Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats
| Autor: | Milena Z. Adzemovic, Ana Mendanha Falcão, Rasmus Berglund, Kedir Hussen Hamza, Pernilla Stridh, Alan Gillett, Gonçalo Castelo-Branco, Hans Lassmann, Maja Jagodic, Monica Marta, André Ortlieb Guerreiro-Cacais, Ola Hermanson |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
CD4-Positive T-Lymphocytes
Myelin 0302 clinical medicine Histone deacetylases Neuroinflammation Medicine Enzyme Inhibitors 0303 health sciences CD11b Antigen Experimental autoimmune encephalomyelitis biology Interleukin-17 Brain Flow Cytometry 3. Good health medicine.anatomical_structure Neurology Epigenetics Interleukin 17 Encephalomyelitis Autoimmune Experimental T cells lcsh:RC321-571 Multiple sclerosis 03 medical and health sciences Immune system Animals lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry 030304 developmental biology Analysis of Variance Dose-Response Relationship Drug business.industry Valproic Acid Oligodendrocyte precursor Myelin Basic Protein medicine.disease Peptide Fragments Oligodendrocyte Rats Myelin basic protein Thyroid hormone Disease Models Animal Thyroxine Ki-67 Antigen Immunology biology.protein business 030217 neurology & neurosurgery |
| Zdroj: | Neurobiology of Disease, Vol 71, Iss, Pp 220-233 (2014) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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