The dynamics of chromatin provides the major regulatory factor underlying gene expression and the major epigenetic modifications of chromatin involve the reversible acetylation and methylation of core histones on key lysine residues and DNA methylation at CpG islands. Both these modifications have been implicated in a range of traumatic brain injury (TBI), ischemic stroke, and other neurodegenerative diseases. The reversible acetylation of histone lysine residues by histone acetyltransferases (HAT) is hence a key regulator of gene expression with acetylation leading to an open chromatin structure facilitating RNA polymerase binding and transcription. HDACs have multiple functions, in particular they are major components of repressive complexes and act to compact the chromatin and repress transcription. This has promoted an intensive search for inhibitors of HDACs as drugs to modulate gene transcription through their effects on the chromatin modifications. Thus, in this proposal, we intend to use our novel patented “indole” compound to conjugated with hydroxamic acid in histone deacetylases inhibitor, VA and further modify its structure to generate novel small-molecule neuroprotective compounds. By screening cortical neuron cultures, we will look for compounds that have shown potential for future drug development. In our preliminary studies, we have identified novel compound, MPT0E014 having marked neuroprotective activity. We will test the lead compounds using in vivo rat TBI and ischemic stroke model for its preclinical evaluation of efficacy and safety. Using this approach, we hope to develop novel compounds with HDAC inhibition that are able to be used in future TBI and ischemic stroke therapy. To delineate the nature and mechanism of MPT0E014 in TBI and ischemic stroke, we will evaluate effects of intravenous MPT0E014 injection on rats after TBI and ischemic stroke in vivo. Furthermore, we will evaluate the effects MPT0E014 on primary culture rat cortical neurons upon excitotoxic insult in vitro. The specific aims were to answer the following questions: (1) Do alterations of motor function occur in TBI or ischemic stroke after MPT0E014 treatment? (2) How about the changes of neuron survival in TBI or ischemic stroke after MPT0E014 treatment? (3) Does MPT0E014 inhibit glial scar and microglia activation after TBI or ischemic stroke? (4) Do p21, p53, cleavage of caspase-3, Bcl-2, brain-derived neurotrophic factor (BDNF), CREB, ERK and apoptosis change in MPT0E014 treated group compared with vehecle controls? The overall objective of this study is to determine the neuroprotective, neurotrophic and anti-inflammatory effects MPT0E014 in TBI and ischemic stroke
|Effective start/end date||12/1/10 → 7/31/11|
- histone deacetylase inhibitor
- traumatic brain injury
- ischemic stroke
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