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

beta-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-kappa B, 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.