Ammonia metabolism in the brain
Oxygen deprivation is associated with disruption of glycolysis, the Krebs cycle, mitochondrial energy production, and nitrogen metabolism. Post-reperfusion oxidative stress leads to the death of cerebral cells. These are the major factors contributing to brain tissue damage in Ischemia/Reperfusion. However, neither the origin of oxidative stress nor the exact mechanisms of energy failure after reperfusion are known. We study how brain oxygen deprivation leads to the degradation of amino acids and purine nucleotides resulting in the accumulation of ammonia (NH4+). Ammonia can activate reactive oxygen species (ROS) production by the mitochondrial enzyme α-ketoglutarate dehydrogenase during reperfusion, causing oxidative injury. We are pursuing a 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. Moreover, 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 preclinical impact of this project is to provide a rationale for therapeutic interventions aimed at the reduction of brain Ischemia/Reperfusion injury.