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Brain vulnerability and viability after ischaemia

Abstract

The susceptibility of the brain to ischaemic injury dramatically limits its viability following interruptions in blood flow. However, data from studies of dissociated cells, tissue specimens, isolated organs and whole bodies have brought into question the temporal limits within which the brain is capable of tolerating prolonged circulatory arrest. This Review assesses cell type-specific mechanisms of global cerebral ischaemia, and examines the circumstances in which the brain exhibits heightened resilience to injury. We suggest strategies for expanding such discoveries to fuel translational research into novel cytoprotective therapies, and describe emerging technologies and experimental concepts. By doing so, we propose a new multimodal framework to investigate brain resuscitation following extended periods of circulatory arrest.

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Fig. 1: Cerebral microvasculature structure, function and dysfunction.
Fig. 2: Excitatory neurotransmission and glutamate-mediated excitotoxicity.
Fig. 3: Neuron–microglial cell interplay and pro-inflammatory signalling.
Fig. 4: Mitochondrial function and dysfunction during ischaemia–reperfusion injury.
Fig. 5: A combined therapeutic strategy for reducing global ischaemic injury.

References

  1. Lowry, O. H., Passonneau, J. V., Hasselberger, F. X. & Schulz, D. W. Effect of ischemia on known substrates and cofactors of the glycolytic pathway in brain. J. Biol. Chem. 239, 18–30 (1964). This is one of the first seminal articles describing the effects of global ischaemia on metabolic compounds in the brain using the decapitation model.

    CAS  PubMed  Article  Google Scholar 

  2. Virani, S. S. et al. Heart disease and stroke statistics-2020 update: a report from the American Heart Association. Circulation 141, e139–e596 (2020).

    PubMed  Google Scholar 

  3. Weisfeldt, M. L. & Becker, L. B. Resuscitation after cardiac arrest: a 3-phase time-sensitive model. JAMA 288, 3035–3038 (2002).

    PubMed  Article  Google Scholar 

  4. Moulaert, V. R., Verbunt, J. A., van Heugten, C. M. & Wade, D. T. Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review. Resuscitation 80, 297–305 (2009).

    PubMed  Article  Google Scholar 

  5. Wagner, S. R. T. & Lanier, W. L. Metabolism of glucose, glycogen, and high-energy phosphates during complete cerebral ischemia. A comparison of normoglycemic, chronically hyperglycemic diabetic, and acutely hyperglycemic nondiabetic rats. Anesthesiology 81, 1516–1526 (1994).

    CAS  PubMed  Article  Google Scholar 

  6. Hossmann, K. A. & Kleihues, P. Reversibility of ischemic brain damage. Arch. Neurol. 29, 375–384 (1973).

    CAS  PubMed  Article  Google Scholar 

  7. Kirino, T. & Sano, K. Selective vulnerability in the gerbil hippocampus following transient ischemia. Acta Neuropathol. 62, 201–208 (1984). This article describes the selective vulnerability of the hippocampus to brief periods of forebrain ischaemia and details the time course of delayed neuronal death in the CA1 region.

    CAS  PubMed  Article  Google Scholar 

  8. Jennings, R. B., Murry, C. E., Steenbergen, C. Jr. & Reimer, K. A. Development of cell injury in sustained acute ischemia. Circulation 82, II2–12 (1990).

    CAS  PubMed  Google Scholar 

  9. Parekh, D. J. et al. Tolerance of the human kidney to isolated controlled ischemia. J. Am. Soc. Nephrol. 24, 506–517 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Lassen, N. A. Normal average value of cerebral blood flow in younger adults is 50 ml/100 g/min. J. Cereb. Blood Flow. Metab. 5, 347–349 (1985).

    CAS  PubMed  Article  Google Scholar 

  11. Vavilala, M. S., Lee, L. A. & Lam, A. M. Cerebral blood flow and vascular physiology. Anesthesiol. Clin. North. Am. 20, 247–264 (2002).

