Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis.
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.
Camelo
Sandra
S
Laboratory of Transcriptional and Immune Regulation, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA 02139, USA.
Iglesias
Antonio H
AH
Hwang
Daehee
D
Due
Brice
B
Ryu
Hoon
H
Smith
Karen
K
Gray
Steven G
SG
Imitola
Jaime
J
Duran
German
G
Assaf
Basel
B
Langley
Brett
B
Khoury
Samia J
SJ
Stephanopoulos
George
G
De Girolami
Umberto
U
Ratan
Rajiv R
RR
Ferrante
Robert J
RJ
Dangond
Fernando
F
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
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