Enhanced Mitochondrial Function to Increase Effectiveness of Post-stroke Rehabilitation

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ABSTRACT The long-term goal of this project is to identify new therapeutics that are effective after a stroke has occurred to stimulate recovery of cognitive and motor function. Stroke-induced dysfunction is the result of neuronal injury and death, and mitochondrial dysfunction is implicated in these processes. Currently, drug therapy to treat stroke is limited to TPA, which must be administered within 6h of a stroke. This window is too short and TPA has significant side effects. In addition, therapies are needed that not only treat the initial phase of stroke- induced celluar dysfunction but also will enhance the chronic phase recovery of function and produce enduring benefits. Our preliminary studies revealed that mitochondrial dysfunction occurred in ispilesion cortex and striatum following focal sensorimotor cortex (SMC) ischemic lesion in adult rats, and persisted over the first week. Consequently, we propose that therapeutics that increases mitochondrial biogenesis (MB) will promote recovery from stroke in both adult and aged rats. As part of our drug discovery program to identify chemicals that induce MB, formoterol, a specific long-acting β2-adrenergic receptor (β2AR) agonist, was identified. Formoterol is an FDA-approved drug to treat asthma. Preliminary studies demonstrated that formoterol- induced MB in naïve rats. Additional our preliminary studies revealed that formoterol administered 24h after stroke improved forelimb motor recovery after six days. Finally, preliminary studies demonstrated that daily formoterol administration, beginning 24h after experimental stroke and continuing daily during forelimb rehabilitative treatment (RT) for 15 days, improved forelimb motor recovery compared to vehicle administration with or without RT. More specifically, we hypothesize that stimulating MB with formoterol after stroke will 1) improve mitochondrial function early after stroke, thus decreasing motor impairments and 2) during RT will improve the efficacy of RT by supporting experience-dependent neuronal remodeling and repair in adult and aged rats. We hypothesize that the combination of formoterol and RT will be most beneficial in aged stroke animals. Specific Aim 1: Elucidate the optimal formoterol dose to induce MB, restore MF, and improve behavioral outcomes after experimental stroke in adult and aged rats. Specific Aim 2: Determine the efficacy of formoterol and forelimb rehabilitative training (RT) following experimental stroke to enhance MF, MB, structural plasticity and behavioral outcomes in adult rats. Specific Aim 3. Determine the efficacy of formoterol and forelimb rehabilitative training (RT) following experimental stroke to enhance MF, MB, structural plasticity and behavioral outcomes in aged rats Successful completion of these studies will provide strong evidence for the dose, timing and persistence of formoterol-induced recovery from stroke and a possible mechanism underlying these findings, providing new targets for rehabilitative training adjunctive treatments. Since formoterol is already an FDA approved drug, successful completion of these studies rapidly lead to translational clinical trials for young and older human stroke survivor.