Abstract
The high energy requirements compared to the low energy reserves render the brain particularly vulnerable to hypoxic conditions. To protect the brain against hypoxia, powerful cerebrovascular regulatory systems assure an increase of blood flow to compensate for the reduced arterial oxygen content. This system is so efficient that during respiratory hypoxia brain metabolism is little disturbed as long as cardiac function does not fail. Only with declining blood pressure cerebral blood flow also declines, and brain energy metabolism rapidly collapses.
Under experimental conditions, oxygen delivery to the brain is therefore more readily impaired by reducing blood flow in the first place, e.g. by occluding a supplying brain artery. With declining flow values metabolic and electrophysiological functions stepwise disappear according to the threshold concept of brain ischemia: first the most complex functions such as protein synthesis or the spontaneous electrical activity are suppressed, followed at much lower flow values by the breakdown of energy state and the depolarisation of cell membranes. The tissue supplied at a flow range between functional impairment and the suppression of vital functions has been called penumbra to characterize its potential revivability, provided oxygen supply is resumed.
Besides its immediate effects, hypoxia causes delayed functional and metabolic disturbances which may even progress to cell death. The brain regions most sensitive to this type of injury are parts of the hippocampus, the dorsolateral caudate nucleus and the reticular nucleus of thalamus. Mechanisms contributing to delayed injury include coupling disturbances between brain function and blood flow, glutamate-propagated functional disturbances such as spreading depression, free radical mediated changes, disturbances of signal transduction pathways and complex abnormalities in the genomic expression patterns leading, in the worst case, to programmed cell death. A key mechanism in this complex stress response is the disturbed calcium homoeostasis of the endoplasmic reticulum which, among others, leads to the inhibition of protein synthesis at the translational level. Modulations of these pathological interactions are a major area of current ischemia research.
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References
Abe K, Yoshidomi M, Kogure K. Arachidonic acid metabolism in ischemic neuronal damage. Ann NY Acad Sci 559:259–268, 1989.
Allen KL, Busza AL, Proctor E, King MD, Williams SR, Crockard HA, Gadian DG. Controllable graded cerebral ischaemia in the gerbil - Studies of cerebral blood flow and energy metabolism by hydrogen clearance and 31P NMR spectroscopy. NMR Biomed 6:181–186, 1993.
Astrup J, Symon L, Branston NM, Lassen NA. Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke 8:51–57, 1977.
Astrup J, Symon L, Branston NM, Lassen NA. Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke 8:51–57, 1977.
Astrup J, Symon L, Siesjö BK. Thresholds in cerebral ischemia - The ischemic penumbra. Stroke 12:723–725, 1981.
Back T, Hoehn-Berlage M, Kohno K, Hossmann K-A. Diffusion nuclear magnetic resonance imaging in experimental stroke. Correlation with cerebral metabolites. Stroke 25:494–500, 1994.
Back T, Kohno K, Hossmann K-A. Cortical negative DC deflections following middle cerebral artery occlusion and KCI-induced spreading depression - Effect on blood flow, tissue oxygenation, and electroencephalogram. J Cereb Blood Flow Metab 14:12–19, 1994.
Benveniste H, Hedlund LW, Johnson GA. Mechanism of detection of acute cerebral ischemia in rats by diffusion-weighted magnetic-resonance microscopy. Stroke 23:746–754,1992.
Branston NM, Strong AJ, Symon L. Extracellular potassium activity, evoked potential and tissue blood flow. Relationships during progressive ischaemia in baboon cerebral cortex. J Neurol Sci 32:305–321, 1977.
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 45:195–208, 1974.
Busza AL, Allen KL, King MD, van den Bruggen N, Williams SR, Gadian DG. Can diffusion-weighted magnetic-resonance-imaging detect critical cerebral blood-flow thresholds and energy failure during cerebral-ischemia? Eur J Neurosci 1992:242, 1992.
Choi DW. Glutamate receptors and the induction of excitotoxic neuronal death, Elsevier Science Publ B V, Amsterdam, 1994.
Choi DW. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 58:293–297, 1985.
Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu. Rev. Neurosci. 13:171–182, 1990.
Degracia DJ, Neumar RW, White BC, Krause GS. Global brain ischemia and reperfusion: Modifications in eukaryotic initiation factors associated with inhibition of translation initiation. J Neurochem 67:2005–2012, 1996.
Djuricic B, Röhn G, Paschen W, Hossmann K-A. Protein synthesis in the hippocampal slice: Transient inhibition by glutamate and lasting inhibition by ischemia. Metab Brain Dis 9:235–247, 1994.
Doutheil J, Gissel C, Oschlies U, Hossmann K-A, Paschen W. Relation of neuronal endoplasmic reticulum calcium homeostasis to ribosomal aggregation and protein synthesis - implications for stress-induced suppression of protein synthesis. Brain Res 775:43–51, 1997.
Du C, Hu R, Csernansky CA, Hsu CY, Choi DW. Very delayed infarction after mild focal cerebral ischemia: A role for apoptosis? J Cereb Blood Flow Metab 16:195–201, 1996.
Ferger D, Krieglstein J. Cerebral ischemia: Pharmacological bases of drug therapy. Dementia 7:161–168, 1996.
Fink K, Zhu J, Namura S, Shimizu-Sasamata M, Endres M, Ma J, Dalkara T, Yuan J, Moskowitz MA. Prolonged therapeutic window for ischemic brain damage caused by delayed caspase activation. J Cereb Blood Flow Metab 18:1071–1076, 1998.
Hagberg H, Andersson P, Lacarewicz J, Jacobson I, Butcher S, Sandberg M. Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purines in rat striatum during transient ischemia. J Neurochem 49:227–231, 1987.
Harper AM. Regulation of cerebral circulation. Sci Basis Med Ann Rev 60–81, 1969.
Harris RJ, Symon L. Extracellular pH, potassium, and calcium activities in progressive ischaemia of rat cortex. J Cereb Blood Flow Metab 4:178–186, 1984.
Harris RJ, Symon L, Branston NM, Bayhan M. Changes in extracellular calcium activity in cerebral ischaemia. J Cereb Blood Flow Metab 1:203–209, 1981.
Hata R, Mies G, Wiessner C, Hossmann KA. Differential expression of c-fos and hsp72 mRNA in focal cerebral ischemia of mice. Neuroreport 9:27–32, 1998.
Heiss W-D, Hayakawa T, Waltz AG. Cortical neuronal function during ischemia. Effects of occlusion of one middle cerebral artery on single-unit activity in cats. Arch Neurol 33:813–820, 1976.
Heiss W-D, Rosner G. Functional recovery of cortical neurons as related to degree and duration of ischemia. Ann Neurol 14:294–301, 1983.
Hoehn-Berlage M, Norris DG, Kohno K, Mies G, Leibfritz D, Hossmann K-A. Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: The relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances. J Cereb Blood Flow Metab 15:1002–1011, 1995.
Hossmann K-A. Viability thresholds and the penumbra of focal ischemia. Ann Neurol 36:557–565, 1994.
Hossmann K-A. Reperfusion of the brain after global ischemia - hemodynamic disturbances. Shock 8:95–101, 1997.
Hossmann K-A. Glutamate-mediated injury in focal cerebral ischemia - The excitotoxin hypothesis revised. Brain Pathol 4:23–36, 1994.
Hossmann K-A. Disturbances of cerebral protein synthesis and ischemic cell death. Progr. Brain Res. 96:161–177, 1993.
Hossmann K-A. Periinfarct depolarizations. Cerebrovasc Brain Metab Rev 8:195–208, 1996.
Hossmann K-A, Hoehn-Berlage M. Diffusion and perfusion MR imaging of cerebral ischemia. Cerebrovasc Brain Metab Rev 7:187–217, 1995.
Hossmann K-A, Schmidt-Kastner R, Grosse Ophoff B. Recovery of integrative central nervous function after one hour global cerebro-circulatory arrest in normothermic cat. J Neurology Sci. 77:305–320, 1987.
Hossmann K-A, Schuier FJ. Experimental brain infarcts in cats. I. Pathophysiological observations. Stroke 11:583–592, 1980.
Imdahl A, Hossmann K-A. Morphometric evaluation of post-ischemic capillary perfusion in selectively vulnerable areas of gerbil brain. Acta Neuropathol 69:267–271, 1986.
Ito U, Kirino T, Kuroiwa T, Klatzo I. Maturation phenomenon in cerebral ischemia, Springer, Berlin, 1992.
Johnson JW, Ascher P. Voltage-dependent block by intracellular Mg2+ of N-methyl-Daspartate-activated channels. Biophys J 57:1085–1090, 1990.
Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 54:773–782, 1981.
Kaku DA, Giffard RG, Choi DW. Neuroprotective effects of glutamate antagonists and extracellular acidity. Science 260:1516–1518, 1993.
Kamiya T, Jacewicz M, Pulsinelli WA, Nowak TSJ. CBF thresholds for mRNA and protein synthesis after focal ischemia and the effect of MK-801. J Cereb Blood Flow Metab 15, Supplement 1:1, 1995.
Kirin T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239:57–69, 1982.
Kloiber O, Miyazawa T, Hoehn-Berlage M, Hossmann K-A. Simultaneous 31P NMR-spectroscopy and laser-Doppler flowmetry of rat brain during global-ischemia and reperfusion. NMR Biomed 6:144–152, 1993.
Kogure K, Hossmann K-A, Siesjö BK, Welsh FA. Molecular mechanisms of ischemic brain damage, Elsevier, Amsterdam, 1985.
Kohno K, Hoehn-Berlage M, Mies G, Back T, Hossmann K-A. Relationship between diffusion-weighted magnetic resonance MR images, cerebral blood flow and energy state in experimental brain infarction. Magn Reson Imaging 13:73–80, 1995.
Koistinaho J, Hokfelt T. Altered gene expression in brain ischemia (review). Neuroreport 8:R:1-R 8, 1997.
Kondoh T, Korosue K, Lee SH, Heros RC, Low WC. Evaluation of monoaminergic neurotransmitters in the rat striatum during varied global cerebral ischemia. Neurosurgery 35:278–285, 1994.
Krause GS, Tiffany BR. Suppression of protein synthesis in the reperfused brain. Stroke 24:747–755, 1993.
Kristian T, Siesjö BK. Calcium-related damage in ischemia. Life Sci 59:357–367, 1996.
Lassen NA, Fieschi C, Lenzi GL. Ischemic penumbra and neuronal death: comments on the therapeutic window in acute stroke with particular reference to thrombolytic therapy. Cerebrovasc Dis 1,Supp1.1:32–35, 1991.
Li Y, Chopp M, Powers C, Jiang N. Apoptosis and protein expression after focal cerebral ischemia in rat. Brain Res 765:301–312, 1997.
Mackay KB, Galbraith S, Patel TR, McCulloch J. Kappa receptor agonist (Ci-977) inhibits glutamate release in the focal ischaemic penumbra. J Cereb Blood Flow Metab 15, Suppl. 1:143, 1995.
MacManus JP, Hill IE, Huang ZG, Rasquinha I, Xue D, Buchan AM. DNA damage consistent with apoptosis in transient focal ischaemic neocortex. NeuroReport 5:493–496, 1994.
MacManus JP, Linnik MD. Gene expression induced by cerebral ischemia - an apoptotic perspective (review). J Cereb Blood Flow Metab 17:815–832, 1997.
Massa SM, Swanson RA, Sharp FR. The stress gene response in brain. Cerebrovasc Brain Metab Rev 8:95–158, 1996.
Matsumoto K, Graf R, Rosner G, Shimada N, Heiss W-D. Flow thresholds for extracellular purine catabolite elevation in cat focal ischemia. Brain Res 579:309–314, 1992.
Matsumoto K, Graf R, Rosner G, Taguchi J, Heiss W-D. Elevation of neuroactive substances in the cortex of cats during prolonged focal ischemia. J Cereb Blood Flow Metab 13:586–594, 1993.
Matsuoka Y, Hossmann K-A. Cortical impedance and extracellular volume changes following middle cerebral artery occlusion in cats. J Cereb Blood Flow Metab 2:466–474, 1982.
Matsuoka Y, Hossmann K-A. Brain tissue osmolality after middle cerebral artery occlusion in cats. Exp Neurol 77:599–611, 1982.
Mies G, Auer LM, Ebhardt G, Traupe H, Heiss W-D. Flow and neuronal density in tissue surrounding chronic infarction. Stroke 14:22–27, 1983.
Mies G, Iijima T, Hossmann K-A. Correlation between periinfarct dc shifts and ischemic neuronal damage in rat. NeuroReport 4:709–711, 1993.
Mies G, Ishimaru S, Xie Y, Seo K, Hossmann K-A. Ischemic thresholds of cerebral protein synthesis and energy state following middle cerebral artery occlusion in rat. J Cereb Blood Flow Metab 11:753–761, 1991.
Morawetz RB, Crowell RH, DeGirolami U, Marcoux FW, Jones TH, Halsey JH. Regional cerebral blood flow thresholds during cerebral ischemia. Fed Proc 38:2493–2494, 1979.
Moseley ME, Cohen Y, Mintorovitch J, Chileuitt L, Shimizu H, Kucharczyk J, Wendland MF, Weinstein PR. Early detection of regional cerebral ischemia in cats: comparison of diffusion-and T2-weighted MRI and spectroscopy. Magn Reson Med 14:330–346, 1990.
Nakagomi T, Asai A, Kanemitsu H, Narita K, Kuchino Y, Tamura A, Kirino T. Up-regulation of c-myc gene expression following focal ischemia in the rat brain. Neurol Res 18:559–563, 1996.
Naritomi H, Sasaki M, Kanashiro M, Kitani M, Sawada T. Flow thresholds for cerebral energy disturbance and Na+ pump failure as studied by in vivo 31P and 23 Na nuclear magnetic resonance spectroscopy. J Cereb Blood Flow Metab 8:16–23, 1988.
Nowak TS, Zhou Q, Valentine WJ, Harrub JB, Abe H. Regulation of heat shock genes by ischemia. Stress Proteins 136:173–199, 1999.
