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). T...

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Veröffentlicht in:	Journal of neuroimmunology 2005-07, Vol.164 (1), p.10-21
Hauptverfasser:	Camelo, Sandra, Iglesias, Antonio H., Hwang, Daehee, Due, Brice, Ryu, Hoon, Smith, Karen, Gray, Steven G., Imitola, Jaime, Duran, German, Assaf, Basel, Langley, Brett, Khoury, Samia J., Stephanopoulos, George, De Girolami, Umberto, Ratan, Rajiv R., Ferrante, Robert J., Dangond, Fernando
Format:	Artikel
Sprache:	eng
Schlagworte:	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 Experimental autoimmune encephalomyelitis Female Gene Expression Profiling - methods Gene Expression Regulation - drug effects Glycoproteins Histone deacetylase Hydroxamic Acids - therapeutic use Immunohistochemistry - methods Mice Mice, Inbred C57BL Microarrays Multiple sclerosis Myelin-Oligodendrocyte Glycoprotein Neurons - drug effects Oligonucleotide Array Sequence Analysis - methods Peptide Fragments Protein Synthesis Inhibitors - therapeutic use Rats Rats, Sprague-Dawley Reverse Transcriptase Polymerase Chain Reaction - methods RNA, Messenger - metabolism Severity of Illness Index Spleen - drug effects Spleen - metabolism Tetrazolium Salts Thiazoles Time Factors Trichostatin A
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Zusammenfassung:	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.
ISSN:	0165-5728 1872-8421
DOI:	10.1016/j.jneuroim.2005.02.022