Home Blog of Signal Transduction DNA Damage/DNA Repair Autophagy The histone deacetylase inhibitor belinostat ameliorates experimental autoimmune encephalomyelitis in mice by inhibiting TLR2/MyD88 and HDAC3/ NF-κB p65-mediated neuroinflammation

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The histone deacetylase inhibitor belinostat ameliorates experimental autoimmune encephalomyelitis in mice by inhibiting TLR2/MyD88 and HDAC3/ NF-κB p65-mediated neuroinflammation

Multiple sclerosis (MS) is a Th cell-mediated inflammatory demyelinating autoimmune disease. MS cannot be cured, and long-term drug treatment is still needed for MS patients. In this study, we examined the effect of belinostat, a pan-histone deacetylase inhibitor (HDACi), on experimental autoimmune encephalomyelitis (EAE) and elucidated its mechanism of action. We found that belinostat alleviates the clinical symptoms, histopathological central nervous system (CNS) inflammation and demyelination outcomes in EAE mice. Compared to the MS oral drug dimethyl fumarate (DMF) (100mg/kg), belinostat (30mg/kg) treatment exhibited better efficacy in improving the clinical symptoms of EAE mice. Belinostat treatment significantly suppressed the activation of M1 microglia and the proinflammatory cytokine expression; but it had no effects on the M2 microglial polarization. Belinostat also decreased both NO and iNOS levels in LPS-stimulated BV2 microglia. Accordingly, belinostat treatment of EAE mice significantly inhibited activation of the TLR2/MyD88 signaling pathway and downregulated the expression of HDAC3 while upregulating the acetylated NF-κB p65 levels. Taken together, these data demonstrate for the first time that belinostat ameliorates EAE in mice through inhibiting neuroinflammation via suppressing M1 microglial polarization, and implicating belinostat as a potential candidate for the treatment of multiple sclerosis.

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S1085 Belinostat Belinostat is a novel HDAC inhibitor with IC50 of 27 nM in a cell-free assay, with activity demonstrated in cisplatin-resistant tumors. Belinostat (PXD101) induces autophagy.

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