title: Combination therapy of normobaric oxygen with hypothermia or ethanol modulates pyruvate dehydrogenase complex in thromboembolic cerebral ischemia.
abstract: Pyruvate dehydrogenase complex (PDH) is a brain mitochondrial matrix enzyme. PDH impairment after stroke is particularly devastating given PDH's critical role in the link between anaerobic and aerobic metabolism. This study evaluates the restoration of oxidative metabolism and energy regulation with a therapeutic combination of normobaric oxygen (NBO) plus either therapeutic hypothermia (TH) or ethanol. Sprague-Dawley rats were subjected to middle cerebral artery occlusion with an autologous embolus. One hour after occlusion, tissue-type plasminogen activator (t-PA) was administered alone or with NBO (60%), EtOH (1.0 g/kg), or TH (33°C), either singly or in combination. Neurological deficit score and infarct volume were assessed 24 hr after t-PA-induced reperfusion. PDH activity and reactive oxygen species (ROS) levels were measured 3 and 24 hr after t-PA. Western blotting was used to detect PDH and pyruvate dehydrogenase kinase (PDK) protein expression. After t-PA in ischemic rats, NBO combined with TH or EtOH most effectively decreased infarct volume and neurological deficit. The combined therapies produced greater increases in PDH activity and protein expression as well as greater decreases in PDK expression. Compared with the monotherapeutic approaches, the combined therapies provided the most significant declines in ROS generation. Reperfusion with t-PA followed by 60% NBO improves the efficacy of EtOH or TH in neuroprotection by ameliorating oxidative injury and improving PDH regulation. Comparable neuroprotective effects were found when treating with either EtOH or TH, suggesting a similar mechanism of neuroprotection and the possibility of substituting EtOH for TH in clinical settings. © 2016 Wiley Periodicals, Inc.
authors.affiliation: China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China.|Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan.|Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Cai
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Alexa
authors.initials: A
authors.lastname: Thibodeau
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Changya
authors.initials: C
authors.lastname: Peng
authors.affiliation: China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors.forename: Xunming
authors.initials: X
authors.lastname: Ji
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Radhika
authors.initials: R
authors.lastname: Rastogi
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan.|Department of Radiology, Luhe Hospital, Capital Medical University, Beijing, China.
authors.forename: Ruiqiang
authors.initials: R
authors.lastname: Xin
authors.affiliation: Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Sunpreet
authors.initials: S
authors.lastname: Singh
authors.affiliation: China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China.|Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan.|Department of Neurology, Luhe Hospital, Capital Medical University, Beijing, China.
authors.forename: Xiaokun
authors.initials: X
authors.lastname: Geng
authors.affiliation: Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Rafols
authors.affiliation: China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing, China.|Department of Neurological Surgery, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Ding
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology / Q000628:therapy*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology; D003131:Combined Modality Therapy; D000431:Ethanol / Q000494:pharmacology*; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D000066829:Neuroprotection; D010102:Oxygen Inhalation Therapy / Q000379:methods*; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013923:Thromboembolism / Q000201:enzymology / Q000628:therapy*; D015912:Thrombolytic Therapy
chemical_list: D002492:Central Nervous System Depressants; D011768:Pyruvate Dehydrogenase Complex; D017382:Reactive Oxygen Species; D000431:Ethanol
keywords: PDK; ROS; autologous embolus; combination therapy; ischemia/reperfusion injury; oxidative injury; t-PA