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Calcium, energy metabolism and the development of selective neuronal loss following short-term cerebral ischemia

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Abstract

Short-term cerebral ischemia results in the delayed loss of specific neuronal subpopulations. This review discusses changes in energy metabolism and Ca2+ distribution during ischemia and recirculation and considers the possible contribution of these changes to the development of selective neuronal loss. Severe ischemia results in a rapid decline of ATP content and a subsequent large movement of Ca2+ from the extracellular to the intracellular space. Similar changes are seen in tissue subregions containing neurons destined to die and those areas largely resistant to short-term ischemia, although differences have been observed in Ca2+ uptake between individual neurons. The large accumulation of intracellular Ca2+ is widely considered as a critical initiating event in the development of neuronal loss but, as yet, definitive evidence has not been obtained. The increased intracellular Ca2+ content activates a number of additional processes including lipolysis of phospholipids and degradation or inactivation of some specific proteins, all of which could contribute to altered function on restoration of blood flow to the brain. Reperfusion results in a rapid recovery of ATP production. Cytoplasmic Ca2+ concentration is also restored during early recirculation as a result of both removal to the extracellular space and uptake into mitochondria. Within a few hours of recirculation, subtle increases in intracellular Ca2+ and a reduced capacity for mitochondrial respiration have been detected in some ischemia-susceptible regions. Both of these changes could potentially contribute to the development of neuronal loss. More pronounced alterations in Ca2+ homeostasis, resulting in a second period of increased mitochondrial Ca2+, develop with further recirculation in ischemia-susceptible regions. The available evidence suggests that these increases in Ca2+, although developing late, are likely to precede the irreversible loss of neuronal function and may be a necessary contributor to the final stages of this process.

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References

  • Abe, K., Kogure, K., Yamamoto, H., Imazawa, M., and Miyamoto, K. (1987). Mechanisms of arachidonic acid liberation during ischemia in gerbil cerebral cortex.J. Neurochem. 48:503–509.

    Google Scholar 

  • Albers, G.W., Goldberg, M.P., and Choi, D.W. (1992). Do NMDA antagonists prevent neuronal injury? Yes.Ann. Neurol. 49:418–420.

    Google Scholar 

  • Alps, B.J. (1992). Drugs acting on calcium channels: potential treatment for ischaemic stroke.Brit. J. Clin. Pharmacol. 34:199–206.

    Google Scholar 

  • Alps, B.J., and Hass, W.K. (1987). The potential beneficial effect of nicardipine in a rat model of transient forebrain ischemia.Neurology 37:809–814.

    Google Scholar 

  • Andiné, P., Jacobson, I., and Hagberg, H. (1988). Calcium uptake evoked by electrical stimulation is enhanced postischemically and precedes delayed neuronal death in CA1 of rat hippocampus: Involvement of N-methyl-D-aspartate receptors.J. Cereb. Blood Flow Metab. 8:799–807.

    Google Scholar 

  • Andiné, P., Jacobson, I., and Hagberg, H. (1992). Enhanced calcium uptake by CA1 pyramidal cell dendrites in the postischemic phase despite subnormal evoked field potentials: Excitatory amino acid receptor dependency and relationship to neuronal damage.J. Cereb. Blood Flow Metab. 12:773–783.

    Google Scholar 

  • Arai, H., Passonneau, J.V., and Lust, W.D. (1986). Energy metabolism in delayed neuronal death of CA1 neurons of the hippocampus following transient ischemia of the gerbil.Metabol. Brain Disease 1:263–278.

    Google Scholar 

  • Aranowski, J., Grotta, J.C., and Waxham, M.N. (1992). Ischemia-induced translocation of Ca2+/calmodulin-dependent protein kinase II: potential role in neuronal damage.J. Neurochem. 58:1743–1753.

    Google Scholar 

  • Aranowski, J., Waxham, M.N. and Grotta, J.C. (1993). Neuronal protection and preservation of calcium/calmodulin-dependent protein kinase II and protein kinase C activity by dextorphan treatment in global ischemia.J. Cereb. Blood Flow Metab. 13:550–557.

    Google Scholar 

  • Astrup, J., Symon, L., Branston, N.M., and Lassen, N.A. (1977). Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia.Stroke 8:51–57.

    Google Scholar 

  • Baker, A.J., Zornow, M.H., Scheller, M.S., Yaksh, T.L., Skilling, S.R., Smullin, D.H.,et al. (1991). Changes in extracellular concentrations of glutamate, aspartate, glycine, dopamine, serotonin, and dopamine metabolites after transient global ischemia in the rabbit brain.J. Neurochem. 57:1370–1379.

    Google Scholar 

  • Bazan, N.G. Jr. (1970). Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain.Biochim. Biophys. Acta 218:1–10.

    Google Scholar 

  • Beal, M.F., Hyman, B.T., and Koroshetz, W. (1993). Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases.Trends Neurosci. 16:125–131.

    Google Scholar 

  • Beck, T., Nuglisch, J., Sauer, D., Bielenberg, G.W., Mennel, H.D., Rossberg, C., and Krieglstein, J. (1988). Effects of flunarizine on postischemic blood flow, energy metabolism and neuronal damage in the rat brain.Eur. J. Pharmacol. 158:271–274.

    Google Scholar 

  • Benveniste, H., and Diemer, H.H. (1988). Early post-ischemic45Ca accumulation in rat dentate hilus.J. Cereb. Blood Flow Metab. 8:713–179.