    PubMed  Article  Google Scholar 

  12. Dienel, G. A. Brain glucose metabolism: integration of energetics with function. Physiol. Rev. 99, 949–1045 (2019).

    CAS  PubMed  Article  Google Scholar 

  13. Zhu, X. H. et al. Quantitative imaging of energy expenditure in human brain. Neuroimage 60, 2107–2117 (2012).

    PubMed  Article  Google Scholar 

  14. Attwell, D. & Laughlin, S. B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow. Metab. 21, 1133–1145 (2001).

    CAS  PubMed  Article  Google Scholar 

  15. Harris, J. J. & Attwell, D. The energetics of CNS white matter. J. Neurosci. 32, 356–371 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Sundt, T. M. Jr., Sharbrough, F. W., Anderson, R. E. & Michenfelder, J. D. Cerebral blood flow measurements and electroencephalograms during carotid endarterectomy. J. Neurosurg. 41, 310–320 (1974).

    PubMed  Article  Google Scholar 

  17. Branston, N. M., Symon, L., Crockard, H. A. & 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  19. Choi, J. et al. Tissue-specific metabolic profiles after prolonged cardiac arrest reveal brain metabolome dysfunction predominantly after resuscitation. J. Am. Heart Assoc. 8, e012809 (2019).

    PubMed  PubMed Central  Google Scholar 

  20. Ljunggren, B., Norberg, K. & Siesjo, B. K. Influence of tissue acidosis upon restitution of brain energy metabolism following total ischemia. Brain Res. 77, 173–186 (1974).

    CAS  PubMed  Article  Google Scholar 

  21. Kleihues, P., Kobayashi, K. & Hossmann, K. A. Purine nucleotide metabolism in the cat brain after one hour of complete ischemia. J. Neurochem. 23, 417–425 (1974).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  23. Ames, A. III, Wright, R. L., Kowada, M., Thurston, J. M. & Majno, G. Cerebral ischemia. II. The no-reflow phenomenon. Am. J. Pathol. 52, 437–453 (1968). This article details the foundational experiments describing the no-reflow phenomenon and its relationship with increasing periods of global ischaemia.

    PubMed  PubMed Central  Google Scholar 

  24. Fischer, M. & Hossmann, K. A. No-reflow after cardiac arrest. Intensive Care Med. 21, 132–141 (1995).

    CAS  PubMed  Article  Google Scholar 

  25. Ginsberg, M. D. & Myers, R. E. The topography of impaired microvascular perfusion in the primate brain following total circulatory arrest. Neurology 22, 998–1011 (1972).

    CAS  PubMed  Article  Google Scholar 

  26. Kagstrom, E., Smith, M. L. & Siesjo, B. K. Local cerebral blood flow in the recovery period following complete cerebral ischemia in the rat. J. Cereb. Blood Flow. Metab. 3, 170–182 (1983).

    CAS  PubMed  Article  Google Scholar 

  27. Harrison, M. J., Sedal, L., Arnold, J. & Russell, R. W. No-reflow phenomenon in the cerebral circulation of the gerbil. J. Neurol. Neurosurg. Psychiatry 38, 1190–1193 (1975).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Fischer, E. G. & Ames III, A. Studies on mechanisms of impairment of cerebral circulation following ischemia: effect of hemodilution and perfusion pressure. Stroke 3, 538–542 (1972).

    CAS  PubMed  Article  Google Scholar 

  29. Olsson, Y. & Hossmann, K. A. The effect of intravascular saline perfusion on the sequelae of transient cerebral ischemia. Light and electron microscopial observations. Acta Neuropathol. 17, 68–79 (1971).

    CAS  PubMed  Article  Google Scholar 

  30. Hossmann, K. A. & Sato, K. Recovery of neuronal function after prolonged cerebral ischemia. Science 168, 375–376 (1970).

    CAS  PubMed  Article  Google Scholar 

  31. Krep, H., Brinker, G., Schwindt, W. & Hossmann, K. A. Endothelin type A-antagonist improves long-term neurological recovery after cardiac arrest in rats. Crit. Care Med. 28, 2873–2880 (2000).

    CAS  PubMed  Article  Google Scholar 

  32. Li, L. et al. Cerebral microcirculatory alterations and the no-reflow phenomenon in vivo after experimental pediatric cardiac arrest. J. Cereb. Blood Flow. Metab. 39, 913–925 (2019).

    PubMed  Article  Google Scholar 

  33. Takagi, S., Cocito, L. & Hossmann, K. A. Blood recirculation and pharmacological responsiveness of the cerebral vasculature following prolonged ischemia of cat brain. Stroke 8, 707–712 (1977). This study examines post-ischaemic hyperaemia and hypoperfusion by correlating post-ischaemic blood flow with intravital microscopy measurements of pial vessel diameter.