Obrenovitch TP, Garofalo O, Harris RJ, Bordi L, Ono M, Momma F, Bachelard HS, Syomon L. Brain tissue concentrations of ATP, phosphocreatine, lactate, and tissue pH in relation to reduced cerebral blood flow following experimental acute middle cerebral artery occlusion. J Cereb Blood Flow Metab 8:866–874, 1988.
Obrenovitch TP, Urenjak J, Richards DA, Ueda Y, Curzon G, Symon L. Extracellular neuroactive amino-acids in the rat striatum during ischemia - comparison between penumbral conditions and ischemia with sustained anoxic depolarization. J Neurochem 61:178–186, 1993.
Paschen W. Disturbances of calcium homeostasis within the endoplasmic reticulum may contribute to the development of ischemic cell damage. Med Hypotheses 47:283–288, 1996.
Paschen W, Linden T, Doutheil J. Effects of transient cerebral ischemia on hsp40 mRNA levels in rat brain. Mol Brain Res 55:341–344, 1998.
Paschen W, Mies G, Hossman K-A. Threshold relationship between cerebral blood-flow, glucose-utilization, and energy metabolites during development of stroke in gerbils. Exp Neurol 117:325–333, 1992.
Prass K, Dirnagl U. Glutamate antagonists in therapy of stroke (review). Restorative Neurology & Neuroscience 13:3–10, 1998.
Pulsinelli WA, Brierley JB, Plum F. Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491–498, 1982.
Schuier FJ, Hossmann K-A. Experimental brain infarcts in cats. II. Ischemic brain edema. Stroke 11:593–601, 1980.
Sharbrough FW, Messick JM, Sundt TM. Correlation of continuous electroencephalograms with cerebral blood flow measurements during carotid endarterectomy. Stroke 4:674–683, 1973.
Shimada N, Graf R, Rosner G, Heiss W-D. Differences in ischemia-induced accumulation of amino acids in the cat cortex. Stroke 21:1445–1451, 1990.
Shimada N, Graf R, Rosner G, Wakayama A, George CP, Heiss W-D. Ischemic flow threshold for extracellular glutamate increase in cat cortex. J Cereb Blood Flow Metab 9:603–606, 1989.
Siesjö BK, Siesjö P. Mechanisms of secondary brain injury. Europ. J. of Anaesthesiol. 13:247–268, 1996.
Spielmeyer W. Zur Pathogenese örtlich elektiver Gehirnveränderungen. Z. ges. Neurol. and Psych. 99:756–776, 1925.
Suzuki R, Yamaguchi T, Li C-L, Klatzo I. The effects of 5-minute ischemia in mongolian gerbils: II. Changes of spontaneous neuronal activity in cerebral cortex and CA 1 sector of hippocampus. Acta Neuropathol 60:217–222, 1984.
Symon L, Branston NM, Strong M., Hope TD. The concepts of thresholds of ischaemia in relation to brain structure and function. J Clin Path 30, Suppl.11:149–154, 1977.
Takagi K, Ginsberg MD, Globus MYT, Dietrich WD, Martinez E, Kraydieh S, Busto R. Changes in amino acid neurotransmitters and cerebral blood flow in the ischemic penumbral region following middle cerebral artery occlusion in the rat - correlation with histopathology. J Cereb Blood Flow Metab 13:575–585, 1993.
Takagi K, Ginsberg MD, Globus MYT, Martinez E, Busto R. Effect of hyperthermia on glutamate release in ischemic penumbra after middle cerebral artery occlusion in rats. American Journal of Physiology - Heart and Circulatory Physiology 36:H1770–H1776, 1994.
Tamura A, Graham DI, McCulloch J, Teasdale GM. Focal cerebral ischaemia in the rat: 2. Regional cerebral blood flow determined by (14C)iodoantipyrine autoradiography following middle cerebral artery occlusion. J Cereb Blood Flow Metab 1:61–69, 1981.
White RI, Austin PE, Austin JC, Taslitz N, Takoaka Y. Recovery of the subhuman primate after deep cerebral hypothermia and prolonged ischaemia. J Resuscitation 2:117–122,1973.
Widmann R, Kuroiwa T, Bonnekoh P, Hossmann K-A. (14C)leucine incorporation into brain proteins in gerbils after transient ischemia: relationship to selective vulnerability of hippocampus. J Neurochem 56:789–796, 1991.
Zhang SX, Zhang JP, Fletcher DL, Zoeller RT, Sun GY. In situ hybridization of mRNA expression for IP3 receptor and IP3–3-kinase in rat brain after transient focal cerebral ischemia. Mol Brain Res 32:252–260, 1995.
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Hossmann, KA. (1999). The Hypoxic Brain. In: Roach, R.C., Wagner, P.D., Hackett, P.H. (eds) Hypoxia. Advances in Experimental Medicine and Biology, vol 474. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4711-2_14
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