Metabolic Failure, Oxidative Stress, and Neurodegeneration Following Cerebral Ischemia and Reperfusion

  • Gary Fiskum
  • Robert E. Rosenthal
Part of the GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia book series (GWUN)


In the United States, 650,000 people die annually from cardiac disease; cardiac arrest accounts for 2/3 (435,000) of these deaths. If an individual suffers a cardiac arrest outside the hospital, he has less than a 15% chance of leaving the hospital alive.1 Even if one survives initial resuscitative efforts, damage to the brain occurring during ischemia and reperfusion often results in neurologic morbidity or mortality. In one recent study of 262 initially comatose survivors of cardiac arrest, 79% of the patients had died within one year; cerebral failure was the cause of death in 37% of cases. Only 14% of patients were either neurologically normal or slightly impaired at 12 months.2 Recent advances in preclinical research on brain injury due to transient, global cerebral ischemia have demonstrated that at least four classes of interrelated molecular mechanisms contribute to ischemic neurological impairment. These classes are excitotoxicity, cellular calcium overload, metabolic failure and oxidative stress. This brief review focuses on mechanisms falling within the last two of these classifications.


Electron Spin Resonance Cerebral Ischemia Glutamine Synthetase Pyruvate Dehydrogenase Hyperbaric Oxygen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Steuven, H.A., White, E.M., Troiano, P. and Mateer, J.R., Prehospital cardiac arrest — a critical analysis of factors affecting survival. Resuscitation 17:251–259 (1989).CrossRefGoogle Scholar
  2. 2.
    Da Garavilla, L., Babbs, C.F. and Tacker, W.A., An experimental circulatory arrest model in the rat to evaluate calcium antagonists in cerebral resuscitation. Am. J. Emerg Med 2:321–326 (1984).PubMedCrossRefGoogle Scholar
  3. 3.
    Fiskum, G., Mitochondrial damage during cerebral ischemia. Ann. Emerg. Med. 14:810–815 (1985).PubMedCrossRefGoogle Scholar
  4. 4.
    Rosenthal, R.E., and Fiskum, G., Brain mitochondrial function in cerebral ischemia and resuscitation, in: “Cerebral Ischemia and Resuscitation”, A. Schurr and B.M. Rigor, eds., CRC Press, New York (1990).Google Scholar
  5. 5.
    Rosenthal, R.E., Hamud, F., Fiskum, G., Varghese, P.J., and Sharpe, S., Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine. J. Cereb. Blood Flow Metab. 7:752–758 (1987).PubMedCrossRefGoogle Scholar
  6. 6.
    Sims, N., and Pulsinelli, W.A., Altered mitochondrial respiration in selectively vulnerable subregions following transient forebrain ischemia in the rat. J. Neurochem. 49:1367–1374 (1987).PubMedCrossRefGoogle Scholar
  7. 7.
    Wagner, K.R., Kleinholz, M., and Myers, R.E., Delayed onset of neurologic deterioration following anoxia/ischemia coincides with appearance of impaired brain mitochondrial respiration and decreased cytochrome oxidase activity. J. Cereb. Blood Flow Metab. 10:417–423 (1990).PubMedCrossRefGoogle Scholar
  8. 8.
    Sciammanna, M.A., Zinkel, J., Fabi, A.Y., Lee, C.P., Ischemic injury to rat forebrain mitochondria and cellular calcium homeostasis. Biochem Biophys. Acta. 1134:223–232 (1992).CrossRefGoogle Scholar
  9. 9.
    Zaidan, E., and Sims. N.R., The calcium content of mitochondria from brain subregions following short-term forebrain ischemia and recirculation in the rat. J. Neurochem. 63:1812–1819 (1994).PubMedCrossRefGoogle Scholar
  10. 10.
    Sun D., and Gilboe D.D., Ischemia-induced changes in cerebral mitochondrial free fatty acids, phospholipids, and respiration in the rat. J. Neurochem. 62:1921–1928 (1994).PubMedCrossRefGoogle Scholar
  11. 11.
    Peeling, J., Wong, D., and Sutherland, G.R., Nuclear magnetic resonance study of regional metabolism after forebrain ischemia in rats. Stroke 20:633–640 (1989).PubMedCrossRefGoogle Scholar
  12. 12.
