Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats
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...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-11-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996114002502 |
| _version_ | 1818651545406799872 |
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| author | Gonçalo Castelo-Branco Pernilla Stridh André Ortlieb Guerreiro-Cacais Milena Z. Adzemovic Ana Mendanha Falcão Monica Marta Rasmus Berglund Alan Gillett Kedir Hussen Hamza Hans Lassmann Ola Hermanson Maja Jagodic |
| author_facet | Gonçalo Castelo-Branco Pernilla Stridh André Ortlieb Guerreiro-Cacais Milena Z. Adzemovic Ana Mendanha Falcão Monica Marta Rasmus Berglund Alan Gillett Kedir Hussen Hamza Hans Lassmann Ola Hermanson Maja Jagodic |
| author_sort | Gonçalo Castelo-Branco |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T02:07:49Z |
| format | Article |
| id | doaj.art-b58e963bfaa34916963b115082a2be09 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T02:07:49Z |
| publishDate | 2014-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-b58e963bfaa34916963b115082a2be092022-12-21T22:07:38ZengElsevierNeurobiology of Disease1095-953X2014-11-0171220233Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA ratsGonçalo Castelo-Branco0Pernilla Stridh1André Ortlieb Guerreiro-Cacais2Milena Z. Adzemovic3Ana Mendanha Falcão4Monica Marta5Rasmus Berglund6Alan Gillett7Kedir Hussen Hamza8Hans Lassmann9Ola Hermanson10Maja Jagodic11Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden; Correspondence to: G. Castelo-Branco, Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-17177 Stockholm, Sweden. Fax: +46 8 34 19 60.Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Center for Brain Research, Vienna, AustriaLaboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Neuroscience, Blizard Institute, Queen Mary University London, London, UKDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, SwedenLaboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, SwedenCenter for Brain Research, Vienna, AustriaDepartment of Neuroscience, Karolinska Institutet, Stockholm, SwedenDepartment of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Correspondence to: M. Jagodic, Center for Molecular Medicine, L8:04 Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Fax: +46 8 517 755 62.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.http://www.sciencedirect.com/science/article/pii/S0969996114002502Multiple sclerosisExperimental autoimmune encephalomyelitisEpigeneticsHistone deacetylasesThyroid hormoneNeuroinflammation |
| spellingShingle | Gonçalo Castelo-Branco Pernilla Stridh André Ortlieb Guerreiro-Cacais Milena Z. Adzemovic Ana Mendanha Falcão Monica Marta Rasmus Berglund Alan Gillett Kedir Hussen Hamza Hans Lassmann Ola Hermanson Maja Jagodic 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 Multiple sclerosis Experimental autoimmune encephalomyelitis Epigenetics Histone deacetylases Thyroid hormone Neuroinflammation |
| title | Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats |
| title_full | Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats |
| title_fullStr | Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats |
| title_full_unstemmed | Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats |
| title_short | Acute treatment with valproic acid and l-thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in DA rats |
| title_sort | acute treatment with valproic acid and l thyroxine ameliorates clinical signs of experimental autoimmune encephalomyelitis and prevents brain pathology in da rats |
| topic | Multiple sclerosis Experimental autoimmune encephalomyelitis Epigenetics Histone deacetylases Thyroid hormone Neuroinflammation |
| url | http://www.sciencedirect.com/science/article/pii/S0969996114002502 |
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