(Stroke. 1996;27:1124-1129.)
© 1996 American Heart Association, Inc.
Articles |
Role of Oxidants in Ischemic Brain Damage
From the Departments of Neurological Surgery and Neurology, University of California, School of Medicine, San Francisco.
Correspondence to Pak H. Chan, PhD, CNS Injury and Edema Research Center, University of California, 521 Parnassus, C-224, San Francisco, CA 94143-0651.
Background and Purpose Oxygen free radicals or oxidants have been proposed to be involved in acute central nervous system injury that is produced by cerebral ischemia and reperfusion. Because of the transient nature of oxygen radicals and the technical difficulties inherent in accurately measuring their levels in the brain, experimental strategies have been focused on the use of pharmacological agents and antioxidants to seek a correlation between the exogenously supplied specific radical scavengers (ie, superoxide dismutase and catalase) and the subsequent protection of cerebral tissues from ischemic injury. However, this strategy entails problems (hemodynamic, pharmacokinetic, toxicity, blood-brain barrier permeability, etc) that may cloud the data interpretation. This mini-review will focus on the oxidant mechanisms in cerebral ischemic brain injury by using transgenic and knockout mice as an alternative approach.
Methods Transgenic and knockout mutants that either overexpress or are deficient in antioxidant enzyme/protein levels have been successfully produced. The availability of these genetically modified animals has made it possible to investigate the role of certain oxidants in ischemic brain cell damage in molecular fashion.
Results It has been shown that an increased level of CuZn–superoxide dismutase and antiapoptotic protein Bcl-2 in the brains of transgenic mice protects neurons from ischemic/reperfusion injury, whereas a deficiency in CuZn–superoxide dismutase or mitochondrial Mn–superoxide dismutase exacerbates ischemic brain damage. Target disruption of neuronal nitric oxide synthase in mice also provides neuronal protection against permanent and transient focal cerebral ischemia.
Conclusions I conclude that molecular genetic approaches in modifying antioxidant levels in the brain offer a unique tool for understanding the role of oxidants in ischemic brain damage.
Key Words: cerebral ischemia • free radicals • oxidants • reperfusion • superoxide dismutase • mice, transgenic • mice, knockout
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M. Fujimura, Y. Morita-Fujimura, M. Kawase, J.-C. Copin, B. Calagui, C. J. Epstein, and P. H. Chan Manganese Superoxide Dismutase Mediates the Early Release of Mitochondrial Cytochrome C and Subsequent DNA Fragmentation after Permanent Focal Cerebral Ischemia in Mice J. Neurosci., May 1, 1999; 19(9): 3414 - 3422. [Abstract] [Full Text] [PDF]
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 C. Iadecola, C. A. Salkowski, F. Zhang, T. Aber, M. Nagayama, S. N. Vogel, and M. Elizabeth Ross The Transcription Factor Interferon Regulatory Factor 1 Is Expressed after Cerebral Ischemia and Contributes to Ischemic Brain Injury J. Exp. Med., February 15, 1999; 189(4): 719 - 727. [Abstract] [Full Text] [PDF]
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M. A. Weigand, A. Laipple, K. Plaschke, H.-H. Eckstein, E. Martin, and H. J. Bardenheuer Concentration Changes of Malondialdehyde Across the Cerebral Vascular Bed and Shedding of L-Selectin During Carotid Endarterectomy Stroke, February 1, 1999; 30(2): 306 - 311. [Abstract] [Full Text] [PDF]
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M. Kawase, M. Fujimura, Y. Morita-Fujimura, P. H. Chan, and C. Iadecola Reduction of Apurinic/Apyrimidinic Endonuclease Expression After Transient Global Cerebral Ischemia in Rats : Implication of the Failure of DNA Repair in Neuronal Apoptosis • Editorial Comment: Implication of the Failure of DNA Repair in Neuronal Apoptosis Stroke, February 1, 1999; 30(2): 441 - 449. [Abstract] [Full Text] [PDF]
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P. H. Chan, M. Kawase, K. Murakami, S. F. Chen, Y. Li, B. Calagui, L. Reola, E. Carlson, and C. J. Epstein Overexpression of SOD1 in Transgenic Rats Protects Vulnerable Neurons Against Ischemic Damage After Global Cerebral Ischemia and Reperfusion J. Neurosci., October 15, 1998; 18(20): 8292 - 8299. [Abstract] [Full Text] [PDF]
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A. Li, J. Segui, S. H. Heinemann, and T. Hoshi Oxidation Regulates Cloned Neuronal Voltage-Dependent Ca2+ Channels Expressed in Xenopus Oocytes J. Neurosci., September 1, 1998; 18(17): 6740 - 6747. [Abstract] [Full Text] [PDF]
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G. J DEL ZOPPO, R. VON KUMMER, and G. F HAMANN Ischaemic damage of brain microvessels: inherent risks for thrombolytic treatment in stroke J. Neurol. Neurosurg. Psychiatry, July 1, 1998; 65(1): 1 - 9. [Full Text]
