Neuroprotection of pH Sensitive NMDAR Antagonists in Cardiopulmonary Bypass Surge

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DESCRIPTION (provided by applicant): Heart operations involving the use of cardiopulmonary bypass (CPB) are among the most common surgical procedures in the world, with over 500,000 performed in the U.S. alone in 2000. Such procedures carry a significant risk of cerebral injury including death, stroke, transient ischemic events and cognitive dysfunction. The etiology of these adverse outcomes is likely multifactorial and not fully understood. However, it is widely accepted that cerebral hypoperfusion and ischemic damage inflicted by emboli to the cerebral circulation are significant contributing factors. Emboli comprising platelet aggregates, lipid droplets, particulate debris from atherosclerotic plaques and air bubbles may be introduced into the cerebral microvasculature during heart surgery. Air bubbles may be entrained during open chamber procedures or generated in large numbers within the CPB circuit. Although over a dozen agents have been evaluated, no drug is approved for the prevention or treatment of neurological or neurocognitive deficit after heart surgery using CPB. A published trial involving 171 cardiac surgery patients of remacemide, a low potency NMDAR antagonist, yielded encouraging results. These findings, together with the robust neuroprotective effects of diverse NMDAR antagonists in various animal models of cerebral ischemia, provide a strong rationale to investigate the potential for NMDAR antagonism to mitigate cerebral injury in heart surgery involving CPB. Our academic collaborators for this project, (Mackensen lab, Duke Medical Center) have an established, validated, clinically relevant, rat model of cerebral injury after CPB combined with cerebral air emboli (CAE). Rats exposed to CPB-CAE suffer infarcts and demonstrate diminished neurological and neurocognitive function. We are developing novel NMDAR antagonists having pH dependent potency. These compounds have little or no effect on receptor function at normal pH in healthy tissue, but effectively inhibit NMDAR in the context of focal ischemia and acidification. NMDAR blockers having efficacy that is temporally and spatially restricted to ischemic conditions, offer protection that is comparable or superior to that shown by prior NMDAR antagonists, but without unwanted effects of NMDAR blockade in healthy tissue. Since NMDAR blockade provides maximal protection when initiated prior to, or very soon after an ischemic event, NeurOp drugs are particularly well suited for the prevention of cerebral injury after cardiac surgery, where it is feasible to administer drug prior to the CPB surgery. The goal and sole AIM of this phase 1 project is to determine whether NeurOp's pH sensitive NMDAR antagonists exert neuroprotective effects in a rat model of cerebral injury induced by CAE superimposed upon CPB. Coronary artery bypass surgery (CABG) with cardiopulmonary bypass (CPB) is one of the most common surgical procedures in the world, with over 500,000 performed in the U.S. alone in 2000 (National Center for Health Statistics, 2000). Patients undergoing revascularization procedures are prone to a spectrum of neurological complications ranging from stroke (0.4-7.2% incidence) to cognitive dysfunction (25-79% incidence) resulting in prolonged hospitalization, increased morbidity and mortality as well as increased overall health care costs. Elderly patients in particular are at substantial risk for cognitive dysfunction, primarily affecting attention, concentration, memory, and speed of cognitive processing after cardiac surgery involving CPB. In this project promising new drugs that may one day protect brain tissue from damage caused during cardiac procedures involving CPB.