Cerebral ischemia as a result of strokes or cardiac arrest remains one of the leading causes of death and disability in the U.S.A. It is now well accepted that mitochondria are key players in cerebral ischemic/reperfusion injury hours to days following the ischemic insult. The main goals were the elucidation of signaling pathways involved in the fate of brain mitochondria following cerebral ischemia. Studies from us and other groups, have demonstrated Protein Kinase C isozyme (PKC?) translocates to mitochondria to activate pathways of neuroprotection. We have identified that PKC? acts as a signaling metabolic master regulator that alters NAD levels, mitochondrial sirtuins and cell metabolism and promotes neuroprotection against cerebral ischemia. Previous studies demonstrated the importance of NAD replenishment in neuroprotection against cerebral ischemia. Thus, we propose experiments to elucidate the mechanisms by which PKC? alters NAD levels in the brain and define its downstream pathways that enhance ischemic tolerance. These goals will be achieved in the following specific aims: 1) To determine if PKC? via Sirt1 promotes increases of the NAD+ biosynthetic pathway and define the role of this pathway in ischemic neuroprotection. Model: Mouse; Paradigm: Oxygen-Glucose Deprivation (OGD); 2) To determine if the PKC?/Sirt1 pathway promotes a `caloric restriction' (CR)-like bioenergetic phenotype in the brain. Model: Mouse; Paradigm: Oxygen-Glucose Deprivation (OGD), Middle Cerebral Artery Occlusion (MCAo); and 3) To determine whether post-treatment with a PKC? activator can rescue the NAD+ salvage pathway and its downstream pathways following MCAo in aged rats. Model: Rat; Paradigm: MCAo.
Cerebral ischemia in the form of stroke or cardiopulmonary arrest remains one of the leading causes of death and disability in the USA. A major pathological consequence of cerebral ischemia is reperfusion injury and oxidative damage. This proposal examines the molecular mechanisms by which brain bioenergetics is impaired following cerebral ischemia. The goal is to find novel therapeutic agents that may benefit patients that undergo strokes or acute myocardial infarction.
