Abstract T P213: Post-stroke Administration of Ethanol and Normobaric Oxygen Preserves Oxidative Metabolism by Modulating Pyruvate Dehydrogenase Complex in Transient and Permanent Ischemic Stroke

Abstract

Background: Ischemic stroke induces metabolic disarray where the entire framework of cellular metabolism is altered. A central regulatory site, Pyruvate Dehydrogenase Complex (PDHC) sits at the cross-roads of two fundamental metabolic systems: the citric acid cycle and glycolysis. Down regulation of PDHC has been proposed to explain impaired brain catabolism after ischemic injury. In this study, we combined ethanol and normobaric oxygen (NBO) to develop a powerful non-drug treatment to modulate PDHC and its regulatory proteins, namely PDPhosphatase and PDKinase, leading to improved metabolism and reduced oxidative damage. Methods: Sprague-Dawley rats were subjected to transient (4h) or permanent (24h) middle cerebral artery occlusion followed by 24 hours reperfusion or no reperfusion. Rats received IP injections of saline, two doses of Ethanol (EtOH, 1.5 at onset of reperfusion followed by 1.0 g/kg in 2 hours) for transient stroke or EtOH+95%NBO (for 6 hours) for permanent stroke. Infract volume and the protein levels of PDHC, PDK, and PDP were all assessed. Oxidative metabolism was determined by ADP/ATP ratios and ROS levels. Results: Our therapy enhanced the oxidative metabolism profile of the cell by decreasing ADP/ATP ratios and ROS levels. In transient ischemia, administration of EtOH significantly raised the levels of PDHC and PDP in the ischemic brain issue and simultaneously decreased PDK levels. NBO combined with EtOH synergistically had better outcomes in the permanent ischemic stroke group, as compared to EtOH or NBO alone. Conclusion: EtOH and NBO treatment confirms neuroprotection in stroke by affecting brain catabolism. It modulates the damaging cascade of events by bringing the concentration of active PDHC activity back to metabolic levels.