title: Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis.
abstract: We demonstrate that the histone deacetylase (HDAC) inhibitor drug trichostatin A (TSA) reduces spinal cord inflammation, demyelination, neuronal and axonal loss and ameliorates disability in the relapsing phase of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). TSA up-regulates antioxidant, anti-excitotoxicity and pro-neuronal growth and differentiation mRNAs. TSA also inhibits caspase activation and down-regulates gene targets of the pro-apoptotic E2F transcription factor pathway. In splenocytes, TSA reduces chemotactic, pro-Th1 and pro-proliferative mRNAs. A transcriptional imbalance in MS may contribute to immune dysregulation and neurodegeneration, and we identify HDAC inhibition as a transcriptional intervention to ameliorate this imbalance.
authors.affiliation: Laboratory of Transcriptional and Immune Regulation, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA 02139, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Camelo
authors.forename: Antonio H
authors.initials: AH
authors.lastname: Iglesias
authors.forename: Daehee
authors.initials: D
authors.lastname: Hwang
authors.forename: Brice
authors.initials: B
authors.lastname: Due
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.forename: Karen
authors.initials: K
authors.lastname: Smith
authors.forename: Steven G
authors.initials: SG
authors.lastname: Gray
authors.forename: Jaime
authors.initials: J
authors.lastname: Imitola
authors.forename: German
authors.initials: G
authors.lastname: Duran
authors.forename: Basel
authors.initials: B
authors.lastname: Assaf
authors.forename: Brett
authors.initials: B
authors.lastname: Langley
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.forename: George
authors.initials: G
authors.lastname: Stephanopoulos
authors.forename: Umberto
authors.initials: U
authors.lastname: De Girolami
authors.forename: Rajiv R
authors.initials: RR
authors.lastname: Ratan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: Fernando
authors.initials: F
authors.lastname: Dangond
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D006023:Glycoproteins; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D063308:Myelin-Oligodendrocyte Glycoprotein; D009474:Neurons / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012720:Severity of Illness Index; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors
chemical_list: D016207:Cytokines; D006023:Glycoproteins; D006877:Hydroxamic Acids; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; C445081:myelin oligodendrocyte glycoprotein (35-55); C012589:trichostatin A; C022616:thiazolyl blue