    Google Scholar 

  • Benveniste, H., Drejer, J., Schousboe, A., and Diemer, N.H. (1984). Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis.J. Neurochem. 43:1369–1374.

    Google Scholar 

  • Benveniste, H., Jørgensen, M.B., Diemer, N.H., and Hansen, A.J. (1988). Calcium accumulation by glutamate receptor activation is involved in hippocampal cell damage after ischemia.Acta Neurol. Scand. 78:529–536.

    Google Scholar 

  • Block, G.A., and Pulsinelli, W.A. (1987). N-methyl-D-aspartate receptor antagonists: Failure to prevent ischemia-induced selective neuronal damage. In Raichle, M.E., and Powers, W.J., (eds),Cerebrovascular Diseases. Raven Press, New York 37–44.

    Google Scholar 

  • Brierley, J.D., and Graham, D.I. (1984). Hypoxia and vascular disorders of the central nervous system. In Adams, J.H., Corsellis, J.A.N. and Duchen, L.W. (Eds.)Greenfield's Neuropathology, Edward Arnold, London, pp 125–126.

    Google Scholar 

  • Brown, A.W., and Brierley, J.B. (1972). Anoxic-ischaemic cell change in the rat brain: Light microscope and fine structural observations.J. Neurol. Sci. 16:59–84.

    Google Scholar 

  • Buchan, A., and Pulsinelli, W.A. (1990). Hypothermia but not theN-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia.J. Neurosci. 10:311–316.

    Google Scholar 

  • Buchan, A.M., Gertler, S.Z., Li, H., Xue, D., Huang, Z., Chaundy, K.E., Barnes, K., and Lesiuk, H.J. (1994). A selective N-type Ca2+-channel blocker prevents CA1 injury 24 h following severe forebrain ischemia and reduces infarction following focal ischemia.J. Cereb. Blood Flow and Metab. 14:903–910.

    Google Scholar 

  • Buchan, A., Li, H., and Pulsinelli, W.A. (1991a). TheN-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats.J. Neurosci. 11:1049–1056.

    Google Scholar 

  • Buchan, A.M., Li, H., Cho, S., and Pulsinelli, W.A. (1991b). Blockade of the AMPA receptor prevents CA1 hippocampal injury following severe but transient forebrain ischemia in adult rats.Neurosci. Lett. 132:255–258.

    Google Scholar 

  • Busto, R., Dietrich, W.D., Globus, M.Y-T., Valdés, I., Scheinberg, P., and Ginsberg, M.D. (1987). Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury.J. Cereb. Blood Flow Metab. 7:729–738.

    Google Scholar 

  • Busto, R., Dietrich, W.D., Globus, M.Y-T., and Ginsberg, M.D. (1989a). Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury.Neurosci. Lett. 101:299–304.

    Google Scholar 

  • Busto, R., Globus, M.Y-T., Dietrich, W.D., Martinez, E., Valdés, I., and Ginsberg, M.D. (1989b). Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain.Stroke 20:904–910.

    Google Scholar 

  • Buzsàki, G., Freund, T.F., Bayardo, F., and Somogyi, P. (1989). Ischemia-induced changes in the electrical activity of the hippocampus.Exp. Brain Res. 78:268–278.

    Google Scholar 

  • Cardell, M., Bingren, H., Wieloch, T., Zivin, J., and Saitoh, T. (1990). Protein kinase C is translocated to cell membranes during cerebral ischemia.Neurosci. Lett. 119:228–232.

    Google Scholar 

  • Cardell, M., Boris-Möller, F. and Wieloch, T. (1991). Hypothermia prevents the ischemia-induced translocation and inhibition of protein kinase C in the rat striatum.J. Neurochem. 57:1814–1817.

    Google Scholar 

  • Cardell, M., Koide, T., and Wieloch, T. (1989). Pyruvate dehydrogenase activity in the rat cerebral cortex following cerebral ischemia.J. Cereb. Blood Flow Metab. 9:350–357.

    Google Scholar 

  • Choi, D.W. (1992). Excitotoxic cell death.J. Neurobiol. 23:1261–1276.

    Google Scholar 

  • Choki, J., Greenberg, J., and Reivich, M. (1983). Regional cerebral glucose metabolism during and after bilateral cerebral ischemia in the gerbil.Stroke 14:568–574.

    Google Scholar 

  • Churn, S.B., Taft, W.C., Billingsley, M.S., Blair, R.E. and DeLorenzo, R.J. (1990). Temperature modulation of ischemic neuronal death and inhibition of calcium/calmodulin-dependent protein kinase II in rat brain.Stroke 21:1715–1721.

    Google Scholar 

  • Clemens, J.A., Saunders, R.D., Ho, P.P., Phebus, L.A., and Panetta, J.A. (1993). The antioxidant LY231617 reduces global ischemic neuronal injury in rats.Stroke 24:716–723.

    Google Scholar 

  • Corbett, D., Evans, S., Thomas, C., Wang, D., and Jonas, R.A. (1990). MK-801 reduced cerebral ischemic injury by inducing hypothermia.Brain Res. 514:300–304.

    Google Scholar 

  • Coyle, J.T., and Puttfarcken, P. (1993). Oxidative stress, glutamate, and neurodegenerative disorders.Science 262:689–695.

    Google Scholar 

  • Cross, A.J., Jones, J.A., Baldwin, H.A., and Green, A.R. (1991). Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil.Br. J. Pharmacol. 104:406–411.

    Google Scholar 

  • Crumrine, R.C., and LaManna, J.C. (1991). Regional cerebral metabolites, blood flow, plasma volume, and mean transit time in total cerebral ischemia in the rat.J. Cereb. Blood Flow Metab. 11:272–282.

