Neuroprotection with serpins during cardiac surgery

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DESCRIPTION (provided by applicant): Brain injury occurs during and after cardiac surgery in both adults and children. It can take the form of either a focal or global neurological insult such as stroke or choreoathetosis. Alternatively it can manifest itself as a generalized decline in cognitive and motor skills. Aprotinin, a "SERPIN" (serine protease inhibitor), reduces bleeding after cardiopulmonary bypass (CPB). An extensive metaanalysis of the cardiac surgery literature concluded that aprotinin also decreases the incidence of stroke after CPB though a recent influential report suggests an increased risk of brain injury. Direct neuronal and neurovascular mechanisms of action of aprotinin during CPB remain largely unexplored though previous work has demonstrated protection of endothelial function by aprotinin. Furthermore recent reports in the neuroscience literature applying cell culture models suggest that some serpins may be neuroprotective through inhibition of excitotoxicity. The proposed study will test the hypothesis that aprotinin is neuroprotective in the setting of CPB. A juvenile piglet model will be employed with exposure to various degrees of flow reduction to a degree known to cause brain injury. Survival for 4 days postoperatively allows assessment of functional evidence of brain injury through behavioral assessment by a blinded observer as well as meaningful histology determined by a blinded neuropathologist. Vascular integrity will be studied with intravital microscopy which allows direct observation of the cerebral microcirculation. Adequacy of cerebral oxygen delivery will be monitored by near infrared spectroscopy. Several dosage levels of aprotinin will be employed to determine optimal dose. The second component of the study will test the hypothesis that one mechanism by which aprotinin is neuroprotective is through inhibition of excitotoxicity. Neuronal cell culture models will be employed. Aprotinin at various dosages will be compared with other serpins which have previously been demonstrated to be neuroprotective. Novel serpins which may have an application in cardiac surgery will also be studied with the cell culture model. Serpins which are found to be protective will be studied in detail in the whole animal model of CPB in the third phase of the study. The final phase will study mechanisms of vascular protection afforded by aprotinin. The proposed study has the potential to reduce the risk of brain injury in children and adults undergoing heart surgery.