(101NP1003) New Drug Development of MPT0E014 for Ischemic Stroke and Dementia (I)

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 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 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 ischemic stroke and dementia therapy. To delineate the nature and mechanism of MPT0E014 in ischemic stroke and dementia, we will evaluate effects of intravenous MPT0E014 injection on rats after ischemic stroke or dementia in vivo. Furthermore, we will evaluate the effects MPT0E014 on primary culture rat cortical neurons upon excitotoxic insult in vitro. The specific aims will answer the following questions: 1 Determine the dosage and golden treatment windows of MPT0E014 in motor function recovery after ischemic stroke/ demetia. 2 Determine neuron survival and apoptosis in ischemic stroke/ dementia after different dosages and treatment time of MPT0E014. 3 Determine glial scar formation and microglia activation in ischemic stroke / dementia after different dosages and treatment time of MPT0E014. 4 Determine the neuroprotective mechanism of MPT0E014 such as p21, p53, cleavage of caspase-3, Bcl-2, brain-derived neurotrophic factor (BDNF), CREB, ERK and apoptosis in ischemic stroke/ dementia (in vitro and in vivo). Aim 4.1: The potency of MPT0E014 in protecting glutamate neurotoxicity. Aim 4.2: Effect of MPT0E014 on the tau hyperphosphorylation induced by excitotoxic insult. Aim 4.3: Does MPT0E014 regulates p21, p53, phospho-AKT, caspase-3 cleavage, Bax, Bcl-2 and BDNF activity via inhibition of HDAC? 5 Besides standard tPA treatment within 3 hours after ischemic stroke, determine the additional effect of MPT0E014 in animal model. The overall objective of this study is to determine the preclinical effects of a novel HDAC inhibitor (MPT0E014) in treating ischemic stroke and dementia.