    Boveris, A., Oshino, N., and Chance, B., The cellular production of hydrogen peroxide. Biochem. J. 128:617–630 (1972).PubMedGoogle Scholar
  13. 13.
    Freeman, B.A., and Crapo, J.D., Hyperoxia increases oxygen radical production in rat lungs and lung mitochondria. J. Biol. Chem. 256:10986–10992 (1981).PubMedGoogle Scholar
  14. 14.
    Dykens, J.A., Isolated cerbral and cerbellar mitochondria produce free radicals when exposed to elevated Ca2+ and Na+: Implications for neurodegeneration. J. Neurochem. 63:584–591 (1994).PubMedCrossRefGoogle Scholar
  15. 15.
    Hasegawa, K., Yoshioka, H., Sawada, T. and Nishikawa, H., Direct measurement of free radicals in the neonatal mouse brain subjected to hypoxia: An electron spin resonance spectroscopic study. Brain Res. 607:161–166 (1993).PubMedCrossRefGoogle Scholar
  16. 16.
    Cino, M., and Del Maestro, R.F., Generation of hydrogen peroxide by brain mitochondria: the effect of reoxygenation following postdecapitative ischemia. Arch. Biochem. Biophys. 269:623–638 (1989).PubMedCrossRefGoogle Scholar
  17. 17.
    Reynolds, I.J., and Hastings, T.G., Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J. Neurosci. 15:3318–3327 (1995).PubMedGoogle Scholar
  18. 18.
    Dugan, L.L., Sensi, S.L., Canzoniero, L.M.T., Handran, S.D., Rothman, S.M., T.-S. Lin, Goldberg, M.P., and Choi, D.W., Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J. Neurosci. 15:6377–6388 (1995).PubMedGoogle Scholar
  19. 19.
    Siesjo, B.K., Elcholm, A., Katsura, K. and Theander, S., Acid-base changes during complete brain ischemia. Stroke 21, Suppl. 11:194–199 (1990).Google Scholar
  20. 20.
    Folbergrova, J., Ljunggren, B., Norberg, K., and Siesjo, B.K., Influence of complete ischemia on glycolytic metabolites, citric acid cycle intermediates and associated amino acids in the rat cerebral cortex. Brain Res. 80:265–279 (1974).PubMedCrossRefGoogle Scholar
  21. 21.
    Cannella, D.M., Kapp, J.P., Munschauer, F.E., Markov, A.K., and Shurcard, D.W., Cerebral resuscitation with succinate and fructose-1,6-diphosphate. Surg. Neurol. 31:177–182 (1989).PubMedCrossRefGoogle Scholar
  22. 22.
    Fucci, L., Oliver, C.N., Coon, M.J., and Stadtman, E.R., Inactivation of key metabolic enzymes by mixed-function oxidation reactions: possible implications in protein turnover and aging. Proc. Natl. Acad. Sci. USA 80: 1521–1526 (1983).PubMedCrossRefGoogle Scholar
  23. 23.
    Katayama, Y., Welsh, F.A., Effect of dichloroacetate on regional energy metabolites and pyruvate dehydrogenase activity during ischemia and reperfusion in gerbil brain. J. Neurochem. 52:1817–1822 (1989).PubMedCrossRefGoogle Scholar
  24. 24.
    Zaidan, E. and Sims, N.R., Selective reductions in the activity of the PDH complex in mitochondria isolated from brain subregions following forebrain ischemia in rats. J. Cereb. Blood Flow Metab. 13:98–104 (1993).PubMedCrossRefGoogle Scholar
  25. 25.
    LeMay, D.R., Zelenock, G.B., and D’Alecy, L.G., Neurological protection by dichloroacetate depending on the severity of injury in the paraplegic rat. J. Neurosurg. 73:118–122 (1990).PubMedCrossRefGoogle Scholar
  26. 26.
    Parks, D.A., Bulkley, G.B., Granger, N., Hamilton, S.R., and McCord, J.M., Ischemic injury in the cat small intestine: Role of Superoxide radical. Gastroenterology 82:9–15 (1982).PubMedGoogle Scholar
  27. 27.
    Schmidley, J.W., Free radicals in central nervous system ischemia. Stroke 21:1086–1090 (1990).PubMedCrossRefGoogle Scholar
  28. 28.
