Hyperoxic reperfusion after global cerebral ischemia promotes inflammation and long-term hippocampal neuronal death.

In this study we tested the hypothesis that long-term neuropathological outcome is worsened by hyperoxic compared to normoxic reperfusion in a rat global cerebral ischemia model. Adult male rats were anesthetized and subjected to bilateral carotid arterial occlusion plus bleeding hypotension for 10 min. The rats were randomized to one of four protocols: ischemia/normoxia (21% oxygen for 1 h), ischemia/hyperoxia (100% oxygen for 1 h), sham/normoxia, and sham/hyperoxia. Hippocampal CA1 neuronal survival and activation of microglia and astrocytes were measured in the hippocampi of the animals at 7 and 30 days post-ischemia. Morris water maze testing of memory was performed on days 23-30. Compared to normoxic reperfusion, hyperoxic ventilation resulted in a significant decrease in normal-appearing neurons at 7 and 30 days, and increased activation of microglia and astrocytes at 7, but not at 30, days of reperfusion. Behavioral deficits were also observed following hyperoxic, but not normoxic, reperfusion. We conclude that early post-ischemic hyperoxic reperfusion is followed by greater hippocampal neuronal death and cellular inflammatory reactions compared to normoxic reperfusion. The results of these long-term outcome studies, taken together with previously published results from short-term experiments performed with large animals, support the hypothesis that neurological outcome can be improved by avoiding hyperoxic resuscitation after global cerebral ischemia such as that which accompanies cardiac arrest.

[1]  R. Neumar,et al.  Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Str , 2008, Circulation.

[2]  M. Obladen History of Neonatal Resuscitation – Part 2: Oxygen and Other Drugs , 2008, Neonatology.

[3]  N. Hailer Immunosuppression after traumatic or ischemic CNS damage: It is neuroprotective and illuminates the role of microglial cells , 2008, Progress in Neurobiology.

[4]  Gary Fiskum,et al.  Hyperoxic Reperfusion After Global Ischemia Decreases Hippocampal Energy Metabolism , 2007, Stroke.

[5]  D. Rabi,et al.  Room air resuscitation of the depressed newborn: a systematic review and meta-analysis. , 2007, Resuscitation.

[6]  R. Rosenthal,et al.  Oximetry-Guided Reoxygenation Improves Neurological Outcome After Experimental Cardiac Arrest , 2006, Stroke.

[7]  R. Rosenthal,et al.  Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity. , 2006, Free radical biology & medicine.

[8]  W. Baumgartner,et al.  Valproic acid prevents brain injury in a canine model of hypothermic circulatory arrest: a promising new approach to neuroprotection during cardiac surgery. , 2006, The Annals of thoracic surgery.

[9]  P. Hof,et al.  Normoxic Resuscitation after Cardiac Arrest Protects against Hippocampal Oxidative Stress, Metabolic Dysfunction, and Neuronal Death , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[10]  Thomas Benner,et al.  A Pilot Study of Normobaric Oxygen Therapy in Acute Ischemic Stroke , 2005, Stroke.

[11]  M. Bullock,et al.  Normobaric hyperoxia--induced improvement in cerebral metabolism and reduction in intracranial pressure in patients with severe head injury: a prospective historical cohort-matched study. , 2004, Journal of neurosurgery.

[12]  P. Hof,et al.  Hyperbaric Oxygen Reduces Neuronal Death and Improves Neurological Outcome After Canine Cardiac Arrest , 2003, Stroke.

[13]  Patrick R Hof,et al.  Recommendations for straightforward and rigorous methods of counting neurons based on a computer simulation approach , 2000, Journal of Chemical Neuroanatomy.

[14]  R. Skelton Modelling recovery of cognitive function after traumatic brain injury: spatial navigation in the Morris water maze after complete or partial transections of the perforant path in rats , 1998, Behavioural Brain Research.

[15]  R. Rosenthal,et al.  Normoxic ventilation after cardiac arrest reduces oxidation of brain lipids and improves neurological outcome. , 1998, Stroke.

[16]  T. Sick,et al.  Oxygen sensitivity of mitochondrial redox status and evoked potential recovery early during reperfusion in post-ischemic rat brain. , 1998, Resuscitation.

[17]  I. Whishaw,et al.  Behavioral deficits revealed by multiple tests in rats with ischemie damage limited to half of the CA1 sector of the hippocampus , 1994, Brain Research Bulletin.

[18]  J. Scheel-Krüger,et al.  Relation of spatial learning of rats in the Morris water maze task to the number of viable CA1 neurons following four-vessel occlusion. , 1994, Behavioral neuroscience.

[19]  S. Whitesall,et al.  Cardiopulmonary-cerebral resuscitation with 100% oxygen exacerbates neurological dysfunction following nine minutes of normothermic cardiac arrest in dogs. , 1994, Resuscitation.

[20]  R. Busto,et al.  Intraischemic but Not Postischemic Brain Hypothermia Protects Chronically following Global Forebrain Ischemia in Rats , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[21]  H. Gundersen,et al.  Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator , 1991, The Anatomical record.

[22]  J. Parisi,et al.  Prominent white matter lesions develop in Mongolian gerbils treated with 100% normobaric oxygen after global brain ischemia , 1990, Acta Neuropathologica.

[23]  G. Feuerstein,et al.  Breathing 100% oxygen after global brain ischemia in Mongolian Gerbils results in increased lipid peroxidation and increased mortality. , 1987, Stroke.

[24]  S. Wiegand,et al.  Use of cryoprotectant to maintain long-term peptide immunoreactivity and tissue morphology , 1986, Peptides.

[25]  B. Siesjö,et al.  The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia , 2004, Acta Neuropathologica.

[26]  T. Sugawara,et al.  Effects of global ischemia duration on neuronal, astroglial, oligodendroglial, and microglial reactions in the vulnerable hippocampal CA1 subregion in rats. , 2002, Journal of neurotrauma.

[27]  R. Pawlinski,et al.  Morphology of reactive microglia in the injured cerebral cortex. Fractal analysis and complementary quantitative methods , 2001, Journal of neuroscience research.

[28]  David S. Liebeskind,et al.  Neuroprotection for Ischaemic Stroke , 2001, CNS drugs.