    Google Scholar 

  • DeMedio, G., Goracci, G., Horrocks, L., Lazarawicz, J., Mazzari, S., Porcellati, G.,et al. (1980). The effect of transient ischemia on fatty acid and lipid metabolism in the gerbil brain.Ital. J. Biochem. 29:412–432.

    Google Scholar 

  • Deshpande, J.K., and Wieloch, T. (1986). Flunarizine, a calcium entry blocker, ameliorates ischemic brain damage in the rat.Anesthesiology 64:215–224.

    Google Scholar 

  • Deshpande, J.K., Siesjö, B.K., and Wieloch, T. (1987). Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia.J. Cereb. Blood Flow Metab. 7:89–95.

    Google Scholar 

  • Diemer, N.H., and Siemkowicz, E. (1980). Increased 2-deoxyglucose uptake in hippocampus, globus pallidus and substantia nigra after cerebral ischemia.Acta Neurol. Scand. 61:56–63.

    Google Scholar 

  • Dienel, G.A. (1984). Regional accumulation of calcium in postischemic rat brain.J. Neurochem. 43:913–925.

    Google Scholar 

  • Dietrich, W.D., Busto, R., Valdes, I., and Loor, Y. (1990). Effects of normothermic versus mild hyperthermic forebrain ischemia in rats.Stroke 21:1318–1325.

    Google Scholar 

  • Domanska-Janik, K., and Zalewska, T. (1992). Effect of brain ischemia on protein kinase C.J. Neurochem. 5:1432–1439.

    Google Scholar 

  • Dux, E., Mies, G., Hossmann, K-A., and Siklos, L. (1987). Calcium in the mitochondria following brief ischemia of gerbil brain.Neurosci. Lett. 78:295–300.

    Google Scholar 

  • Folbergrová, J., Minamisawa, H., Ekholm, A., and Siesjö, B.K. (1990). Phosphorylasea and labile metabolites during anoxia: Correlation to membrane fluxes of K+ and Ca2+.J. Neurochem. 55:1690–1696.

    Google Scholar 

  • Gill, R., and Woodruff, G.N. (1990). The neuroprotective actions of kynurenic acid and MK-801 in gerbils are synergistic and not related to hypothermia.Eur. J. Pharmacol. 176:143–149.

    Google Scholar 

  • Ginsberg, M.D., Mela, L., Wrobel-Kuhl, K., and Reivich, J. (1977). Mitochondrial metabolism following bilateral cerebral ischemia in the gerbil.Ann. Neurol. 1:519–527.

    Google Scholar 

  • Globus, M.Y-T., Busto, R., Martinez, E., Valdés, I., Dietrich, W.D., and Ginsberg, M.D. (1991). Comparative effect of transient global ischemia on extracellular levels of glutamate, glycine, and gamma-aminobutyric acid in vulnerable and nonvulnerable brain regions in the rat.J. Neurochem. 57:470–478.

    Google Scholar 

  • Gunter, T.E., and Pfeiffer, D.R. (1990). Mechanisms by which mitochondria transport calcium.Am. J. Physiol. 258:C755-C786.

    Google Scholar 

  • Hagberg, H., Lehmann, A., Sandberg, M., Nyström, B., Jacobson, I., and Hamberger, A. (1985). Ischemia-induced shift of inhibitory and excitatory amino acids from intracellular to extracellular compartments.J. Cereb. Blood Flow Metab. 5:413–419.

    Google Scholar 

  • Hansen, A.J., and Zeuthen, T. (1981). Extracellular ion concentrations during depression and ischemia in the rat brain cortex.Acta Physiol. Scand. 113:437–445.

    Google Scholar 

  • Hansen, A.J. (1985). Effects of anoxia on ion distribution in the brain.Physiol. Rev. 65:101–148.

    Google Scholar 

  • Hara, H., Onodera, H., and Kogure, K. (1992). Effects of hyperthermia on the effectiveness of MK-801 treatment in the gerbil hippocampus following transient forebrain ischemia.Brain Res. Bull. 29:659–665.

    Google Scholar 

  • Harris, R.J., and Symon, L. (1984). Extracellular pH, potassium, and calcium activities in progressive ischaemia of rat cortex.J. Cereb. Blood Flow Metab. 4:178–186.

    Google Scholar 

  • Harris, R.J., Symon, L., Branston, N.M., and Bayhan, M. (1981). Changes in extracellular calcium activity in cerebral ischaemia.J. Cereb. Blood Flow Metab. 1:203–209.

    Google Scholar 

  • Héron, A., Lasbennes, F., and Seylaz, J. (1993). Adenosine modulation of amino acid release in rat hippocampus during ischemia and veratridine depolarization.Brain Res. 608:27–32.

    Google Scholar 

  • Hillered, L., and Chan, P.H. (1988). Role of arachidonic acid and other free fatty acids in mitochondria dysfunction in brain ischemia.J. Neurosci. Res. 20:451–456.

    Google Scholar 

  • Hillered, L., and Ernster, L. (1983). Respiratory activity of isolated rat brain mitochondria followingin vitro exposure to oxygen radicals.J. Cereb. Blood Flow Metab. 3:207–214.

    Google Scholar 

  • Hillered, L., Siesjö, B.K., and Arfors, K-E. (1984). Mitochondrial response to transient forebrain ischemia and recirculation in the rat.J. Cereb. Blood Flow Metab. 4:438–446.

    Google Scholar 

  • Hillered, L., Smith, M-L., and Siesjö, B.K. (1985). Lactic acidosis and recovery of mitochondrial function following forebrain ischemia in the rat.J. Cereb. Blood Flow Metab. 5:259–266.

    Google Scholar 

  • Hossmann, K-A., Sakaki, S., and Kimoto, K. (1976). Cerebral uptake of glucose and oxygen in the cat brain after prolonged ischemia.Stroke 7:301–305.

    Google Scholar 

  • Izumiyama, K., Kogure, K., Kataoka, S., and Nagata, T. (1987). Quantitative analysis of glucose after transient ischemia in the gerbil hippocampus by light and electron microscope radioautography.Brain Res. 416:175–179.

    Google Scholar 

  • Johansen, F.F., Zimmer, J., and Diemer, N.H. (1987). Early loss of somatostatin neurons in dentate hilus after cerebral ischaemia in the rat precedes CA-1 pyramidal cell loss.Acta Neuropathol. 73:110–114.

    Google Scholar 

  • Jørgensen, M.B., Wright, D.C., and Diemer, N.H. (1990). Postischemic glucose metabolism is modified in the hippocampal CA1 region depleted of excitatory input or pyramidal cells.J. Cereb. Blood Flow Metab. 10:243–251.

    Google Scholar 

  • Katayama, Y., and Welsh, F.A. (1989). Effect of dichloroacetate on regional energy metabolites and pyruvate dehydrogenase activity during ischemia and reperfusion in gerbil brain.J. Neurochem. 52:1817–1822.

    Google Scholar 

  • Katsura, K., Rodriguez de Turco, E.B., Folbergrová, J., Bazan, N.G., and Siesjö B.K. (1993). Coupling among energy failure, loss of ion homeostasis, and phospholipase A2 and C activation during ischemia.J. Neurochem. 61:1677–1684.

    Google Scholar 

  • Katsura, K., Folbergrová, J., Gido, G., and Siesjo, B.K. (1994). Functional, metabolic and circulatory changes associated with seizure activity in the post-ischemic brain.J. Neurochem. 62:1511–1515.

    Google Scholar 

  • Kauppinen, R.A., McMahon, H.T., and Nicholls, D.G. (1988). Ca2+-dependent and Ca2+-independent glutamate release, energy status and cytosolic free Ca2+ concentration in isolated nerve terminals following metabolic inhibition: possible relevance to hypoglycaemia and anoxia.Neuroscience 27:175–182.

    Google Scholar 

  • Kirino, T. (1982). Delayed neuronal death in the gerbil hippocampus following ischemia.Brain Res. 239:57–69.

    Google Scholar 

  • Kobayashi, M., Lust, W.D., and Passonneau, J.V. (1977). Concentrations of energy metabolites and cyclic nucleotides during and after bilateral ischemia in the gerbil cerebral cortex.J. Neurochem. 29:53–59.

    Google Scholar 

  • Kopf, G.S., Mirvis, D.M., and Myers, R.E. (1975). Central nervous system tolerance to cardiac arrest during profound hypothermia.J. Surg. Res. 18:29–34.

    Google Scholar 

  • Kozuka, M., Smith, M-L., and Siesjö, B.K. (1989). Pre-ischemic hyperglycemia enhances postischemic depression of cerebral metabolic rate.J. Cereb. Blood Flow Metab. 9:478–490.

    Google Scholar 

  • Kramer, R.S., Sanders, A.P., Lesage, A.M., Woodhall, B., and Sealy, W.C. (1968). The effect of profound hypothermia on preservation of cerebral ATP content during circulatory arrest.J. Thorac. Cardiovasc. Surg. 56:699–709.

    Google Scholar 

  • Kristián, T., Katsura, K., and Siesjö, B.K. (1992). The influence of moderate hypothermia on cellular calcium uptake in complete ischaemia: Implications for the excitotoxic hypothesis.Acta Physiol. Scand 146:531–532.

    Google Scholar 

  • Kristián, T., Katsura, K., Gidö, G., and Siesjö, B.K. (1994). The influence of pH on cellular calcium influx during ischemia.Brain Res. 641:295–302.

    Google Scholar 

  • Lanier, W.L., Perkins, W.J., Karlsson, B.R., Milde, J.H., Scheithauer, B.W., Shearman, G.T., and Michenfelder, J.D. (1990). The effects of dizocilpine maleate (MK-801), an antagonist of the N-methyl-D-aspartate receptor, on neurologic recovery and histopathology following complete cerebral ischemia in primates.J. Cereb. Blood Flow Metab. 10:252–261.

    Google Scholar 

  • Lazarewicz, J.W., Strosznajder, J., and Gromek, A. (1972). Effects of ischemia and exogenous fatty acids on the energy metabolism in brain mitochondria.Bull. Acad. Pol. Sci. 20:599–606.

    Google Scholar 

  • Lee, K.S., Frank, S., Vanderklish, D., Arai, A., and Lynch, G. (1991). Inhibition of proteolysis protects hippocampal neurons from ischemia.Proc. Nat. Acad. Sci. 88:7233–7237.

    Google Scholar 

  • Le Peillet, E., Arvin, B., Moncada, C., and Meldrum, B.S. (1992). The non-NMDA antagonists, NBQX and GYKI 52466, protect against cortical and striatal cell loss following transient global ischaemia in the rat.Brain Res. 571:115–120.

    Google Scholar 

  • Li, H., and Buchan, A.M. (1993). Treatment with an AMPA antagonist 12 hours following severe normothermic forebrain ischemia prevents CA1 neuronal injury.J. Cereb. Blood Flow Metab. 13:933–939.

    Google Scholar 

  • Lin, T-A., Zhang, J-P., and Sun, G.Y. (1993). Metabolism of inositol 1,4,5-trisphosphate in mouse brain due to decapitation ischemic insult: effects of acute lithium administration and temporal relationships to diacylglycerols, free fatty acids and energy metabolites.Brain Res. 606:200–206.

    Google Scholar 

  • Louis, J-C., Magal, E., Brixi, A., Steinberg, R., Yavim, E., and Vincendon, G. (1991). Reduction of protein kinase C activity in the adult rat brain following transient forebrain ischemia.Brain Res. 541:171–174.

    Google Scholar 

  • Lowry, O.H., Passonneau, J.V., Hasselberger, F.X., and Schultz, D.W. (1964). Effect of ischemia on known substrates and cofactors of the glycolytic pathway in the brain.J. Biol. Chem. 239:18–30.

    Google Scholar 

  • Lundgren, J., Cardell, M., Wieloch, T., Siesjö, B.K. (1990). Pre-ischemic hyperglycemia and postischemic alteration of rat brain pyruvate dehydrogenase activity.J. Cereb. Blood Flow Metab. 10:536–541.

    Google Scholar 

  • Lust, W.D., Arai, H., Yasumoto, Y., Whittingham, T.S., Djuricic, B., Mrsulja, B.B., and Passonneau J.V. (1985). Ischemic encephalopathy. InCerebral Energy Metabolism and Metabolic Encephalopathy, McCandless D.W. (Ed.) Plenum Press, New York pp 74–117.

    Google Scholar 

  • Marie, C., Bralet, A.-M., and Bralet, J. (1987). Protective action of 1,3-butanediol in cerebral ischemia. A neurologic, histologic, and metabolic study.J. Cereb. Blood Flow Metab. 7: 794–800.

    Google Scholar 

  • Marshall, S.B., Owens, J.C., and Swan, H. (1956). Temporary circulatory occlusion to the brain of the hypothermic dog.Arch. Surg. 72:98–106.

    Google Scholar 

  • Martins, E., Inamura, K., Themner, K., Malmqvist, K.G. and Siesjö, B.K. (1988). Accumulation of calcium and loss of potassium in the hippocampus following transient cerebral ischemia: A proton microprobe study.J. Cereb. Blood Flow Metab. 8:531–538.

    Google Scholar 

  • McCormack, J.G., and Denton R.M. (1993). Mitochondrial Ca2+ transport and the role of intramitochondrial Ca2+ metabolism in the regulation of energy metabolism.Dev. Neurosci. 15:165–173.

    Google Scholar 

  • Michenfelder, J.D., and Milde, J.H. (1990). Postischemic canine cerebral blood flow appears to be determined by cerebral metabolic needs.J. Cereb. Blood Flow Metab. 10:71–76.

    Google Scholar 

  • Mies, G., Paschen, W., and Hossmann, K-A. (1990). 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. 10:638–645.

    Google Scholar 

  • Minamisawa, H., Nordstrom, C.H., Smith, M-L., and Siesjö, B.K. (1990a). The influence of mild body and brain hypothermia on ischemic brain damage.J. Cereb. Blood Flow Metab. 10:365–374.

    Google Scholar 

  • Minamisawa, H., Smith, M.-L., and Siesjö, B.K. (1990b). The effect of mild hyperthermia and hypothermia on brain damage following 5, 10 and 15 minutes of forebrain ischemia.Ann. Neurol. 28:26–33.

    Google Scholar 

  • Mitani, A., and Kataoka, K. (1991). Critical levels of extracellular glutamate mediating gerbil hippocampal delayed neuronal death during hypothermia: Brain microdialysis study.Neuroscience 42:661–670.

    Google Scholar 

  • Mitani, A., Andou, Y., and Kataoka, K. (1992). Selective vulnerability of hippocampal CA1 neurons cannot be explained in terms of an increase in glutamate concentration during ischemia in the gerbil: brain microdialysis study.Neuroscience 49:307–313.

    Google Scholar 

  • Mitani, A., Andou, Y., Matsuda, S., Arai, T., Sakanaka, M., and Kataoka, K. (1994). Origin of ischemia-induced glutamate efflux in the CA1 field of the gerbil hippocampus: anin vivo brain microdialysis study.J. Neurochem. 63:2152–2164.

    Google Scholar 

  • Miyazaki, S., Katayama, Y., Furuichi, M., Kano, T., Yoshino, A., and Tsubokawa, T. (1994). N-methyl-D-aspartate receptor-mediated prolonged afterdischarges of CA1 pyramidal cells following transient cerebral ischemia in the rat hippocampusin vivo.Brain Res. 657:325–329.

    Google Scholar 

  • Morioka, M., Fukunaga, K., Yasugawa, S., Nagahiro, S., Ushio, Y., and Miyamoto, E. (1992). Regional and temporal alterations in Ca2+/calmodulin-dependent protein kinase II and calcineurin in the hippocampus of rat brain after transient forebrain ischemia.J. Neurochem. 58:1798–1809.

    Google Scholar 

  • Murase, K., Kato, H., and Kogure, K. (1993). Limited but evident protective effects of MK-801 and pentobarbital on neuronal damage following forebrain ischemia in the gerbil under normothermic conditions.Neurosci. Lett. 149:229–232.

    Google Scholar 

  • Nakahara, I., Kikuchi, H., Taki, W., Nishi, S., Kito, M., Yonekawa, Y.,et al. (1992). Changes in major phospholipids of mitochondria during postischemic reperfusion in rat brain.J. Neurosurg 76:244–250.

    Google Scholar 

  • Nakamura, K., Hatakeyama, T., Furuta, S., and Sakaki, S. (1993). The role of Ca2+ in the pathogenesis of delayed neuronal death after brief forebrain ischemia in gerbils.Brain Res. 181–192.

  • Nakanishi, S. (1992). Molecular diversity of glutamate receptors and implications for brain functions.Sicence 258:597–603.

    Google Scholar 

  • Nellgård, B., and Wieloch, T. (1992). Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe cerebral ischemia.J. Cereb. Blood Flow Metab. 12:2–11.

    Google Scholar 

  • Nishijima, M.K., Koehler, R.C., Hum, P.D., Eleff, S.M., Norris, S., Jacobus, W.E., and Traystman, R.E. (1989). Postischemic recovery rate of cerebral ATP phosphocreatine, pH, and evoked potentials.Am. J. Physiol. 257:H1860-H1870.

    Google Scholar 

  • Nowak, T.S. Jr., Fried, R.L., Lust, W.D., and Passonneau, J.V. (1985). Changes in brain energy metabolism and protein synthesis following transient bilateral ischemia in the gerbil.J. Neurochem. 44:487–494.

    Google Scholar 

  • Nuglisch, J., Karkoutly, C., Mennel, H.D., Rossberg, C., and Krieglstein, J. (1990). Protective effect of nimodipine against ischemic neuronal damage in rat hippocampus without changing postischemic cerebral blood flow.J. Cereb. Blood Flow Metab. 10:654–659.

    Google Scholar 

  • Ohta, S., Smith, M-L., and Siesjö, B.K. (1991). The effect of a dihydropyridine calcium antagonist (isaprine) on selective neuronal necrosis.J. Neurol. Sci. 103:109–115.

    Google Scholar 

  • Onodera, H., Iijima, K., and Kogure, K. (1986). Mononucleotide metabolism in the rat brain after transient ischemia.J. Neurochem. 46:1704–1710.

    Google Scholar 

  • Ozawa, K., Seta, K., Takeda, H., Ando, K., Handa, H., and Araki, C. (1966). On the isolation of mitochondria with high respiratory control from rat brain.J. Biochem. (Tokyo)59:501–510.

    Google Scholar 

  • Ozawa, K., Seta, K., Araki, H., and Handa, H. (1967). The effect of ischemia on mitochondrial metabolism.J. Biochem. (Tokyo)61:512–514.

    Google Scholar 

  • Pahlmark, K., Folbergrová, J., Smith, M-L., and Siesjö, B.K. (1993). Effects of dimethylthiourea on selective neuronal vulnerability in forebrain ischemia in rats.Stroke 24:731–737.

    Google Scholar 

  • Pellegrini-Giampietro, D.E., Zukin, R.S., Bennett, M.V.L., Cho, S., and Pulsinelli, W.A. (1992). Switch in glutamate receptor subunit gene expression in CA1 subfield of hippocampus following global ischemia in rats.Proc. Natl. Acad. Sci. USA 89:10499–10503.

    Google Scholar 

  • Pellegrini-Giampietro, D.E., Pulsinelli, W.A., and Zukin, R.S. (1994). NMDA and non-NMDA receptor gene expression following global brain ischemia in rats: Effect of NMDA and non-NMDA receptor antagonists.J. Neurochem. 62:1067–1073.

    Google Scholar 

  • Petito, C.K., Feldmann, E., Pulsinelli, W.A., and Plum, F. (1987). Delayed hippocampal damage in humans following cardiorespiratory arrest.Neurology 37:1281–1286.

    Google Scholar 

  • Poignet, H., Beaughard, M., Lecoin, G., and Massingham, R. (1989). Functional, behavioral, and histological changes induced by transient global cerebral ischemia in rats: Effects of cinnarizine and flunarizine.J. Cereb. Blood Flow Metab. 9:646–654.

    Google Scholar 

  • Pulsinelli, W. (1992). Pathophysiology of acute ischaemic stroke.Lancet 339:533–536.

    Google Scholar 

  • Pulsinelli, W.A., and Brierley, J.B. (1979). A new model of bilateral hemispheric ischemia in the unanaesthetized rat.Stroke 10:267–272.

    Google Scholar 

  • Pulsinelli, W.A., and Duffy, T.E. (1983). Regional energy balance in rat brain after transient forebrain ischemia.J. Neurochem. 40:1500–1503.

    Google Scholar 

  • Pulsinelli, W.A., Brierley, J.B., and Plum, F. (1982a). Temporal profile of neuronal damage in a model of transient forebrain ischemia.Ann. Neurol. 11:491–498.

    Google Scholar 

  • Pulsinelli, W.A., Levy, D.E., and Duffy, T.E. (1982b). Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia.Ann. Neurol. 11:499–509.

    Google Scholar 

  • Rami, A., and Krieglstein, J. (1993). Protective effects of calpain inhibitors against neuronal damage caused by cytotoxic hypoxiain vitro and ischemiain vivo.

  • Rehncrona, S., Mela, L., and Siesjö, B.K. (1979). Recovery of brain mitochondrial function in the rat after complete and incomplete cerebral ischemia.Stroke 10:437–446.

    Google Scholar 

  • Rehncrona, S., Westerberg, E., Akesson, B., and Siesjö, B.K. (1982). Brain cortical fatty acids and phospholipids during and following complete and severe incomplete ischemia.J. Neurochem. 38:84–93.

    Google Scholar 

  • Rischke, R., and Krieglstein, J. (1991). Postischemic neuronal damage causes astroglial activation and increase in local cerebral glucose utilization of rat hippocampus.J. Cereb. Blood Flow Metab. 11:106–113.

    Google Scholar 

  • Roberts-Lewis, J.M., Savage, M.J., Marcus, V.R., Pinsker, L.R., and Simon, R. (1994). Immunolocalization of calpain I-mediated spectrin degradation to vulnerable neurons in the ischemic gerbil brain.J. Neurosci. 14:3934–3944.

    Google Scholar 

  • Rod, M.R., and Auer, R.N. (1992). Combination therapy with nimodipine and dizocilpine in a rat model of transient forebrain ischemia.Stroke 23:725–732.

    Google Scholar 

  • Rosenthal, R.E., Hamud, E., Fiskum, G., Varghese, P.J., and Sharpe, S. (1987). Cerebral ischemia and reperfusion: Prevention of brain mitochondrial injury by lidoflazine.J. Cereb. Blood Flow Metab. 7:752–758.

    Google Scholar 

  • Schmidt-Kastner, R., and Freund, T.F. (1991). Selective vulnerability of the hippocampus in brain ischemia.Neuroscience 40:599–636.

    Google Scholar 

  • Sciamanna, M.A., Zinkel, J., Fabi, A.Y., and Lee, C.P. (1992). Ischemic injury to rat forebrain mitochondria and cellular calcium homeostasis.Biochim. Biophys. Acta 1134:223–232.

    Google Scholar 

  • Sciamanna, M.A., and Lee, C.P. (1993). Ischemia/reperfusion-induced injury of forebrain mitochondria and protection by ascorbate.Arch. Biochem. Biophys. 305:215–224.

    Google Scholar 

  • Seubert, P., Lee, K., and Lynch, G. (1989). Ischemia triggers NMDA receptor-linked cytoskeletal proteolysis in hippocampus.Brain Res. 492:366–370.

    Google Scholar 

  • Sheardown, M.J., Nielsen, E.O., Hansen, A.J., Jacobsen, P., and Honoré, T. (1990). 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline: A neuroprotectant for cerebral ischemia.Science 247:571–574.

    Google Scholar 

  • Sheardown, M.J., Suzdak, P.D., and Nordholm, L. (1993). AMPA, but not NMDA, receptor antagonism is neuroprotective in gerbil global ischaemia, even when delayed 24 h.Eur. J. Pharmacol. 236:347–353.

    Google Scholar 

  • Siemkowicz, E., and Hansen, A.J. (1981). Brain extracellular ion composition and EEG activity following 10 minutes ischemia in normo- and hyperglycemic rats.Stroke 12:236–240.

    Google Scholar 

  • Siesjö, B.K. (1992a). Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology.J. Neurosurg. 77:169–184.

    Google Scholar 

  • Siesjö, B.K. (1992b). Pathophysiology and treatment of focal cerebral ischemia. Part II: Mechanisms of damage and treatment.J. Neurosurg. 77:337–354.

    Google Scholar 

  • Siesjö, B.K., and Bengtsson, F. (1989). Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia and spreading depression: A unifying hypothesis.J. Cereb. Blood Flow Metab. 9:127–140.

    Google Scholar 

  • Siesjö, B.K., Katsura, K., Pahlmark, K., and Smith, M-L. (1992). The multiple causes of ischemic brain damage: a speculative synthesis. In Krieglstein, J. and Oberpichler-Schwent, H. (eds.),Pharmacology of Cerebral Ischemia, 1992 Wissen-Schaftliche Verlagsgellschaft, Stuttgart pp 511–525.

    Google Scholar 

  • Silver, I.A., and Erecinska, M. (1990). Intracellular and extracellular changes of [Ca2+] in hypoxia and ischemia in rat brainin vivo.J. Gen. Physiol. 95:837–866.

    Google Scholar 

  • Silver, I.A., and Erecinska, M. (1992). Ion homeostasis in rat brainin vivo: Intra- and extracellular [Ca2+] and [H+] in the hippocampus during recovery from short-term, transient ischemia.J. Cereb. Blood Flow Metab. 12:759–772.

    Google Scholar 

  • Simon, R.P., Swan, J.H., Griffiths, T., and Meldrum, B.S. (1984). Blockade ofN-methyl-D-aspartate receptors may protect against ischemic damage in the brain.Science 226:850–852.

    Google Scholar 

  • Simpson, R.E., O'Regan, M.H., Perkins, L.M., and Phillis, J.W. (1992). Excitatory transmitter amino acid release from the ischemic rat cerebral cortex: Effects of adenosine receptor agonists and antagonists.J. Neurochem. 58:1683–1690.

    Google Scholar 

  • Sims, N.R. (1991). Selective impairment of respiration in mitochondria isolated from brain subregions following transient forebrain ischemia in the rat.J. Neurochem. 56:1836–1844.

    Google Scholar 

  • Sims, N.R., and Pulsinelli, W.A. (1987). Altered mitochondrial respiration in selectively vulnerable brain subregions following transient forebrain ischemia in the rat.J. Neurochem. 49:1367–1374.

    Google Scholar 

  • Sims, N.R., and Heward, S.L. (1994). Delayed treatment with 1,3-butanediol reduces loss of CA1 neurons in the hippocampus of rats following brief forebrain ischaemia.Brain Res. 662:216–222.

    Google Scholar 

  • Sims, N.R., Finegan, J.M., and Blass, J.P. (1986). Effects of postdecapitative ischaemia on mitochondrial respiration in brain tissue homogenates.J. Neurochem. 47:506–511.

    Google Scholar 

  • Smith, M.L., Auer, R.N., and Siesjö, B.K. (1984). The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia.Acta Neuropathol. (Berl)64:319–332.

    Google Scholar 

  • Snyder, J.V., Nemoto, E.M., Carroll, R.G., and Safar, P. (1975). Global ischemia in dogs: intracranial pressures, brain blood flow and metabolism.Stroke 6:21–27.

    Google Scholar 

  • Steen, P.A., Milde, J.H., and Michenfelder, J.D. (1978). Cerebral metabolic and vascular effects of barbiturate therapy following complete global ischemia.J. Neurochem. 31:1317–1324.

    Google Scholar 

  • Sun, D., and Gilboe, D.D. (1994). Ischemia-induced changes in cerebral mitochondrial free fatty acids, phospholipids, and respiration in the rat.J. Neurochem. 62:1921–1928.

    Google Scholar 

  • Suzuki, R., Yamaguchi, T., Kirino, T., Orzi, F., and Klatzo I. (1983). The effects of 5-minute ischemia in mongolian gerbils: I. Blood-brain barrier, cerebral blood flow, and local cerebral glucose utilization changes.Acta Neuropathol. (Berl)60:207–216.

    Google Scholar 

  • Swan, J.H., and Meldrum, B.S. (1990). Protection by NMDA antagonists against selective cell loss following transient ischaemia.J. Cereb. Blood Flow Metab. 10:343–351.

    Google Scholar 

  • Takeuchi, Y., Morii, H., Tamura, M., Hayaishi, O., and Watanabe, Y. (1991). A possible mechanism of mitochondrial dysfunction during cerebral ischemia: Inhibition of mitochondrial respiration activity by arachidonic acid.Arch. Biochem. Biophys. 289:33–38.

    Google Scholar 

  • Urban, L., Neill, K.H., Crain, B.J., Nadler, J.V., and Somjen, G.G. (1989). Postischemic synaptic physiology in area CA1 of the gerbil hippocampus studiedin vitro.J. Neurosci. 9:3966–3975.

    Google Scholar 

  • Valentino, K., Newcomb, R., Gadbois, T., Singh, T., Bowersox, S., Bitner, S.,et al. (1993). A selective N-type calcium channel antagonist protects against neuronal loss after global cerebral ischemia.Proc. Natl. Acad. Sci. 90:7894–7897.

    Google Scholar 

  • Welsh, F.A., Sims, R.E., and Harris, V.A. (1990). Mild hypothermia prevents ischemic injury in gerbil hippocampus.J. Cereb. Blood Flow Metab. 10:557–563.

    Google Scholar 

  • Welsh, M., Nuglisch, J., and Krieglstein, J. (1990). Neuroprotective effect of nimodipine is not mediated by increased cerebral blood flow after transient forebrain ischemia in rats.Stroke 21: Suppl., IV105-IV107.

    Google Scholar 

  • Wieloch, T., Cardell, M., Bingren, H., Zivin, J., and Saitoh, T. (1991). Changes in the activity of protein kinase C and the differential subcellular redistribution of its isozymes in the rat striatum during and following transient forebrain ischemia.J. Neurochem. 56:1227–1235.

    Google Scholar 

  • Yamamoto, H., Fukunaga, K., Lee, K., and Soderling, T.R. (1992). Ischemia induced loss of brain calcium/calmodulin-dependent protein kinase II.J. Neurochem. 58:1110–1117.

    Google Scholar 

  • Yoshida, S., Inoh, S., Asano, T., Sano, K., Kubota, M., Shimazaki, H., and Ueta, N. (1980). Effect of transient ischemia on free fatty acids and phospholipids in the gerbil brain.J. Neurosurg. 53:323–331.

    Google Scholar 

  • Yoshida, S., Busto, R., Watson, B.D., Kogure, K., and Ginsberg, M.D. (1982). Influence of transient ischemia on lipid-soluble antioxidants, free fatty acids and energy metabolites in rat brain.Brain Res. 245:307–316.

    Google Scholar 

  • Zaidan, E., and Sims, N.R. (1990). Alterations in the production of14CO2 and [14C] acetylcholine from [U-14C] glucose in brain subregions following transient forebrain ischemia in the rat.J. Neurochem. 55:1882–1889.

    Google Scholar 

  • Zaidan, E., and Sims, N.R. (1993). Selective reductions in the activity of the pyruvate dehydrogenase complex in mitochondria isolated from brain subregions following forebrain ischemia in rats.J. Cereb. Blood Flow Metab. 13:98–104.

    Google Scholar 

  • Zaidan, E., and Sims, N.R. (1994). The calcium content of mitochondria from brain subregions following short-term forebrain ischemia and recirculation in the rat.J. Neurochem. 63:1812–1819. A0431005 00002 CS-SPJRNPDF [HEADSUP]

    Google Scholar 

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  1. Department of Medical Biochemistry, School of Medicine, Flinders University of South Australia, G.P.O. Box 2100, 5001, Adelaide, South Australia, Australia

    Neil R. Sims

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Sims, N.R. Calcium, energy metabolism and the development of selective neuronal loss following short-term cerebral ischemia. Metab Brain Dis 10, 191–217 (1995). https://doi.org/10.1007/BF02081026

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