Editors' ChoicePharmacology

Repurposing Antiepileptic Drugs for Multiple Sclerosis

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Science Signaling  28 Aug 2012:
Vol. 5, Issue 239, pp. ec223
DOI: 10.1126/scisignal.2003538

Valproic acid is a histone deacetylase inhibitor that is used clinically to treat epilepsy. Lv et al. suggest that this drug may also be effective in the treatment of multiple sclerosis. Administration of valproic acid (either intraperitoneally or orally) reduced disease severity in a mouse model of multiple sclerosis called experimental autoimmune encephalomyelitis (EAE) when administered either before or after the onset of symptoms. Spinal cords from the treated mice had fewer proinflammatory T cells, specifically TH17 and TH1 cells. Spleens of EAE mice were significantly larger than those of control mice, and this increase in spleen size and in the percentage of TH17 and TH1 cells in the active T cell population was reduced by administering valproic acid to the EAE mice. In vitro analysis of isolated T cells showed that valproic acid reduced antigen-stimulated T cell proliferation and inhibited T cell differentiation into TH17 and TH1 cells. Valproic acid also promoted apoptosis of TH17 and TH1 cells differentiated in culture. T cells from the spleens of EAE mice treated with valproic acid exhibited increased abundance of transcripts encoding the caspases involved in apoptosis (caspase-3, -8, and -9), and cleaved (and activated) caspase-3 was more abundant in the EAE group treated with valproic acid. T cells isolated from the spleens of EAE mice had lower proportions of apoptotic cells than did T cells isolated from wild-type mice when activated in culture, and administration of valproic acid to the EAE mice increased the proportion of apoptotic cells. Exposure of T cells from three human multiple sclerosis patients to valproic acid produced a similar increase in the proportion of apoptotic cells, suggesting that this antiepileptic drug may be repurposed as a treatment for multiple sclerosis.

J. Lv, C. Du, W. Wei, Z. Wu, G. Zhao, Z. Li, X. Xie, The antiepileptic drug valproic acid restores T cell homeostasis and ameloriates pathogenesis of experimental autoimmune encephalomyelitis. J. Biol. Chem. 287, 28656–28665 (2012). [Abstract] [Full Text]

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