Tetramethylpyrazine promotes remyelination by conversing M1 to M2 polarization of microglia via JAK2-STAT1/3 and GSK3-NFκB signaling pathways in ischemic stroke

Abstract

Abstract Ischemic stroke results in demyelination that underlies neurological disfunction.Promoting oligodendrogenesis will rescue the injured axons and accelerate remyelination after stroke. Microglia react to stroke and polarize to M1/M2 phenotypes. M1 microglia secrete proinflammatory factors to inhibit oligodendrocyte precursor cell (OPC)proliferation and differentiation, inversely, M2 microglia favor the remyelinating process. Tetramethylpyrazine (TMP) has been routinely used in treating cerebrovascular disorders, whereas the role of TMP-mediated microglial polarization on remyelination and the underlying mechanisms remain unknown. In this study, magnetic resonance imaging (MRI) and histopathological evaluation were performed to characterize TMP’s efficacy on remyelinated axon preservation and oligodendrogenesis, particularly, TMP inhibited M1 and enhanced M2 polarization of microglia in cerebral ischemic rats. Moreover, we firstly demonstrated that TMP reversed M1/M2 phenotype via JAK2-STAT1/3 and GSK3-NFκB pathway in lipopolysaccharide (LPS) plus interferon-γ (IFN-γ)-stimulated BV2 microglia. Blocking the crucial target JAK2 will counteract TMP’s effect on mediating M2 polarization of microglia. This study uncovers that TMP’s facilitation on remyelination warrants promising targets for stroke therapy.