trichostatin-a and myelin-oligodendrocyte-glycoprotein-(35-55)

Multiple sclerosis is a T cell mediated chronic demyelinating disease of the central nervous system. Although currently available therapies reduce relapses, they do not facilitate tolerization of myelin antigen-specific T lymphocytes to ensure prolonged protection against multiple sclerosis. Here, we show that treatment of NOD mice with the histone deacetylase inhibitor, Trichostatin A affords robust protection against myelin peptide induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Protection was accompanied by histone hyperacetylation, and reduced inflammation and axonal damage in the spinal cord. Drug treatment diminished the generation of CD4

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Epigenesis, Genetic; Female; Histones; Hydroxamic Acids; Lymphoid Tissue; Mice, Inbred NOD; Myelin-Oligodendrocyte Glycoprotein; Neuroprotective Agents; Peptide Fragments; Random Allocation; Spinal Cord; T-Lymphocyte Subsets

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.

Topics: Animals; Cell Death; Cells, Cultured; Cerebral Cortex; Cytokines; Disease Models, Animal; Drug Administration Schedule; Drug Interactions; Embryo, Mammalian; Encephalomyelitis, Autoimmune, Experimental; Female; Gene Expression Profiling; Gene Expression Regulation; Glycoproteins; Hydroxamic Acids; Immunohistochemistry; Mice; Mice, Inbred C57BL; Myelin-Oligodendrocyte Glycoprotein; Neurons; Oligonucleotide Array Sequence Analysis; Peptide Fragments; Protein Synthesis Inhibitors; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Severity of Illness Index; Spleen; Tetrazolium Salts; Thiazoles; Time Factors