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J. M. Gidday, T.S. Park, A. R. Shah, E. R. Gonzales, P. M. Kochanek, R. S.B. Clark, and M. J. Whalen Modulation of Basal and Postischemic Leukocyte-Endothelial Adherence by Nitric Oxide • Editorial Comment Stroke, July 1, 1998; 29(7): 1423 - 1430. [Abstract] [Full Text] [PDF]
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 K.-A. Hossmann Experimental models for the investigation of brain ischemia Cardiovasc Res, July 1, 1998; 39(1): 106 - 120. [Full Text] [PDF]
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B. Ancona, L. Facci, D. Franceschini, and P. Giusti Melatonin prevents the delayed death of hippocampal neurons induced by enhanced excitatory neurotransmission and the nitridergic pathway FASEB J, June 1, 1998; 12(9): 725 - 731. [Abstract] [Full Text]
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M. Soehle, A. Heimann, O. Kempski, and C. Iadecola Postischemic Application of Lipid Peroxidation Inhibitor U-101033E Reduces Neuronal Damage After Global Cerebral Ischemia in Rats • Editorial Comment Stroke, June 1, 1998; 29(6): 1240 - 1247. [Abstract] [Full Text] [PDF]
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E. H. Lo, P. Bosque-Hamilton, W. Meng, and N. Panahian Inhibition of Poly(ADP-Ribose) Polymerase : Reduction of Ischemic Injury and Attenuation of N-Methyl-D-Aspartate–Induced Neurotransmitter Dysregulation • Editorial Comment: Reduction of Ischemic Injury and Attenuation of N-Methyl-D-Aspartate–Induced Neurotransmitter Dysregulation Stroke, April 1, 1998; 29(4): 830 - 836. [Abstract] [Full Text] [PDF]
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B.-R. Hu, M. Park, M. E. Martone, W. H. Fischer, M. H. Ellisman, and J. A. Zivin Assembly of Proteins to Postsynaptic Densities after Transient Cerebral Ischemia J. Neurosci., January 15, 1998; 18(2): 625 - 633. [Abstract] [Full Text] [PDF]
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G. T. Gobbel, M. Bellinzona, A. R. Vogt, N. Gupta, J. R. Fike, and P. H. Chan Response of Postmitotic Neurons to X-Irradiation: Implications for the Role of DNA Damage in Neuronal Apoptosis J. Neurosci., January 1, 1998; 18(1): 147 - 155. [Abstract] [Full Text] [PDF]
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H.-J. Bidmon, K. Kato, A. Schleicher, O. W. Witte, K. Zilles, and R. J. Traystman Transient Increase of Manganese–Superoxide Dismutase in Remote Brain Areas After Focal Photothrombotic Cortical Lesion • Editorial Comment Stroke, January 1, 1998; 29(1): 203 - 211. [Abstract] [Full Text] [PDF]
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A. Armengou, A. Davalos, J. M. Fernandez-Real, and J. Castillo Serum Ferritin Concentrations Are Not Modified in the Acute Phase of Ischemic Stroke Stroke, January 1, 1998; 29(1): 258 - 260. [Full Text]
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C. Iadecola, F. Zhang, R. Casey, M. Nagayama, and M. E. Ross Delayed Reduction of Ischemic Brain Injury and Neurological Deficits in Mice Lacking the Inducible Nitric Oxide Synthase Gene J. Neurosci., December 1, 1997; 17(23): 9157 - 9164. [Abstract] [Full Text] [PDF]
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M. Spranger, S. Krempien, S. Schwab, S. Donneberg, and W. Hacke Superoxide Dismutase Activity in Serum of Patients With Acute Cerebral Ischemic Injury : Correlation With Clinical Course and Infarct Size Stroke, December 1, 1997; 28(12): 2425 - 2428. [Abstract] [Full Text]
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R. Schmid-Elsaesser, S. Zausinger, E. Hungerhuber, N. Plesnila, A. Baethmann, and H.-J. Reulen Superior Neuroprotective Efficacy of a Novel Antioxidant (U-101033E) With Improved Blood-Brain Barrier Permeability in Focal Cerebral Ischemia Stroke, October 1, 1997; 28(10): 2018 - 2024. [Abstract] [Full Text]
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I. Kruman, A. J. Bruce-Keller, D. Bredesen, G. Waeg, and M. P. Mattson Evidence that 4-Hydroxynonenal Mediates Oxidative Stress-Induced Neuronal Apoptosis J. Neurosci., July 1, 1997; 17(13): 5089 - 5100. [Abstract] [Full Text] [PDF]
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S. Nogawa, F. Zhang, M. E. Ross, and C. Iadecola Cyclo-Oxygenase-2 Gene Expression in Neurons Contributes to Ischemic Brain Damage J. Neurosci., April 15, 1997; 17(8): 2746 - 2755. [Abstract] [Full Text] [PDF]
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 A. I. Faden Pharmacologic Treatment of Acute Traumatic Brain Injury JAMA, August 21, 1996; 276(7): 569 - 570. [Abstract] [PDF]
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E. H. Lo, H. Hara, J. Rogowska, M. Trocha, A. R. Pierce, P. L. Huang, M. C. Fishman, G. L. Wolf, M. A. Moskowitz, and P. H. Chan Temporal Correlation Mapping Analysis of the Hemodynamic Penumbra in Mutant Mice Deficient in Endothelial Nitric Oxide Synthase Gene Expression Stroke, August 1, 1996; 27(8): 1381 - 1385. [Abstract] [Full Text]
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