    CAS  PubMed  Article  Google Scholar 

  34. Shaik, J. S. et al. 20-Hydroxyeicosatetraenoic acid inhibition by HET0016 offers neuroprotection, decreases edema, and increases cortical cerebral blood flow in a pediatric asphyxial cardiac arrest model in rats. J. Cereb. Blood Flow. Metab. 35, 1757–1763 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Yemisci, M. et al. Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat. Med. 15, 1031–1037 (2009).

    CAS  PubMed  Article  Google Scholar 

  36. Hill, R. A. et al. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes. Neuron 87, 95–110 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Little, J. R., Kerr, F. W. L. & Sundt, T. M. Microcirculatory obstruction in focal cerebral ischemia: an electron microscopic investigation in monkeys. Stroke 7, 25–30 (1976).

    PubMed  Article  Google Scholar 

  38. del Zoppo, G. J. & Mabuchi, T. Cerebral microvessel responses to focal ischemia. J. Cereb. Blood Flow. Metab. 23, 879–894 (2003).

    PubMed  Article  Google Scholar 

  39. Fischer, E. G., Ames III, A., Hedley-Whyte, E. T. & O’Gorman, S. Reassessment of cerebral capillary changes in acute global ischemia and their relationship to the “no-reflow phenomenon”. Stroke 8, 36–39 (1977).

    CAS  PubMed  Article  Google Scholar 

  40. Del Zoppo, G. J. et al. Experimental acute thrombotic stroke in baboons. Stroke 17, 1254–1265 (1986).

    PubMed  Article  Google Scholar 

  41. del Zoppo, G. J., Schmid-Schonbein, G. W., Mori, E., Copeland, B. R. & Chang, C. M. Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22, 1276–1283 (1991).

    PubMed  Article  Google Scholar 

  42. Mori, E., del Zoppo, G. J., Chambers, J. D., Copeland, B. R. & Arfors, K. E. Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 23, 712–718 (1992).

    CAS  PubMed  Article  Google Scholar 

  43. Okada, Y. et al. P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion. Stroke 25, 202–211 (1994).

    CAS  PubMed  Article  Google Scholar 

  44. Grogaard, B., Schurer, L., Gerdin, B. & Arfors, K. E. Delayed hypoperfusion after incomplete forebrain ischemia in the rat. The role of polymorphonuclear leukocytes. J. Cereb. Blood Flow. Metab. 9, 500–505 (1989).

    CAS  PubMed  Article  Google Scholar 

  45. Uhl, E., Beck, J., Stummer, W., Lehmberg, J. & Baethmann, A. Leukocyte-endothelium interactions in pial venules during the early and late reperfusion period after global cerebral ischemia in gerbils. J. Cereb. Blood Flow. Metab. 20, 979–987 (2000).

    CAS  PubMed  Article  Google Scholar 

  46. Krupickova, P. et al. Microcirculatory blood flow during cardiac arrest and cardiopulmonary resuscitation does not correlate with global hemodynamics: an experimental study. J. Transl. Med. 14, 163 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. Ristagno, G., Tang, W., Sun, S. & Weil, M. H. Cerebral cortical microvascular flow during and following cardiopulmonary resuscitation after short duration of cardiac arrest. Resuscitation 77, 229–234 (2008).

    PubMed  Article  Google Scholar 

  48. Lipton, P. Ischemic cell death in brain neurons. Physiol. Rev. 79, 1431–1568 (1999).

    CAS  PubMed  Article  Google Scholar 

  49. Harukuni, I. & Bhardwaj, A. Mechanisms of brain injury after global cerebral ischemia. Neurol. Clin. 24, 1–21 (2006).

    PubMed  Article  Google Scholar 

  50. Sekhon, M. S., Ainslie, P. N. & Griesdale, D. E. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a “two-hit” model. Crit. Care 21, 90 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  51. Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R. & Begley, D. J. Structure and function of the blood-brain barrier. Neurobiol. Dis. 37, 13–25 (2010).

    CAS  PubMed  Article  Google Scholar 

  52. Iadecola, C. The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96, 17–42 (2017). This is an important review examining the neurovascular unit and its relation to health and disease.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Butt, A. M., Jones, H. C. & Abbott, N. J. Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. J. Physiol. 429, 47–62 (1990).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Ogawa, S. et al. Hypoxia-induced increased permeability of endothelial monolayers occurs through lowering of cellular cAMP levels. Am. J. Physiol. 262, C546–554 (1992).

