Finding interventions that improve outcome from ischemic stroke has proved to be challenging and current treatment is limited to thrombolysis, aspirin, and management in a stroke unit. An ideal stroke therapeutic would minimize damage to mature neurons and white matter, and also maximize the generation of new neurons from endogenous progenitors. Recent findings of our own and of others, both in vitro and in animal models of stroke, suggest that histone deacetylase (HDAC) inhibitors meet these criteria. Drug administration protects isolated neurons from induced apoptotic cell death and white matter from oxygen-glucose deprivation, results in improved histologic and functional outcomes following cerebral ischemia, and appears to drive 'neuronal'differentiation of multipotent neural progenitor cells. Therefore, we hypothesize that HDAC inhibition in stroke may have acute effects (to ameliorate white matter excitotoxicity), and in the intermediate and longer term, added benefit by reducing apoptosis and encouraging regeneration. As a number of HDAC inhibitors are either already approved by the FDA (vorinostat), or well-advanced in clinical trials (MS-275) for other reasons, then re- purposing one or more of these drugs for stroke could be expedited. In addition, development of new and specific inhibitors is ongoing, especially against the Class I HDACs which are the focus of interest here. Studies described in Aim 1 are designed to identify the specific HDACs which account for the beneficial actions of these inhibitors, using in vitro and ex vivo preparations in which individual HDACs are knocked down with shRNA and transduced cells/tissues then subjected to oxygen-glucose deprivation. Having identified specific HDACs, we shall explore in Aim 2 the potential substrates and mechanisms responsible for the beneficial actions of HDAC inhibition. Finally, in the last aim we consider whether treatment of mice with MS-275, a Class I HDAC inhibitor, preserves anatomic integrity and promotes long term functional (motor, sensory, cognitive) recovery from transient cerebral ischemia (middle cerebral artery occlusion), and whether restoration of function correlates with the extent of 'neuronogenesis'. Two recently developed transgenic lines, p53+/+ and p53 -/- mitoCFP mice, will be employed so that we can monitor ischemic pathology in CFP+ fiber tracts, assess drug-associated changes in mitochondrial frequency and distribution within neuronal cell bodies and their processes, and also determine whether HDAC inhibition ultimately involves targets in addition to neuronal p53.
This proposal is submitted in response to PA-08-099 Mechanisms of functional recovery after stroke, "a funding opportunity to promote research to understand the processes of brain repair that lead to functional recovery in order to develop methods to optimize existing practices and to develop new approaches to improve post-stroke outcomes". Currently, there is no drug available to enhance neuroprotection and restore function following human stroke. Experimental animal studies suggest that broad inhibition of histone deacetylase (HDAC) activities in the brain following injury results in neuronal protection and also promotes the generation of new neurons. The purpose of the studies outlined in this proposal is to identify which HDACs are involved in order to select specific drugs to target these particular enzymes. Selected drugs will be tested to reveal what functional benefits they confer on the recovery of mice from stroke injury.
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