Project Summary / Abstract This application builds on our laboratory's pioneering work delineating critical neurochemical mechanisms of excitotoxicity and neuroinflammation in a translational model of brain injury from hypothermic circulatory arrest (HCA) that is directly relevant to the techniques currently used in patients undergoing complex heart and aortic surgery. We propose to test these mechanisms, specifically N-methyl-D-aspartate (NMDA) antagonism with ketamine and mitochondrial adenosine triphosphate potassium (KATP) activation with diazoxide, using targeted delivery with dendrimer conjugation in our translational HCA model with the addition of antegrade cerebral perfusion. Prolongation of the safe HCA time during complex aortic surgery with such agents will dramatically reduce neurological injury and improve outcomes in these patients. By identifying the underlying mechanisms of injury and testing them in a pre-clinical large animal model, the work proposed in this application will advance the field because there are no currently available pharmacologic agents that have been proven in randomized trials to provide significant improvement to the current use of hypothermia. We propose the following aims: 1) To determine if the NMDA receptor antagonist ketamine is a neuroprotectant during hypothermic circulatory arrest in a canine model, 2) To determine the mechanisms of mitochondrial injury during hypothermic circulatory arrest and the effectiveness of mitochondrial KATP channel openers as neuroprotective agents in a canine model, and 3) To evaluate targeted neuroprotective strategies in a hypothermic circulatory arrest model with antegrade cerebral perfusion (ACP) Our multidisciplinary team includes a practicing cardiac surgeon who experiences the current challenges when performing complex aortic surgery, a practicing neurologist specializing in brain injury and mitochondrial stress, a practicing neurosurgeon who specializes in brain injury, a neuroscientist with expertise in brain injury and mechanisms of neurorepair and microglial activation, the co-director of the Center for Nanomedicine with expertise in dendrimer-drug nanodevices for targeted therapy to attenuate neuroinflammation, and a neuropathologist that specializes in neural cell death and mitochondrial pathobiology. Together we possess the unique ability to translate our findings to clinical practice. The proposed experiments provide a comprehensive approach to understanding the mechanisms of neurological injury due to hypothermic circulatory arrest. The knowledge gained could potentially provide benefit for any patient with cardiovascular disease who requires cardiac surgery, which remains the #1 killer of men and women in the United States.