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

Neurobiology of Disease

Rasmus Berglund¹  André Ortlieb Guerreiro-Cacais²  Pernilla Stridh³  Hans Lassmann⁴  Kedir Hussen Hamza⁵  Milena Z. Adzemovic⁵  Ana Mendanha Falcão⁵  Monica Marta⁵  Maja Jagodic⁵  Ola Hermanson⁵  Alan Gillett⁶  Gonçalo Castelo-Branco⁶ 

[1] Center for Brain Research, Vienna, Austria;Correspondence to: G. Castelo-Branco, Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden. Fax: [phone].;Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden;Neuroscience, Blizard Institute, Queen Mary University London, London, UK;Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden;Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden;

关键词: Multiple sclerosis;    Experimental autoimmune encephalomyelitis;    Epigenetics;    Histone deacetylases;    Thyroid hormone;    Neuroinflammation;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown