Blood Flow, Energy Failure, and Vulnerability to Stroke

  • James J. Vornov


In recent years, the study of mechanisms of ischemic neuronal injury has focused on the cascade of intracellular events triggered by ischemic conditions, emphasizing the role of glutamate receptor activation. The focus on intracellular mechanisms has led to an approach of identifying individual mechanisms of injury in simple systems and then examining their role in more intact systems. Rarely, however, are these mechanisms placed into their proper context as events that occur during reduced blood flow, interacting with cellular energy status. Simple models of ischemic injury based on one or two of these basic mechanisms do not reflect what is known about the dynamics of blood flow and metabolism in ischemia. For example, it has been suggested that at the point of energy failure, there is massive release of glutamate into the extracellular space, triggering a cascade that resembles glutamate toxicity. Although glutamate receptors certainly play an important role in mediating ischemic neuronal injury, blockade of glutamate receptors has no effect in some models. In other models, glutamate toxicity can be observed in the absence of massive glutamate release. Thus, whereas glutamate receptors are often critical mediators of ischemic neuronal injury, energy failure and reperfusion are fundamental factors as well.


Glutamate Receptor Middle Cerebral Artery Occlusion Ischemic Injury Global Ischemia Focal Ischemia 
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  1. 1.
    Gatfield PD, Lowry OH, Schulz DW, Passonneau JV. Regional energy reserves in mouse brain and changes with ischaemia and anaesthesia. J Neurochem 1966, 13: 185–195.PubMedCrossRefGoogle Scholar
  2. 2.
    King LJ, Schoepfle GM, Lowry OH, Passonneau JV, Wilson S. Effects of electrical stimulation on metabolites in brain of decapitated mice. J Neurochem 1967, 14: 613–618.PubMedCrossRefGoogle Scholar
  3. 3.
    Michenfelder JD, Theye RA. The effects of anesthesia and hypothermia on canine cerebral ATP and lactate during anoxia produced by decapitation. Anesthesiology 1970, 33: 430–439.PubMedCrossRefGoogle Scholar
  4. 4.
    Laptook AR, Corbett RJ, Burns D, Sterett R. Neonatal ischemicneuroprotection by modest hypothermia is associated with attenuated brain acidosis. Stroke 1995, 26: 1240–1246.PubMedCrossRefGoogle Scholar
  5. 5.
    Verhaegen M, Iaizzo PA, Todd MM. A comparison of the effects of hypothermia, pentobarbital, and isoflurane on cerebral energy stores at the time of ischemicdepolarization Anesthesiology 1995, 82: 1209–1215.PubMedCrossRefGoogle Scholar
  6. 6.
    Yager JY, Asselin J. Effect of mild hypothermia on cerebral energy metabolism during the evolution of hypoxic-ischemic brain damage in the immature rat. Stroke 1996, 27: 919–925.PubMedCrossRefGoogle Scholar
  7. 7.
    Schmidt-Kastner R, Freund TF. Selective vulnerability of the hippocampus in brain ischemia. Neuroscience 1991, 40: 599–636.PubMedCrossRefGoogle Scholar
  8. 8.
    Gahwiler BH. Organotypic monolayer cultures of nervous tissue. J Neurosci Methods 1981, 4: 329–342.PubMedCrossRefGoogle Scholar
  9. 9.
    Stoppini L, Buchs PA, Muller D. A simple method for organotypic cultures of nervous tissue. J Neurosci Methods 1991, 37: 173–182.PubMedCrossRefGoogle Scholar
  10. 10.
    Zimmer J, Gahwiler BH. Cellular and connective organization of slice cultures of the rat hippocampus and fascia dentate. J Comp Neurol 1984, 228: 432–446.PubMedCrossRefGoogle Scholar
  11. 11.
    Newell DW, Malouf AT, Franck JE, Glutamate-mediated selective vunerability to ischemia is present in organotypic cultures of hippocampus. Neurosci Lett 1990, 116: 325–330.PubMedCrossRefGoogle Scholar
  12. 12.
    Vornov JJ, Tasker RC, Coyle JT. Delayed protection by MK-801 and tetrodotoxin in a rat organotypic hippocampal culture model of ischemia. Stroke 1994, 25: 457–464.PubMedCrossRefGoogle Scholar
  13. 13.
    Vornov JJ, Tasker RC, Coyle JT. Direct observation of the agonist-specific regional vulnerability to glutamate, NM DA, and kainate neurotoxicity in organotypic hippocampal cultures. Experimental Neurology 1991, 114: 11–22.PubMedCrossRefGoogle Scholar
  14. 14.
    Tasker RC, Coyle JT, Vornov JJ. The regional vulnerability to hypoglycemia-induced neurotoxicity in organotypic hippocampal culture: protection by early tetrodotoxin or delayed MK-801. J Neurosci 1992, 12: 4298–4308.PubMedGoogle Scholar
  15. 15.
    Vornov JJ, Tasker RC, Park J. Neurotoxicity of acute glutamate transport blockade depends on coactivation of both NMDA and AMPA/Kainate receptors in organotypic hippocampal cultures. Exp Neurol 1995, 133: 7–17.PubMedCrossRefGoogle Scholar
  16. 16.
    Brierley JB, Brown AW, Meldrum BS. The nature and time course of the neuronal alterations resulting from oligaemia and hypoglycaemia in the brain of Macaca mulatta. Brain Res 1971, 25: 483–499.PubMedCrossRefGoogle Scholar
  17. 17.
    Salford LG, Plum F, Brierley JB. Graded hypoxia-oligemia in rat brain. II. Neuropathological alterations and their implications. Arch Neurol 1973, 29: 234–238.PubMedCrossRefGoogle Scholar
  18. 18.
    Branston NM, Symon L, Crockard HA, Pasztor E. Relationship between the cortical evoked potential and local cortical blood flow following acute middle cerebral artery occlusion in the baboon. Exp Neurol 1974, 45: 195–208.PubMedCrossRefGoogle Scholar
  19. 19.
    Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol 1994b, 36: 557–565.PubMedCrossRefGoogle Scholar
  20. 20.
    Mies G, Ishimaru S, Xie Y, Seo K, Hossmann KA. ischemicthresholds of cerebral protein synthesis and energy state following middle cerebral artery occlusion in rat. J Cereb Blood Flow Metab 1991, 11: 753–761.PubMedCrossRefGoogle Scholar
  21. 21.
    Mies G, Paschen W, Hossmann KA. Cerebral blood flow, glucose utilization, regional glucose, and ATP content during the maturation period of delayed ischemic injury in gerbil brain. J Cereb Blood Flow Metab 1990, 10: 638–645.PubMedCrossRefGoogle Scholar
  22. 22.
    Nowak T Jr, Jacowicz M. The heat shock/stress response in focal cerebral ischemia. Brain Pathol 1994, 4: 67–76.PubMedCrossRefGoogle Scholar
  23. 23.
    Shiraishi K, Sharp FR, Simon RP. Sequential metabolic changes in rat brain following middle cerebral artery occlusion: a 2-deoxyglucose study. J Cereb Blood Flow Metab 1989, 9: 765–773.PubMedCrossRefGoogle Scholar
  24. 24.
    Mies G, Kohno K, Hossmann KA. MK-801, a glutamate antagonist, lowers flow threshold for inhibition of protein synthesis after middle cerebral artery occlusion of rat. Neurosci Lett 1993, 155: 65–68.PubMedCrossRefGoogle Scholar
  25. 25.
    Simon R, Shiraishi K. N-methyl-D-aspartate antagonist reduces stroke size and regional glucose metabolism. Ann Neurol 1990, 27: 606–611.PubMedCrossRefGoogle Scholar
  26. 26.
    Ratan RR, Murphy TH, Baraban JM. Macromolecular synthesis inhibitors prevent oxidative stress-induced apoptosis in embryonic cortical neurons by shunting cysteine from protein synthesis to glutathione. J Neurosci 1994a, 14: 4385–4392.PubMedGoogle Scholar
  27. 27.
    Choi DW. NMDA receptors and AMPA/kainate receptors mediate parallel injury in cerebral cortical cultures subjected to oxygen-glucose deprivation. Prog Brain Res 1993, 96: 137–143.PubMedCrossRefGoogle Scholar
  28. 28.
    Peng L, Hertz L. Potassium-induced stimulation of oxidative metabolism of glucose in cultures of intact cerebellar granule cells but not in corresponding cells with dendritic degeneration. Brain Res 1993, 629: 331–334.PubMedCrossRefGoogle Scholar
  29. 29.
    Taylor CP. Na+ currents that fail to inactivate. Trends Neurosci 1993, 16: 455–460.PubMedCrossRefGoogle Scholar
  30. 30.
    Siesjo BK. Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. J Neurosurg 1992, 77: 169–184.PubMedCrossRefGoogle Scholar
  31. 31.
    Siesjo BK, Ekholm A, Katsura K, Theander S. Acid-base changes during complete brain ischemia. Stroke 1990, 21: 194–199.Google Scholar
  32. 33.
    Obrenovitch TP, Richards DA. Extracellular neurotransmitter changes in cerebral ischaemia. Cerebrovasc Brain Metab Rev 1995, 7: 1–54.PubMedGoogle Scholar
  33. 34.
    Szatkowskik M, Attwell D. Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms. Trends Neurosci 1994, 17: 359–365.CrossRefGoogle Scholar
  34. 35.
    Deshpande J, Bergstedt K, Linden T, Kalimo H, Wieloch T. Ultrastructural changes in the hippocampal CA1 region following transient cerebral ischemia: evidence against programmed cell death. Exp Brain Res 1992, 88: 91–105.PubMedCrossRefGoogle Scholar
  35. 36.
    Kim H, Koehler RC, Hum PD, Hall ED, Traystman RJ. Amelioration of impaired cerebral metabolism after severe acidotic ischemia by tirilazad posttreatment in dogs. Stroke 1996, 27: 114–121.PubMedCrossRefGoogle Scholar
  36. 37.
    Nishijima MK, Koehler RC, Hum PD, Eleff SM, Norris S, Jacobus WE, Traystman RJ. Postischemic recovery rate of cerebral ATP, phosphocreatine, pH, and evoked potentials. Am J Physiol 1989, 257: H1860–1870.Google Scholar
  37. 38.
    Arai H, Passonneau JV, Lust WD. Energy metabolism in delayed neuronal death of CA1 neurons of the hippocampus following transient ischemia in the gerbil. Met Brain Dis 1986, 1: 263–278.CrossRefGoogle Scholar
  38. 39.
    Gill R, Foster AC, Woodruff GN. MK-801 is neuroprotective in gerbils when administered during the post-ischaemic period. Neuroscience 1988, 25: 847–855.PubMedCrossRefGoogle Scholar
  39. 40.
    Hossmann KA. Glutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised. Brain Pathol 1994a, 4: 23–36.PubMedCrossRefGoogle Scholar
  40. 41.
    Buchan R, Pulsinelli WA. Hypothermia but not the N-methyl-D-aspartate antagonist, MK801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci 1990, 10: 311–316.PubMedGoogle Scholar
  41. 42.
    Rothman SM. The neurotoxicity of excitatory amino acids is produced by passive chloride influx. J Neurosci 1985, 5: 1483–1489.PubMedGoogle Scholar
  42. 43.
    Ellren K, Lehmann A. Calcium dependency of N-methyl-D-aspartate toxicity in slices from the immature rat hippocampus. Neuroscience 1989, 32: 371–379.PubMedCrossRefGoogle Scholar
  43. 44.
    Garthwaite J, Garthwaite G. Mechanisms of excitatory amino acid neurotoxicity in rat brain slices. Adv Exp Med Biol 1990, 268: 505–518.PubMedGoogle Scholar
  44. 45.
    Olney JW, deGubareff T, Sloviter RS. “Epileptic” brain damage in rats induced by sustained electrical stimulation of the perforant path. II. Ultrastructural analysis of acute hippocampal pathology. Brain Res Bull 1983, 10: 699–712.PubMedCrossRefGoogle Scholar
  45. 46.
    Dietrich WD, Busto R, Yoshida S, Ginsberg MD. Histopathological and hemodynamic consequences of complete versus incomplete ischemia in the rat. J Cereb Blood Flow Metab 1987, 7: 300–308.PubMedCrossRefGoogle Scholar
  46. 47.
    Kalimo H, Paljarvi L, Vapalahti M. The early ultrastructural alterations in the rabbit cerebral and cerebellar cortex after compression ischaemia. Neuropathol Appl Neurobiol 1979, 5: 211–223.PubMedCrossRefGoogle Scholar
  47. 48.
    Simon RP, Griffiths T, Evans MC, Swan JH, Meldrum BS. Calcium overload in selectively vulnerable neurons of the hippocampus during and after ischemia: an electron microscopy study in the rat. J Cereb Blood Flow Metab 1984, 4: 350–361.PubMedCrossRefGoogle Scholar
  48. 49.
    Vornov JJ. Toxic NMDA receptor activation occurs during recovery in a tissue culture model of ischemia. J Neurochem 1995, 65: 1681–1691.PubMedCrossRefGoogle Scholar
  49. 50.
    Vornov JJ, Thomas AG, Jo D. Protective effects of extracellular acidosis and blockade of sodium/hydrogen ion exchange during recovery from metabolic inhibition in neuronal tissue culture. J Neurochemistry, 1996, 67: 2379–2388.CrossRefGoogle Scholar
  50. 51.
    Randall RD, Thayer SA. Glutamate-induced calcium transient triggers delayed calcium overload and neurotoxicity in rat hippocampal neurons. J Neurosci 1992, 12: 1882–1895.PubMedGoogle Scholar
  51. 52.
    Hartley DM, Choi DW. Delayed rescue of N-methyl-D-aspartate receptor-mediated neuronal injury in cortical culture. J Pharm Exp Ther 1989, 250: 752–758.Google Scholar
  52. 53.
    Hartley DM, Kurth MC, Bjerkness L, Weiss JH, Choi DW. Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. J Neurosci 1993, 13: 1993–2000.PubMedGoogle Scholar
  53. 54.
    Djuricic B, Rohn G, Paschen W, Hossmann KA. Protein synthesis in the hippocampal slice: transient inhibition by glutamate and lasting inhibition by ischemia. Metab Brain Dis 1994, 9: 235–247.PubMedCrossRefGoogle Scholar
  54. 55.
    Whittingham TS, Assaf H, Selman WR, Ratcheson RA, Lust WD. Glutamate-induced energetic stress in hippocampal slices: evidence against NMDA and glutamate uptake as mediators. Metab Brain Dis 1992, 7: 77–92.PubMedCrossRefGoogle Scholar
  55. 56.
    Hartley Z, Dubinsky JM. Changes in intracellular pH associated with glutamate excitotoxicity. J Neurosci 1993, 13: 4690–4699.PubMedGoogle Scholar
  56. 57.
    Irwin RP, Lin SZ, Long RT, Paul SM. N-methyl-D-aspartate induces a rapid, reversible, and calcium-dependent intracellular acidosis in cultured fetal rat hippocampal neurons. J Neurosci 1994, 14: 1352–1357.PubMedGoogle Scholar
  57. 58.
    Thayer SA, Miller RJ. Regulation of the intracellular free calcium concentration in single rat dorsal root ganglion neurones in vitro. J Physiol 1990, 425: 85–115.PubMedGoogle Scholar
  58. 59.
    Duchen MR. Ca(2+)-dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons. Biochem J 1992, 283: 41–50.PubMedGoogle Scholar
  59. 60.
    Duchen MR, Biscoe TJ. Relative mitochondrial membrane potential and [Ca2+]i in type I cells isolated from the rabbit carotid body. J Physiol 1992, 450: 33–61.PubMedGoogle Scholar
  60. 61.
    Chan PH. Role of oxidants in ischemic brain damage. Stroke 1996, 27: 1124–1129.PubMedCrossRefGoogle Scholar
  61. 62.
    Coyle JT, Puttfarcken P. Oxidative stress, glutamate, and neurodegenerative disorders. Science 1993, 262: 689–695.PubMedCrossRefGoogle Scholar
  62. 63.
    Dugan LL, Lin TS, He YY, Hsu CY, Choi DW. Detection of free radicals by microdialysis/spin trapping EPR following focal cerebral ischemia-reperfusion and a cautionary note on the stability of 5,5-dimethyl-l-pyrroline N-oxide (DMPO). Free Radic Res 1995, 23: 27–32.PubMedCrossRefGoogle Scholar
  63. 64.
    Chacon E, Acosta D. Mitochondrial regulation of Superoxide by Ca2+: an alternate mechanism for the cardiotoxicity of doxorubicin. Toxicol Appl Pharmacol 1991, 107: 117–128.PubMedCrossRefGoogle Scholar
  64. 65.
    Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ. Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol 1993, 264: C961–C967.PubMedGoogle Scholar
  65. 66.
    Pulsinelli WA, Levy DE, Duffy TE. Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia. Ann Neurol 1982, 11: 499–502.PubMedCrossRefGoogle Scholar
  66. 67.
    Araki T, Inoue T, Kato H, Kogure K, Murakami M. Neuronal damage and calcium accumulation following transient cerebral ischemia in the rat. Mol Chem Neuropathol 1990, 12: 203–213.PubMedCrossRefGoogle Scholar
  67. 68.
    Ratan RR, Murphy TH, Baraban JM. Oxidative stress induces apoptosis in embryonic cortical neurons. J Neurochem 1994b, 62: 376–379.PubMedCrossRefGoogle Scholar
  68. 69.
    Johnson EM JR, Greenlund LJ, Akins PT, Hsu CY. Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury. J Neurotrauma 1995, 12: 843–852.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 1999

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  • James J. Vornov

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