β-hydroxybutyrate attenuates demyelination, modulates microglial phenotype and supports blood-brain barrier integrity in a cuprizone-induced mouse model of demyelination

Abstract

β-hydroxybutyrate has been reported to have neuroprotective activity. In this study, the neuroprotective effects of BHB were investigated on a demyelination model, the cuprizone model. We found that BHB reduced demyelination, which was confirmed by western blot for myelin-oligodendrocyte glycoprotein (MOG) and myelin proteolipid protein (PLP). Following BHB treatment, the number of connexin43+ (Cx43+) + GFAP+ cells and Iba-1+ + CD16/32+ cells decreased, whereas the number of Cx47+ + oligo2+ cells and Iba-1+ + Arginase-1+ cells increased significantly. Furthermore, BHB significantly repressed the expression of MMP-9/12, and increased the expression of blood-brain barrier (BBB) markers (such as PECAM-1 and ZO-1) in CPZ mice. We report that BHB promotes M2 microglia polarization and ameliorates BBB dysfunction caused by downregulation of HDAC3, NF-κB, Aim2 and NLRP3, as well as upregulation of SIRT1 in CPZ mice. Thus, these findings suggest that BHB may be a therapeutic approach for preventing demyelinating diseases.