    Choi, D.W., Methods for antagonizing glutamate neurotoxicity. Cerebrovasc. Brain Metabol Rev. 2:105–147 (1990).Google Scholar
  29. 29.
    Pellegrini-Giampietro, D.E., Cherici, G., Alesiani, M. Carla, V., and Moroni, F., Excitatory amino acid release and free radical formation may cooperate in the genesis of ischemia-induced neuronal damage. J. Neurosci. 10:1035–1041 (1990).PubMedGoogle Scholar
  30. 30.
    Bredt, D.S., Synder, S.H., Nitric oxide: A novel neuronal messenger. Neuron 8:3–11 (1992).PubMedCrossRefGoogle Scholar
  31. 31.
    Rordi, R. Beckman, J.S., Bush, K.M. and Freeman, B.A., Peroxynitrite-induced membrane lipid peroxidation: the cytotoxic potential of Superoxide and nitric oxide. Arch Biochem. Biophys. 228:481–487 (1984).Google Scholar
  32. 32.
    Imaizumi, S. et al. Free radicals and lipid changes in cerebral ischemia, in: “Cerebral Ischemia and Resuscitation”, A. Schurr and B.M. Rigor, eds.), CRC Press, New York, (1990).Google Scholar
  33. 33.
    Oliver, C.N., Starke-Reed, P.E., Stadtman, E.R. Liu, G.J., Carney, J.M., and Floyd, R.A., Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of freee radicals during ischemia/reperfusion-induced injury to gerbil brain. Proc. Natl. Acad Sci. USA 87:5144–5147 (1990).PubMedCrossRefGoogle Scholar
  34. 34.
    Krause, G.S., Degracia, D.J., Skjaerlund, J.M., and O’Neill, B.J., Assessment of free radical-induced damage in brain proteins after ischemia and reperfusion. Resuscitation 23:59–69 (1992).PubMedCrossRefGoogle Scholar
  35. 35.
    Liu, Y., Rosenthal, R., Starke-Reed, P., and Fiskum, G., Inhibition of post-cardiac arrest brain protein oxidation by acetyl-L-carnitine, Free Rad. Biol Med. 15:667–670 (1993).PubMedCrossRefGoogle Scholar
  36. 36.
    Folbergrova, J., Kiyota, Y., Pahlmark, K., Memezawa, H., Smith, M.-L., and Siesjo, B.K., Eoes ischemia with reperfusion lead to oxidative damage to proteins in the brain? J. Cereb. Blood Flow Metab. 13:145–152 (1993).PubMedCrossRefGoogle Scholar
  37. 37.
    Ischiropoulos, H., Zhu, L., Chen, J., Tsai, M., Martin, J.C., Smith, C.D. and Beekman, J.S., Peroxynitrite-mediated tyrosine nitration catalyzed by Superoxide dismutase. Arch. Biochem. Biophys. 298:431–437 (1992).PubMedCrossRefGoogle Scholar
  38. 38.
    Beekman, J.S., Ischiropoulos, H., Zhu, L., van der Woerd, M., Smith, C. Chen, J., Harrison, J., Martin, J.C. and Tsai, M.H., Kinetics of Superoxide dismutase and iron catalyzed nitration of phenolics by peroxynitrite. Arch. Biochem. Biophys. 298:483–445 (1992).Google Scholar
  39. 39.
    Janing, G.R., Kraft, R., Blank, J., Ristau, O., Rabe, H., and Ruckpaul, K. Chemical modification of cytochrome P-450 LM4. Identification of functionally linked tyrosine residues. Biochem. Biophys. Acta. 916:512–523 (1987).CrossRefGoogle Scholar
  40. 40.
    Beckman, J.S., Peroxynitrite, Superoxide dismutase and tyrosine nitration in neurodegeneration, Abstract of presentation at “Neurodegenerative Diseases ′95”, the XVth International Washington Spring Symposium, Washington D.C. (1995).Google Scholar
  41. 41.
    Beckmann, J.S., Ye, Y.Z., Anderson, P.G., Chen, J., Accavitti, M.A., Tarpey, M.M. and White, C.R., Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. Biol. Chem. Hoppe-Seyler 375:81–88 (1994).PubMedCrossRefGoogle Scholar
  42. 42.
