机构:[1]China-America Institute of Neuroscience, Luhe Hospital中美神经科学研究所首都医科大学宣武医院[2]Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing, China神经外科首都医科大学宣武医院[3]Departments of Neurological Surgery,Wayne State University School of Medicine, Detroit, MI[4]Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI[5]Beijing Institute for Brain Disorders, Beijing, China
Background and Purpose-Ischemic 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. Methods-Sprague-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. Results-EtOH 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. Conclusions-Both 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.
基金:
Wayne State University Neurosurgery Fund, American Heart Association Grant-in-Aid (14GRNT20460246),
National Basic Research Program of China(973 Program, No. 2011CB707804),
National Outstanding Youth Science Fund of China (No. 81325007).
第一作者机构:[1]China-America Institute of Neuroscience, Luhe Hospital[3]Departments of Neurological Surgery,Wayne State University School of Medicine, Detroit, MI
共同第一作者:
通讯作者:
通讯机构:[*1]Department of Neurological Surgery, Wayne State University School of Medicine, 550 E Canfield, Detroit, MI 48201,[*2]Cerebral Vascular Diseases Research Institute (China-America Institute of Neuroscience), Department of Neurosurgery, Xuanwu Hospital, Capital Medical University, Beijing 100053, China
推荐引用方式(GB/T 7714):
Xiaokun Geng,Omar Elmadhoun,Changya Peng,et al.Ethanol and Normobaric Oxygen Novel Approach in Modulating Pyruvate Dehydrogenase Complex After Severe Transient and Permanent Ischemic Stroke[J].STROKE.2015,46(2):492-499.doi:10.1161/STROKEAHA.114.006994.
APA:
Xiaokun Geng,Omar Elmadhoun,Changya Peng,Xunming Ji,Adam Hafeez...&Yuchuan Ding.(2015).Ethanol and Normobaric Oxygen Novel Approach in Modulating Pyruvate Dehydrogenase Complex After Severe Transient and Permanent Ischemic Stroke.STROKE,46,(2)
MLA:
Xiaokun Geng,et al."Ethanol and Normobaric Oxygen Novel Approach in Modulating Pyruvate Dehydrogenase Complex After Severe Transient and Permanent Ischemic Stroke".STROKE 46..2(2015):492-499