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

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

  • Pharmacol Res. 2022 Feb;176:105969. doi: 10.1016/j.phrs.2021.105969.
Yanjia Shen 1,  Ran Yang 1,  Jiaying Zhao 1,  Miao Chen 1,  Shuhan Chen 1,  Baixi Ji 1,  Houzao Chen 2,  Depei Liu 2,  Li Li 3,  Guanhua Du 4
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, NO.2, Nan Wei Road, Beijing 100050, China.
  • 2 State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
  • 3 Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, NO.2, Nan Wei Road, Beijing 100050, China. Electronic address: [email protected].
  • 4 Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, NO.2, Nan Wei Road, Beijing 100050, China. Electronic address: [email protected].
PMID: 34758400 DOI: 10.1016/j.phrs.2021.105969
Abstract

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) (100 mg/kg), belinostat (30 mg/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.

Keywords

Belinostat; HDAC3; Histone deacetylase inhibitor; Multiple sclerosis; Neuroinflammation; TLR2/MyD88 signaling pathway.

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