title: Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats.
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.
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Goncalo.Castelo-Branco@ki.se.
authors.forename: Gonçalo
authors.initials: G
authors.lastname: Castelo-Branco
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Stridh
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: André Ortlieb
authors.initials: AO
authors.lastname: Guerreiro-Cacais
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Center for Brain Research, Vienna, Austria.
authors.forename: Milena Z
authors.initials: MZ
authors.lastname: Adzemovic
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ana Mendanha
authors.initials: AM
authors.lastname: Falcão
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Neuroscience, Blizard Institute, Queen Mary University London, London, UK.
authors.forename: Monica
authors.initials: M
authors.lastname: Marta
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Berglund
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Alan
authors.initials: A
authors.lastname: Gillett
authors.affiliation: Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kedir Hussen
authors.initials: KH
authors.lastname: Hamza
authors.affiliation: Center for Brain Research, Vienna, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Hermanson
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address: Maja.Jagodic@ki.se.
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D039481:CD11b Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005434:Flow Cytometry; D020381:Interleukin-17 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D004676:Myelin Basic Protein / Q000276:immunology / Q000633:toxicity; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D051381:Rats; D013974:Thyroxine / Q000627:therapeutic use*; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D039481:CD11b Antigen; D004791:Enzyme Inhibitors; D020381:Interleukin-17; D019394:Ki-67 Antigen; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C079716:myelin basic protein 68-88; D014635:Valproic Acid; D013974:Thyroxine
keywords: Epigenetics; Experimental autoimmune encephalomyelitis; Histone deacetylases; Immune system; Multiple sclerosis; Myelin; Neuroinflammation; Oligodendrocyte precursor; T cells; Thyroid hormone