Brain Injury During CPR Prevented by Vascular Nitroxide

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DESCRIPTION (provided by applicant): The brain damage that frequently accompanies cardiac arrest and resuscitation is devastating. Fewer than 10% of cardiopulmonary resuscitation (CPR) attempts result in survival without brain damage when treatment occurs in pre-hospital or a non-special care hospital environment (Safar, 1993). We propose that a novel vascular-compartmentalized nitroxide, polynitroxyl albumin (PNA), which is an enzyme-mimic antioxidant, can reduce brain damage after CPR. We present preliminary results in a CPR model showing PNA attenuates CA1 hippocampal cell loss 7 days after cardiac compression and resuscitation in rats. Published results also support this premise. In a middle cerebral artery occlusion model of stroke, mice treated with PNA were significantly protected against neural damage. We propose to further establish the cerebral protective activity of PNA in a cardiac compression model of CPR. Our specific aims are: 1) to address quality assurance issues in PNA production and in vitro documentation of efficacy, and 2) to compare the impact of PNA, human serum albumin (HSA) and saline treatment on the structure and function of the hippocampus. The end-points for the second aim will include measures of pyramidal cell viability, NMDA receptor 1 immunoreactivity, and in vitro electrophysiology of hippocampal slices. This combined morphological and electrophysiological approach in a whole body ischemia model should further document the value of PNA as a potent neuroprotectant. Attainment of these goals will fulfill the feasibility requirement for further study of PNA in a Phase II SBIR grant, which will emphasize dose response, extended time course, neurological recovery and the therapeutic index of PNA.