title: Oxygen-inducible glutamate oxaloacetate transaminase as protective switch transforming neurotoxic glutamate to metabolic fuel during acute ischemic stroke.
abstract: This work rests on our previous report (J Cereb Blood Flow Metab 30: 1275-1287, 2010) recognizing that glutamate (Glu) oxaloacetate transaminase (GOT) is induced when brain tissue hypoxia is corrected during acute ischemic stroke (AIS). GOT can metabolize Glu into tricarboxylic acid cycle intermediates and may therefore be useful to harness excess neurotoxic extracellular Glu during AIS as a metabolic substrate. We report that in cultured neural cells challenged with hypoglycemia, extracellular Glu can support cell survival as long as there is sufficient oxygenation. This effect is abrogated by GOT knockdown. In a rodent model of AIS, supplemental oxygen (100% O(2) inhaled) during ischemia significantly increased GOT expression and activity in the stroke-affected brain tissue and prevented loss of ATP. Biochemical analyses and in vivo magnetic resonance spectroscopy during stroke demonstrated that such elevated GOT decreased Glu levels at the stroke-affected site. In vivo lentiviral gene delivery of GOT minimized lesion volume, whereas GOT knockdown worsened stroke outcomes. Thus, brain tissue GOT emerges as a novel target in managing stroke outcomes. This work demonstrates that correction of hypoxia during AIS can help clear extracellular neurotoxic Glu by enabling utilization of this amino acid as a metabolic fuel to support survival of the hypoglycemic brain tissue. Strategies to mitigate extracellular Glu-mediated neurodegeneration via blocking receptor-mediated excitotoxicity have failed in clinical trials. We introduce the concept that under hypoglycemic conditions extracellular Glu can be transformed from a neurotoxin to a survival factor by GOT, provided there is sufficient oxygen to sustain cellular respiration.
authors.affiliation: Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Rink
authors.forename: Surya
authors.initials: S
authors.lastname: Gnyawali
authors.forename: Laura
authors.initials: L
authors.lastname: Peterson
authors.forename: Savita
authors.initials: S
authors.lastname: Khanna
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D024443:Aspartate Aminotransferase, Cytoplasmic / Q000235:genetics / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology*; D000860:Hypoxia / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008279:Magnetic Resonance Imaging; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000235:genetics / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D018698:Glutamic Acid; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D024443:Aspartate Aminotransferase, Cytoplasmic; D001219:Aspartate Aminotransferases; D010100:Oxygen