Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats

Neurobiol Dis. 2014 Nov:71:220-33. doi: 10.1016/j.nbd.2014.08.019. Epub 2014 Aug 19.

Abstract

Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system (CNS) in young adults. Chronic treatments with histone deacetylase inhibitors (HDACis) have been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), a rodent model of MS, by targeting immune responses. We have recently shown that the HDAC inhibition/knockdown in the presence of thyroid hormone (T3) can also promote oligodendrocyte (OL) differentiation and expression of myelin genes in neural stem cells (NSCs) and oligodendrocyte precursors (OPCs). In this study, we found that treatment with an HDACi, valproic acid (VPA), and T3, alone or in combination, directly affects encephalitogenic CD4+ T cells. VPA, but not T3, compromised their proliferation, while both molecules reduced the frequency of IL-17-producing cells. Transfer of T3, VPA and VPA/T3 treated encephalitogenic CD4+ T cells into naïve rats induced less severe EAE, indicating that the effects of these molecules are persistent and do not require their maintenance after the initial stimuli. Thus, we investigated the effect of acute treatment with VPA and l-thyroxine (T4), a precursor of T3, on myelin oligodendrocyte glycoprotein-induced EAE in Dark Agouti rats, a close mimic of MS. We found that a brief treatment after disease onset led to sustained amelioration of EAE and prevention of inflammatory demyelination in the CNS accompanied with a higher expression of myelin-related genes in the brain. Furthermore, the treatment modulated immune responses, reduced the number of CD4+ T cells and affected the Th1 differentiation program in the brain. Our data indicate that an acute treatment with VPA and T4 after the onset of EAE can produce persistent clinically relevant therapeutic effects by limiting the pathogenic immune reactions while promoting myelin gene expression.

Keywords: Epigenetics; Experimental autoimmune encephalomyelitis; Histone deacetylases; Immune system; Multiple sclerosis; Myelin; Neuroinflammation; Oligodendrocyte precursor; T cells; Thyroid hormone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Brain / drug effects*
  • Brain / pathology
  • CD11b Antigen / metabolism
  • CD4-Positive T-Lymphocytes / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / etiology
  • Encephalomyelitis, Autoimmune, Experimental / pathology*
  • Enzyme Inhibitors / therapeutic use*
  • Flow Cytometry
  • Interleukin-17 / metabolism
  • Ki-67 Antigen / metabolism
  • Myelin Basic Protein / immunology
  • Myelin Basic Protein / toxicity
  • Peptide Fragments / immunology
  • Peptide Fragments / toxicity
  • Rats
  • Thyroxine / therapeutic use*
  • Valproic Acid / therapeutic use*

Substances

  • CD11b Antigen
  • Enzyme Inhibitors
  • Interleukin-17
  • Ki-67 Antigen
  • Myelin Basic Protein
  • Peptide Fragments
  • myelin basic protein 68-88
  • Valproic Acid
  • Thyroxine