    CAS  PubMed  Article  Google Scholar 

  55. Sharma, H. S., Miclescu, A. & Wiklund, L. Cardiac arrest-induced regional blood-brain barrier breakdown, edema formation and brain pathology: a light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain. J. Neural Transm. 118, 87–114 (2011).

    PubMed  Article  Google Scholar 

  56. Rehm, M. et al. Shedding of the endothelial glycocalyx in patients undergoing major vascular surgery with global and regional ischemia. Circulation 116, 1896–1906 (2007).

    CAS  PubMed  Article  Google Scholar 

  57. Baldea, I. et al. Effects of different hypoxia degrees on endothelial cell cultures — time course study. Mech. Ageing Dev. 172, 45–50 (2018).

    CAS  PubMed  Article  Google Scholar 

  58. Shreeniwas, R. et al. Hypoxia-mediated induction of endothelial cell interleukin-1 alpha. An autocrine mechanism promoting expression of leukocyte adhesion molecules on the vessel surface. J. Clin. Invest. 90, 2333–2339 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Karakurum, M. et al. Hypoxic induction of interleukin-8 gene expression in human endothelial cells. J. Clin. Invest. 93, 1564–1570 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Geng, J. G. et al. Rapid neutrophil adhesion to activated endothelium mediated by GMP-140. Nature 343, 757–760 (1990).

    CAS  PubMed  Article  Google Scholar 

  61. Pinsky, D. J. et al. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J. Clin. Invest. 97, 493–500 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Patel, K. D., Zimmerman, G. A., Prescott, S. M., McEver, R. P. & McIntyre, T. M. Oxygen radicals induce human endothelial cells to express GMP-140 and bind neutrophils. J. Cell Biol. 112, 749–759 (1991).

    CAS  PubMed  Article  Google Scholar 

  63. Iadecola, C. & Anrather, J. The immunology of stroke: from mechanisms to translation. Nat. Med. 17, 796–808 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Deng, G., Carter, J., Traystman, R. J., Wagner, D. H. & Herson, P. S. Pro-inflammatory T-lymphocytes rapidly infiltrate into the brain and contribute to neuronal injury following cardiac arrest and cardiopulmonary resuscitation. J. Neuroimmunol. 274, 132–140 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Zhang, C. et al. Invasion of peripheral immune cells into brain parenchyma after cardiac arrest and resuscitation. Aging Dis. 9, 412–425 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  66. Caceres, M. J., Schleien, C. L., Kuluz, J. W., Gelman, B. & Dietrich, W. D. Early endothelial damage and leukocyte accumulation in piglet brains following cardiac arrest. Acta Neuropathol. 90, 582–591 (1995).

    CAS  PubMed  Article  Google Scholar 

  67. Anderson, M. L. et al. Experimental brain ischaemia: assessment of injury by magnetic resonance spectroscopy and histology. Neurol. Res. 12, 195–204 (1990).

    CAS  PubMed  Article  Google Scholar 

  68. Forstermann, U. & Sessa, W. C. Nitric oxide synthases: regulation and function. Eur. Heart J. 33, 829–837, 837a-837d (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Gautier, C., van Faassen, E., Mikula, I., Martasek, P. & Slama-Schwok, A. Endothelial nitric oxide synthase reduces nitrite anions to NO under anoxia. Biochem. Biophys. Res. Commun. 341, 816–821 (2006).

    CAS  PubMed  Article  Google Scholar 

  70. Kubes, P., Suzuki, M. & Granger, D. N. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc. Natl Acad. Sci. USA 88, 4651–4655 (1991).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Hudetz, A. G., Wood, J. D. & Kampine, J. P. Nitric oxide synthase inhibitor augments post-ischemic leukocyte adhesion in the cerebral microcirculation in vivo. Neurol. Res. 21, 378–384 (1999).

    CAS  PubMed  Article  Google Scholar 

  72. Astrup, J., Sorensen, P. M. & Sorensen, H. R. Oxygen and glucose consumption related to Na+-K+ transport in canine brain. Stroke 12, 726–730 (1981).

    CAS  PubMed  Article  Google Scholar 

  73. Jiang, C., Agulian, S. & Haddad, G. G. Cl- and Na+ homeostasis during anoxia in rat hypoglossal neurons: intracellular and extracellular in vitro studies. J. Physiol. 448, 697–708 (1992).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. Szatkowski, M. & Attwell, D. Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms. Trends Neurosci. 17, 359–365 (1994).

