Journal
PHARMACOLOGICAL RESEARCH
Volume 176, Issue -, Pages -Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2021.105969
Keywords
Histone deacetylase inhibitor; Belinostat; Neuroinflammation; Multiple sclerosis; TLR2; MyD88 signaling pathway; HDAC3
Categories
Funding
- National Natural Science Foundation of China, China [82073863, 82030017]
- CAMS Innovation Fund for Medical Sciences (CIFMS), China [2021-I2M-1-016, 2016-I2M3-007]
- Major Scientific and Technological Special Project for Significant New Drug Creation, China [2018ZX09711001-003-005]
- China Scholarship Council, China [201808110107]
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This study demonstrates the potential of belinostat in treating multiple sclerosis by inhibiting neuroinflammation and M1 microglial polarization.
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-xB 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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