Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis

Sandra Camelo; Antonio H Iglesias; Daehee Hwang; Brice Due; Hoon Ryu; Karen Smith; Steven G Gray; Jaime Imitola; German Duran; Basel Assaf; Brett Langley; Samia J Khoury; George Stephanopoulos; Umberto De Girolami; Rajiv R Ratan; Robert J Ferrante; Fernando Dangond

doi:10.1016/j.jneuroim.2005.02.022

Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis

J Neuroimmunol. 2005 Jul;164(1-2):10-21. doi: 10.1016/j.jneuroim.2005.02.022.

Authors

Sandra Camelo¹, Antonio H Iglesias, Daehee Hwang, Brice Due, Hoon Ryu, Karen Smith, Steven G Gray, Jaime Imitola, German Duran, Basel Assaf, Brett Langley, Samia J Khoury, George Stephanopoulos, Umberto De Girolami, Rajiv R Ratan, Robert J Ferrante, Fernando Dangond

Affiliation

¹ Laboratory of Transcriptional and Immune Regulation, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA 02139, USA.

PMID: 15885809
DOI: 10.1016/j.jneuroim.2005.02.022

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.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Cell Death / drug effects
Cells, Cultured
Cerebral Cortex / cytology
Cytokines / genetics
Cytokines / metabolism
Disease Models, Animal
Drug Administration Schedule
Drug Interactions
Embryo, Mammalian
Encephalomyelitis, Autoimmune, Experimental / chemically induced
Encephalomyelitis, Autoimmune, Experimental / drug therapy*
Encephalomyelitis, Autoimmune, Experimental / genetics
Encephalomyelitis, Autoimmune, Experimental / pathology
Female
Gene Expression Profiling / methods
Gene Expression Regulation / drug effects*
Glycoproteins
Hydroxamic Acids / therapeutic use*
Immunohistochemistry / methods
Mice
Mice, Inbred C57BL
Myelin-Oligodendrocyte Glycoprotein
Neurons / drug effects
Oligonucleotide Array Sequence Analysis / methods
Peptide Fragments
Protein Synthesis Inhibitors / therapeutic use*
RNA, Messenger / metabolism
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction / methods
Severity of Illness Index
Spleen / drug effects
Spleen / metabolism
Tetrazolium Salts
Thiazoles
Time Factors

Substances

Cytokines
Glycoproteins
Hydroxamic Acids
Myelin-Oligodendrocyte Glycoprotein
Peptide Fragments
Protein Synthesis Inhibitors
RNA, Messenger
Tetrazolium Salts
Thiazoles
myelin oligodendrocyte glycoprotein (35-55)
trichostatin A
thiazolyl blue

Abstract

Publication types

MeSH terms

Substances

Grants and funding