    CAS  PubMed  Article  Google Scholar 

  75. Xie, Y., Dengler, K., Zacharias, E., Wilffert, B. & Tegtmeier, F. Effects of the sodium channel blocker tetrodotoxin (TTX) on cellular ion homeostasis in rat brain subjected to complete ischemia. Brain Res. 652, 216–224 (1994).

    CAS  PubMed  Article  Google Scholar 

  76. Blaustein, M. P. & Lederer, W. J. Sodium/calcium exchange: its physiological implications. Physiol. Rev. 79, 763–854 (1999).

    CAS  PubMed  Article  Google Scholar 

  77. Choi, D. W. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage. Trends Neurosci. 11, 465–469 (1988).

    CAS  PubMed  Article  Google Scholar 

  78. Kawano, T. et al. Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat. Med. 12, 225–229 (2006).

    CAS  PubMed  Article  Google Scholar 

  79. Aarts, M. et al. A key role for TRPM7 channels in anoxic neuronal death. Cell 115, 863–877 (2003).

    CAS  PubMed  Article  Google Scholar 

  80. Gao, J. et al. Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death. Neuron 48, 635–646 (2005).

    CAS  PubMed  Article  Google Scholar 

  81. Benveniste, H., Drejer, J., Schousboe, A. & Diemer, N. H. 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 (1984).

    CAS  PubMed  Article  Google Scholar 

  82. Rothman, S. M. & Olney, J. W. Glutamate and the pathophysiology of hypoxic–ischemic brain damage. Ann. Neurol. 19, 105–111 (1986). This review is an excellent summary of the evidence demonstrating the neurotoxic effects of glutamate.

    CAS  PubMed  Article  Google Scholar 

  83. Olney, J. W., Sharpe, L. G. & Feigin, R. D. Glutamate-induced brain damage in infant primates. J. Neuropathol. Exp. Neurol. 31, 464–488 (1972).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  85. Zipfel, G. J., Lee, J. M. & Choi, D. W. Reducing calcium overload in the ischemic brain. N. Engl. J. Med. 341, 1543–1544 (1999).

    CAS  PubMed  Article  Google Scholar 

  86. Pellegrini-Giampietro, D. E., Gorter, J. A., Bennett, M. V. & Zukin, R. S. The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders. Trends Neurosci. 20, 464–470 (1997).

    CAS  PubMed  Article  Google Scholar 

  87. Petralia, R. S. et al. Organization of NMDA receptors at extrasynaptic locations. Neuroscience 167, 68–87 (2010).

    CAS  PubMed  Article  Google Scholar 

  88. Zhang, S. J. et al. Decoding NMDA receptor signaling: identification of genomic programs specifying neuronal survival and death. Neuron 53, 549–562 (2007).

    CAS  PubMed  Article  Google Scholar 

  89. Hardingham, G. E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414 (2002).

    CAS  PubMed  Article  Google Scholar 

  90. Sattler, R. et al. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284, 1845–1848 (1999).

    CAS  PubMed  Article  Google Scholar 

  91. Cook, D. J., Teves, L. & Tymianski, M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 483, 213–217 (2012).

    CAS  PubMed  Article  Google Scholar 

  92. Hill, M. D. et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 11, 942–950 (2012).

    CAS  PubMed  Article  Google Scholar 

  93. Hill, M. D. et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet 395, 878–887 (2020).

    CAS  PubMed  Article  Google Scholar 

  94. Choi, D. W. Ionic dependence of glutamate neurotoxicity. J. Neurosci. 7, 369–379 (1987). This is the first study to demonstrate that cell death following glutamate neurotoxicity is calcium dependent.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Taunyane, I. C. et al. Preserved brain morphology after controlled automated reperfusion of the whole body following normothermic circulatory arrest time of up to 20 minutes. Eur. J. Cardiothorac. Surg. 50, 1025–1034 (2016). This article demonstrates 7-day 90% survival with intact neurological function in pigs after 20min of normothermic CA using controlled reperfusion.

    PubMed  Article  Google Scholar 

  96. Kristian, T. & Siesjo, B. K. Calcium in ischemic cell death. Stroke 29, 705–718 (1998).

    CAS  PubMed  Article  Google Scholar 

  97. Orrenius, S., Zhivotovsky, B. & Nicotera, P. Regulation of cell death: the calcium-apoptosis link. Nat. Rev. Mol. Cell Biol. 4, 552–565 (2003).

