• Xiaokun Geng, Omar Elmadhoun, Changya Peng, Xunming Ji, Adam Hafeez, Zongjian Liu, Huishan Du, Jose A Rafols, and Yuchuan Ding.
• From the China-America Institute of Neuroscience, Luhe Hospital (X.G., X.J., Z.L., H.D., Y.D.) and Department of Neurosurgery, Xuanwu Hospital (X.J.), Capital Medical University, Beijing, China; Departments of Neurological Surgery (X.G., O.E., C.P., A.H., Y.D.) and Anatomy and Cell Biology (J.A.R.), Wayne State University School of Medicine, Detroit, MI; and Beijing Institute for Brain Disorders, Beijing, China (X.J.).
• Stroke. 2015 Feb 1; 46 (2): 492-9.

Background And PurposeIschemic stroke induces metabolic disarray. A central regulatory site, pyruvate dehydrogeanse complex (PDHC) sits at the cross-roads of 2 fundamental metabolic pathways: aerobic and anaerobic. In this study, we combined ethanol (EtOH) and normobaric oxygen (NBO) to develop a novel treatment to modulate PDHC and its regulatory proteins, namely pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase, leading to improved metabolism and reduced oxidative damage.MethodsSprague-Dawley rats were subjected to transient (2, 3, or 4 hours) middle cerebral artery occlusion followed by 3- or 24-hour reperfusion, or permanent (28 hours) middle cerebral artery occlusion without reperfusion. At 2 hours after the onset of ischemia, rats received either an intraperitoneal injection of saline, 1 dose of EtOH (1.5 g/kg) for 2- and 3-hour middle cerebral artery occlusion, 2 doses of EtOH (1.5 g/kg followed by 1.0 g/kg in 2 hours) in 4 hours or permanent middle cerebral artery occlusion, and EtOH+95% NBO (at 2 hours after the onset of ischemia for 6 hours) in permanent stroke. Infarct volumes and neurological deficits were examined. Oxidative metabolism and stress were determined by measuring ADP/ATP ratio and reactive oxygen species levels. Protein levels of PDHC, pyruvate dehydrogenase kinase, and pyruvate dehydrogenase phosphatase were assessed.ResultsEtOH induced dose-dependent neuroprotection in transient ischemia. Compared to EtOH or NBO alone, NBO+EtOH produced the best outcomes in permanent ischemia. These therapies improved brain oxidative metabolism by decreasing ADP/ATP ratios and reactive oxygen species levels, in association with significantly raised levels of PDHC and pyruvate dehydrogenase phosphatase, as well as decreased pyruvate dehydrogenase kinase.ConclusionsBoth EtOH and EtOH+NBO treatments conferred neuroprotection in severe stroke by affecting brain metabolism. The treatment may modulate the damaging cascade of metabolic events by bringing the PDHC activity back to normal metabolic levels.© 2015 American Heart Association, Inc.

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