Metabolic Origin of Oxidative Stress Injury in Brain Ischemia/Reperfusion

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Summary: The annual worldwide mortality from perinatal hypoxic-ischemic (HI) insult is ~1.2 million. In the US, perinatal HI-brain injury remains one of the major causes of cerebral palsy and life- long neurological disability. The lifetime cost for patients with cerebral palsy is estimated to be $11.5 billion per affected individual. This dictates a need for therapeutic strategies based on a better understanding of the mechanisms of HI injury. HI-reperfusion-associated disruption in glycolysis, the Krebs cycle, mitochondrial energy production, nitrogen metabolism, and oxidative stress negatively affect the survival of cerebral brain cells. These are the major factors contributing to brain tissue damage in HI. However, neither the exact mechanisms of the so-called secondary energy failure nor the origin of oxidative stress in ischemia/reperfusion are known. We propose that brain oxygen deprivation leads to degradation of amino acids and purine nucleotides resulting in the accumulation of ammonia (NH4+). This, in turn, activates reactive oxygen species (ROS) production by the mitochondrial enzyme -ketoglutarate dehydrogenase during reperfusion causing oxidative injury. Our preliminary data identify the presence of this metabolic cascade in the HI brain prompting further study. In the proposed study, we will pursue the novel hypothesis that increased ROS generation and mitochondrial bioenergetics failure correlated with ischemic NH4+ accumulation. This is consistent with all experimental data observed in HI and stroke models. This is a new, insofar unrecognized, and unexplored mechanism of injury, which explains the published experimental data showing the transient burst of ROS during brain ischemia/reperfusion. The data obtained in this study will significantly alter the current paradigm of the origin of neuronal ischemia/reperfusion damage. We aim to define the major role of NH4+ in stimulation of mitochondria ROS production during bioenergetics failure in neonatal HI. The preclinical impact of this project is to provide a rationale for further clinical studies aimed at the reduction of post- HI brain injury.