Increased cerebral output of free radicals during hypoxia: implications for acute mountain sickness?

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2009-11, Vol.297 (5), p.R1283-R1292
• Main Authors: Bailey, Damian M, Taudorf, Sarah, Berg, Ronan M. G, Lundby, Carsten, McEneny, Jane, Young, Ian S, Evans, Kevin A, James, Philip E, Shore, Angharad, Hullin, David A, McCord, Joe M, Pedersen, Bente K, Moller, Kirsten
• Format: Article
• Language: English
• Subjects: Acute Disease; Adult; Altitude Sickness - epidemiology; Altitude Sickness - metabolism; Altitude Sickness - physiopathology; Biomarkers - metabolism; Blood; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - physiopathology; Brain; Brain - blood supply; Brain - metabolism; Free radicals; Free Radicals - metabolism; Headache - metabolism; Headache - physiopathology; Health Surveys; Humans; Hypoxia; Hypoxia - metabolism; Male; Medical disorders; Metabolism; Nerve Growth Factors - metabolism; Nervous system; Oxidation; Oxidative Stress - physiology; Oxygen - metabolism; Phosphopyruvate Hydratase - metabolism; Regional Blood Flow - physiology; Retrospective Studies; Risk Factors; S100 Calcium Binding Protein beta Subunit; S100 Proteins - metabolism; Tyrosine - analogs & derivatives; Tyrosine - metabolism
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00366.2009

1 Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, Mid-Glamorgan, United Kingdom; 2 Centre of Inflammation and Metabolism, Department of Infectious Diseases and 3 Copenhagen Muscle Research Centre, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; and 4 Centre for Public Health, Queen's University Belfast, Belfast, N. Ireland; 5 Wales Heart Research Institute, School of Medicine, Cardiff University, Cardiff; and 6 Department of Medical Biochemistry, Royal Glamorgan Hospital, Mid-Glamorgan, United Kingdom; 7 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado-Denver, Denver, Colorado; and 8 Department of Cardiothoracic Anesthesia and Intensive Care Unit 4131, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Submitted June 29, 2009 ; accepted in final form August 26, 2009 This study examined whether hypoxia causes free radical-mediated disruption of the blood-brain barrier (BBB) and impaired cerebral oxidative metabolism and whether this has any bearing on neurological symptoms ascribed to acute mountain sickness (AMS). Ten men provided internal jugular vein and radial artery blood samples during normoxia and 9-h passive exposure to hypoxia (12.9% O 2 ). Cerebral blood flow was determined by the Kety-Schmidt technique with net exchange calculated by the Fick principle. AMS and headache were determined with clinically validated questionnaires. Electron paramagnetic resonance spectroscopy and ozone-based chemiluminescence were employed for direct detection of spin-trapped free radicals and nitric oxide metabolites. Neuron-specific enolase (NSE), S100β, and 3-nitrotyrosine (3-NT) were determined by ELISA. Hypoxia increased the arterio-jugular venous concentration difference (a-v D ) and net cerebral output of lipid-derived alkoxyl-alkyl free radicals and lipid hydroperoxides ( P < 0.05 vs. normoxia) that correlated with the increase in AMS/headache scores ( r = –0.50 to –0.90, P < 0.05). This was associated with a reduction in a-v D and hence net cerebral uptake of plasma nitrite and increased cerebral output of 3-NT ( P < 0.05 vs. normoxia) that also correlated against AMS/headache scores ( r = 0.74–0.87, P < 0.05). In contrast, hypoxia did not alter the cerebral exchange of S100β and both global cerebral oxidative metabolism (cerebral metabolic rate of oxygen) and neuronal integrity (NSE) were preserved ( P > 0.05 vs. normoxia). These findings indicate tha