    Haddad, I.Y., Pataki, G., Hu, P., Galliani, C., Beckman, J.S. and Matalon, S., Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. J. Clin. Invest. 94:2407–2413 (1994).PubMedCrossRefGoogle Scholar
  43. 43.
    Rosenthal, R.E., Chanderbhan, R.F., Marshall, Jr., G.H. and Fiskum, G., Prevention of post-ischemic brain lipid conjugated diene production and neurological injury by hydroxyethylstarch-conjugated deferoxamine. Free Rad. Biol. Med. 12:29–33 (1992).PubMedCrossRefGoogle Scholar
  44. 44.
    Standards and guidelines for cardiopulmonary resuscitation and emergency cardiac care. Part III: Adult advanced cardiac life support. JAMA 255:2933–2954 (1986).Google Scholar
  45. 45.
    Zwemer, C.F., Whitesall, S.E. and D’Alecy, L.G., Cardiopulmonary-cerebral resuscitation with 100% oxygen exacerbates neurological dysfunction following nine minutes of normothermic cardiac arrest in dogs. Resuscitation 27:159–170 (1994).PubMedCrossRefGoogle Scholar
  46. 46.
    Mickel, H.S., Vaishav, Y.N., Kempski, O., von Lubitz, D., Weiss, J.F., and Feuerstein, G., Breathing 100% oxygen after global brain ischemia in mongolian gerbils results in increased lipid peroxidation and increased mortality. Stroke 18:426–430 (1987).PubMedCrossRefGoogle Scholar
  47. 47.
    Rosenthal, R.E., Miljkovic-Lolic, M., Haywood, Y. and Fiskum, G., Cerebral ischemia/reperfusion: Neurologic effects of hyperoxic resuscitation from experimental cardiac arrest in dogs. Ann. Emerg. Med. 25:137 (1995).Google Scholar
  48. 48.
    Wilson D.F., Pastuszko, A., DiGiacomo, J.E., Pawlowski, M. Schneiderman, R., and Delivoria-Papadopoulos, M., Effect of hyperventilation on oxygenation of the brain cortex of newborn piglets. J. Appl. Physiol 70:2691–2696 (1991).PubMedGoogle Scholar
  49. 49.
    Halsey, J.H., Conger, K.A., Garcia, J.H., and Sarvary, E., The contribution of reoxygenation to ischemic brain damage. J. Cereb. Blood Flow Metab. 11:994–1000 (1991).PubMedCrossRefGoogle Scholar
  50. 50.
    Danielisova, V., Marsala, M., Chavko, M., and Marsala, J., Postischemic hypoxia improves metabolic and functional recovery of the spinal cord. Neurology 40:1125–1129 (1990).PubMedCrossRefGoogle Scholar
  51. 51.
    Thorn, S.R., Antagonism of carbon monoxide mediated brain lipid peroxidation by hyperbaric oxygen. Toxicol Appl Pharmacol. 105:340–344 (1990).CrossRefGoogle Scholar
  52. 52.
    Kapp, J.P., Phillips, M., Markov, A., and Smith, R.R., Hyperbaric oxygen after circulatory arrest: modification of post-ischemic encephalopathy. Neurosurg. 11:496–499 (1982).CrossRefGoogle Scholar
  53. 53.
    Iwatsuki, N., Hyperbaric oxygen combined with nicardipine administration accelerates neurologic recovery after cerebral ischemia in a canine model. Crit. Car Med. 22:858–863 (1994).CrossRefGoogle Scholar
  54. 54.
    Bogaert, Y.E., Rosenthal, R.E. and Fiskum, G., Post-ischemic inhibition of cerebral cortex pyruvate dehydrogenase. Free Rad. Biol Med. 16:811–820 (1994).PubMedCrossRefGoogle Scholar
  55. 55.
    Nowicki, J.P., Duval, D., Poignet, H., and Scatton, B., Nitric oxide mediates neuronal death after focal cerebral ischemia in the mouse. Eur. J. Pharmacol 204:339–340 (1991).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Gary Fiskum
    • 1
  • Robert E. Rosenthal
    • 1
  1. 1.Departments of Biochemistry and Molecular Biology and Emergency MedicineThe George Washington University Medical CenterUSA

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