Approximately 750,000 Americans experience a new or recurrent stroke each year, and 80% of these experience impairment of motor function of the extremities. Partial recovery of motor function occurs even without pharmacological interventions. Clinical studies and animal models suggest that this recovery results from adaptive plasticity and reorganization in intact cortical areas. At the cellular level, reorganizaton following ischemic injury has been found to correlate with dendritic remodeling, increased levels of presynaptic growth- associated proteins and synaptogenesis in peri-infarct regions. Though the precise mechanisms promoting axonal growth and synaptogenesis are unclear, the relationship between these markers of plasticity and recovery provides compelling evidence for investigating plasticity as a target for therapeutic intervention. The therapeutic agent, inosine, stimulates axonal growth and has been shown to enhance functional recovery in rodent models of stroke. Following unilateral stroke, inosine enhances the ability of neurons in the undamaged hemisphere to extend axon collaterals into brainstem and spinal cord areas that have lost normal innervation. This rewiring is accompanied by improved use of an impaired limb. Inosine is a naturally occurring purine nucleoside that crosses the cell membrane and activates Mst3b, a protein kinase that plays a central role in the cell-signaling pathway through which trophic factors stimulate axonal growth. The plasticity enhancing properties of inosine are currently being tested clinically in patients with multiple sclerosis and Parkinson's Disease (Parkinson's Disease Study Group, 2011;Markowitz et al, 2009). The goal of this proposal is to use our rhesus monkey model of cortical ischemic stroke developed with R21 AG-028680 to explore the efficacy of inosine in the recovery of motor function following cortical ischemia in a gyrencephalic animal with brain structure and fine motor dexterity highly similar to humans. !
Brain damage from stroke commonly results in permanent disability.While a great deal of research has focused on limiting damage through neuroprotective strategies, it has provided limited benefits, as treatments must be administered within hours of onset. Consequently, alternative strategies to improve recovery of function in the weeks and months following stroke are needed and this proposal seeks to assess the efficacy of inosine on recovery of function and associated brain plasticity in rhesus monkeys.
|Orczykowski, Mary E; Arndt, Kevin R; Palitz, Lauren E et al. (2018) Cell based therapy enhances activation of ventral premotor cortex to improve recovery following primary motor cortex injury. Exp Neurol 305:13-25|