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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.
AuthorsSandra 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
JournalJournal of neuroimmunology (J Neuroimmunol) Vol. 164 Issue 1-2 Pg. 10-21 (Jul 2005) ISSN: 0165-5728 [Print] Netherlands
PMID15885809 (Publication Type: Comparative Study, Journal Article, 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.)
Chemical References
  • 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
Topics
  • Animals
  • Cell Death (drug effects)
  • Cells, Cultured
  • Cerebral Cortex (cytology)
  • Cytokines (genetics, metabolism)
  • Disease Models, Animal
  • Drug Administration Schedule
  • Drug Interactions
  • Embryo, Mammalian
  • Encephalomyelitis, Autoimmune, Experimental (chemically induced, drug therapy, genetics, 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, metabolism)
  • Tetrazolium Salts
  • Thiazoles
  • Time Factors

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