New approach to sustained neuroprotection and enhanced recovery following acute ischemic stroke - Ischemic stroke is a devastating health problem, affecting approximately 795,000 patients in the US every year, making it one of the leading causes of death and disability in the country. Recent clinical advances have shown great promise in acute stroke therapy, with the use of mechanical endovascular thrombectomy (EVT), with or without standard of care thrombolysis, significantly improving outcomes. Despite these promising advances, long-term neurologic sequelae persist in the post-stroke patient population. Therefore, the use of neuroprotective agents in combination with current methods of reperfusion provides renewed hope for the improvement of stroke outcomes. Indeed, >1000 drugs have been shown to reduce stroke injury in experimental stroke models, but have failed to translate to clinical benefit. The Stroke Therapy Academic Industry Roundtable (STAIR) convened in 1999 and provided important guidelines to improve the rigor of pre-clinical models to improve translational success. More recently, STAIR IX-X provided updates in light of endovascular therapy, advising increased research into adjunct therapies to be combined with EVT reperfusion. The current study is a pre-clinical study that follows the STAIR criteria to characterize a novel neuroprotectant to be utilized in combination with EVT following large vessel occlusion (LVO). The STAIR group identified multiple factors contributing failure to translate, chief among them being over- reliance on acute histological measurements of outcome and poor correspondence between experimental and clinical study designs. To address long-term functional outcomes in our rodent model, we have moved beyond measurements of motor deficits and add cognitive recovery to our outcome measures to assess therapies that may provide real-world improvements in ‘quality of life’ outcomes. Experimental evidence from our group, and others, show that tMCAo induces synaptic derangements in various brain regions, including the hippocampus. This, coupled with the increasing evidence of cognitive impairments and memory loss following AIS (post-stroke cognitive impairment: PSCI), makes synaptic dysfunction (synaptoprotection) a novel new target for neuroprotective strategies. We have developed a drug that 1) provides acute neuroprotection and 2) causes sustained synaptoprotection that enhances long-term cognitive recovery. We focus the current proposal on the interaction between acute injury, delayed neuronal cell death, conversion to chronic dysfunction and therapeutic approaches aimed at synaptoprotection to provide sustained functional benefit. The overarching premise of this proposal is that ischemic stroke causes acute injury within the MCA territory (cortical/subcortical), delayed diffuse neuronal injury and syanptotoxicity which contributes to the conversion to chronic cognitive decline. We will assess dosing regimen of our novel agent, tat-M2NX, that provides optimal long-term functional recovery following tMCAo and assess the mechanism(s) of tMCAo-induced activation of TRPM2 channels.