    CAS  PubMed  Article  Google Scholar 

  98. Xiong, Z. G. et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 118, 687–698 (2004).

    CAS  PubMed  Article  Google Scholar 

  99. Dewar, D., Underhill, S. M. & Goldberg, M. P. Oligodendrocytes and ischemic brain injury. J. Cereb. Blood Flow. Metab. 23, 263–274 (2003).

    PubMed  Article  Google Scholar 

  100. Garcia, J. H., Kalimo, H., Kamijyo, Y. & Trump, B. F. Cellular events during partial cerebral ischemia. I. Electron microscopy of feline cerebral cortex after middle-cerebral-artery occlusion. Virchows Arch. B Cell Pathol. 25, 191–206 (1977).

    CAS  PubMed  Google Scholar 

  101. Stokum, J. A., Gerzanich, V. & Simard, J. M. Molecular pathophysiology of cerebral edema. J. Cereb. Blood Flow. Metab. 36, 513–538 (2016).

    CAS  PubMed  Article  Google Scholar 

  102. Goldberg, M. P. & Choi, D. W. Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. J. Neurosci. 13, 3510–3524 (1993).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Marrif, H. & Juurlink, B. H. Astrocytes respond to hypoxia by increasing glycolytic capacity. J. Neurosci. Res. 57, 255–260 (1999).

    CAS  PubMed  Article  Google Scholar 

  104. Callahan, D. J., Engle, M. J. & Volpe, J. J. Hypoxic injury to developing glial cells: protective effect of high glucose. Pediatr. Res. 27, 186–190 (1990).

    CAS  PubMed  Article  Google Scholar 

  105. Giffard, R. G., Monyer, H. & Choi, D. W. Selective vulnerability of cultured cortical glia to injury by extracellular acidosis. Brain Res. 530, 138–141 (1990).

    CAS  PubMed  Article  Google Scholar 

  106. Plum, F. What causes infarction in ischemic brain?: the Robert Wartenberg Lecture. Neurology 33, 222–233 (1983).

    CAS  PubMed  Article  Google Scholar 

  107. Lascola, C. & Kraig, R. P. Astroglial acid-base dynamics in hyperglycemic and normoglycemic global ischemia. Neurosci. Biobehav. Rev. 21, 143–150 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Garcia, J. H. et al. Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Am. J. Pathol. 142, 623–635 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Magistretti, P. J. & Allaman, I. A cellular perspective on brain energy metabolism and functional imaging. Neuron 86, 883–901 (2015).

    CAS  PubMed  Article  Google Scholar 

  110. Lin, C. H. et al. Protection of ischemic brain cells is dependent on astrocyte-derived growth factors and their receptors. Exp. Neurol. 201, 225–233 (2006).

    CAS  PubMed  Article  Google Scholar 

  111. Witcher, M. R. et al. Three-dimensional relationships between perisynaptic astroglia and human hippocampal synapses. Glia 58, 572–587 (2010).

    PubMed  PubMed Central  Google Scholar 

  112. Eulenburg, V. & Gomeza, J. Neurotransmitter transporters expressed in glial cells as regulators of synapse function. Brain Res. Rev. 63, 103–112 (2010).

    CAS  PubMed  Article  Google Scholar 

  113. Ouyang, Y. B., Voloboueva, L. A., Xu, L. J. & Giffard, R. G. Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia. J. Neurosci. 27, 4253–4260 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Swanson, R. A., Ying, W. & Kauppinen, T. M. Astrocyte influences on ischemic neuronal death. Curr. Mol. Med. 4, 193–205 (2004).

    CAS  PubMed  Article  Google Scholar 

  115. Seki, Y., Feustel, P. J., Keller, R. W. Jr., Tranmer, B. I. & Kimelberg, H. K. Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker. Stroke 30, 433–440 (1999).

    CAS  PubMed  Article  Google Scholar 

  116. Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

    CAS  Article  PubMed  Google Scholar 

  117. Masuda, T., Croom, D., Hida, H. & Kirov, S. A. Capillary blood flow around microglial somata determines dynamics of microglial processes in ischemic conditions. Glia 59, 1744–1753 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  118. Zanier, E. R., Fumagalli, S., Perego, C., Pischiutta, F. & De Simoni, M. G. Shape descriptors of the “never resting” microglia in three different acute brain injury models in mice. Intensive Care Med. Exp. 3, 39 (2015).

