNS), has not been revealed yet. The purpose of this study was to investigate pharmacological effects of G-Re and related molecular mechanisms using a myelin oligodendrocyte glycoprotein peptide-immunized experimental autoimmune encephalomyelitis (EAE) animal model of MS and lipopolysaccharide (LPS)-stimulated bEND.3 cells as an in vitro model of the blood-brain barrier (BBB). G-Re attenuated motor impairment of EAE, demyelination, and inflammation in spinal cords of EAE mice. G-Re reduced infiltration/activation of microglia/macrophages and decreased mRNA expression levels of pro-inflammatory cytokines (IL-1β and IL-6), chemokines (MIP-1α, MCP-1, and RANTES), and enzymes (iNOS) in spinal cords of EAE mice. G-Re inhibited alterations of BBB constituents (such as astrocytes, cell adhesion molecule (platelet endothelial cell adhesion molecule-1), and tight junctional molecules (occludin and zonula occludens-1)) and toll like receptor 4 (TLR4)/MyD88/nuclear factor kappa-B (NF-κB) signaling pathways in spinal cords of EAE mice and LPS-stimulated bEND.3 cells. Interestingly, combination treatment with G-Re and TLR4 inhibitor (TAK242) significantly inhibited the upregulation of TLR4/MyD88/NF-κB pathway in LPS-stimulated bEND.3 cells. TLR4 inhibitor- and activator-treated EAE mice showed conflicting behavior patterns. G-Re might alleviate motor impairment of EAE and its pathological/inflammatory events in the spinal cord by preventing BBB disruption via downregulation of TLR4/MyD88/NF-κB signaling pathways. These findings for the first time suggest that G-Re might be a potential therapeutic for MS through maintenance of BBB integrity. [Display omitted]