    PubMed  Article  Google Scholar 

  119. Vrselja, Z. et al. Restoration of brain circulation and cellular functions hours post-mortem. Nature 568, 336–343 (2019). This study shows that circulation and cellular functions can be restored in the post-mortem large mammalian brain up to 4h after death using appropriate multimodal interventions.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Eyo, U. & Dailey, M. E. Effects of oxygen-glucose deprivation on microglial mobility and viability in developing mouse hippocampal tissues. Glia 60, 1747–1760 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  121. Hearse, D. J., Humphrey, S. M. & Chain, E. B. Abrupt reoxygenation of the anoxic potassium-arrested perfused rat heart: a study of myocardial enzyme release. J. Mol. Cell Cardiol. 5, 395–407 (1973).

    CAS  PubMed  Article  Google Scholar 

  122. Hayman, E. G., Patel, A. P., Kimberly, W. T., Sheth, K. N. & Simard, J. M. Cerebral edema after cardiopulmonary resuscitation: a therapeutic target following cardiac arrest? Neurocrit Care 28, 276–287 (2018).

    CAS  PubMed  Article  Google Scholar 

  123. Hoek, R. M. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000).

    CAS  PubMed  Article  Google Scholar 

  124. Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Melani, A. et al. ATP extracellular concentrations are increased in the rat striatum during in vivo ischemia. Neurochem. Int. 47, 442–448 (2005).

    CAS  PubMed  Article  Google Scholar 

  126. Hide, I. et al. Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J. Neurochem. 75, 965–972 (2000).

    CAS  PubMed  Article  Google Scholar 

  127. Amadio, S. et al. P2 receptor modulation and cytotoxic function in cultured CNS neurons. Neuropharmacology 42, 489–501 (2002).

    CAS  PubMed  Article  Google Scholar 

  128. Park, J. S. et al. Involvement of Toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J. Biol. Chem. 279, 7370–7377 (2004).

    CAS  PubMed  Article  Google Scholar 

  129. Hua, F. et al. Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion. J. Neuroimmunol. 190, 101–111 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. Moro, M. A., Cardenas, A., Hurtado, O., Leza, J. C. & Lizasoain, I. Role of nitric oxide after brain ischaemia. Cell Calcium 36, 265–275 (2004).

    CAS  PubMed  Article  Google Scholar 

  131. Qiu, J. et al. High-mobility group box 1 promotes metalloproteinase-9 upregulation through Toll-like receptor 4 after cerebral ischemia. Stroke 41, 2077–2082 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Lee, S. R., Tsuji, K., Lee, S. R. & Lo, E. H. Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J. Neurosci. 24, 671–678 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. Lee, J. Y. et al. Fluoxetine inhibits transient global ischemia-induced hippocampal neuronal death and memory impairment by preventing blood-brain barrier disruption. Neuropharmacology 79, 161–171 (2014).

    CAS  PubMed  Article  Google Scholar 

  134. Park, H. S. et al. Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B. J. Immunol. 173, 3589–3593 (2004).

    CAS  PubMed  Article  Google Scholar 

  135. Suzuki, Y. et al. Pharmacological inhibition of TLR4-NOX4 signal protects against neuronal death in transient focal ischemia. Sci. Rep. 2, 896 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. Kunz, A. et al. Nuclear factor-kappaB activation and postischemic inflammation are suppressed in CD36-null mice after middle cerebral artery occlusion. J. Neurosci. 28, 1649–1658 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Iadecola, C., Zhang, F., Casey, R., Clark, H. B. & Ross, M. E. Inducible nitric oxide synthase gene expression in vascular cells after transient focal cerebral ischemia. Stroke 27, 1373–1380 (1996).

    CAS  PubMed  Article  Google Scholar 

  138. Forster, C., Clark, H. B., Ross, M. E. & Iadecola, C. Inducible nitric oxide synthase expression in human cerebral infarcts. Acta Neuropathol. 97, 215–220 (1999).

    CAS  PubMed  Article  Google Scholar 

  139. Yrjanheikki, J., Keinanen, R., Pellikka, M., Hokfelt, T. & Koistinaho, J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc. Natl Acad. Sci. USA 95, 15769–15774 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P. & Lipton, S. A. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc. Natl Acad. Sci. USA 92, 7162–7166 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. Iadecola, C., Zhang, F. & Xu, X. Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am. J. Physiol. 268, R286–292 (1995).

    CAS  PubMed  Google Scholar 

  142. Iadecola, C., Zhang, F., Casey, R., Nagayama, M. & Ross, M. E. Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J. Neurosci. 17, 9157–9164 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. Vandenabeele, P., Galluzzi, L., Vanden Berghe, T. & Kroemer, G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat. Rev. Mol. Cell Biol. 11, 700–714 (2010).

    CAS  PubMed  Article  Google Scholar 

  144. Sairanen, T. R., Lindsberg, P. J., Brenner, M. & Siren, A. L. Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level. J. Cereb. Blood Flow. Metab. 17, 1107–1120 (1997).

    CAS  PubMed  Article  Google Scholar 

  145. Barone, F. C. et al. Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke 28, 1233–1244 (1997).

    CAS  PubMed  Article  Google Scholar 

  146. Emsley, H. C. et al. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J. Neurol. Neurosurg. Psychiatry 76, 1366–1372 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Rosenberg, G. A. et al. Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res. 893, 104–112 (2001).

    CAS  PubMed  Article  Google Scholar 

  148. Rosenberg, G. A., Estrada, E. Y. & Dencoff, J. E. Matrix metalloproteinases and TIMPs are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke 29, 2189–2195 (1998).

    CAS  PubMed  Article  Google Scholar 

  149. Rosenberg, G. A. & Navratil, M. Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 48, 921–926 (1997).

    CAS  PubMed  Article  Google Scholar 

  150. Garcia-Bonilla, L., Racchumi, G., Murphy, M., Anrather, J. & Iadecola, C. Endothelial CD36 contributes to postischemic brain injury by promoting neutrophil activation via CSF3. J. Neurosci. 35, 14783–14793 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. Iadecola, C., Zhang, F., Xu, S., Casey, R. & Ross, M. E. Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J. Cereb. Blood Flow. Metab. 15, 378–384 (1995).

    CAS  PubMed  Article  Google Scholar 

  152. Garcia-Bonilla, L. et al. Inducible nitric oxide synthase in neutrophils and endothelium contributes to ischemic brain injury in mice. J. Immunol. 193, 2531–2537 (2014).

    CAS  PubMed  Article  Google Scholar 

  153. Neumann, J. et al. Microglia provide neuroprotection after ischemia. FASEB J. 20, 714–716 (2006).

    CAS  PubMed  Article  Google Scholar 

  154. Imai, F. et al. Neuroprotective effect of exogenous microglia in global brain ischemia. J. Cereb. Blood Flow. Metab. 27, 488–500 (2007).

    CAS  PubMed  Article  Google Scholar 

  155. Montero, M., Gonzalez, B. & Zimmer, J. Immunotoxic depletion of microglia in mouse hippocampal slice cultures enhances ischemia-like neurodegeneration. Brain Res. 1291, 140–152 (2009).

    CAS  PubMed  Article  Google Scholar 

  156. Lalancette-Hebert, M., Gowing, G., Simard, A., Weng, Y. C. & Kriz, J. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J. Neurosci. 27, 2596–2605 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. Cherry, J. D., Olschowka, J. A. & O’Banion, M. K. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J. Neuroinflammation 11, 98 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  158. Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. Voll, R. E. et al. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997).

    CAS  PubMed  Article  Google Scholar 

  160. Batchelor, P. E. et al. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J. Neurosci. 19, 1708–1716 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. Thannickal, V. J. & Fanburg, B. L. Reactive oxygen species in cell signaling. Am. J. Physiol. Lung Cell Mol. Physiol 279, L1005–1028 (2000).

    CAS  PubMed  Article  Google Scholar 

  162. Chan, P. H. Reactive oxygen radicals in signaling and damage in the ischemic brain. J. Cereb. Blood Flow. Metab. 21, 2–14 (2001).

    CAS  PubMed  Article  Google Scholar 

  163. Abramov, A. Y., Scorziello, A. & Duchen, M. R. Three distinct mechanisms generate oxygen free radicals in neurons and contribute to cell death during anoxia and reoxygenation. J. Neurosci. 27, 1129–1138 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. Murphy, M. P. How mitochondria produce reactive oxygen species. Biochem. J. 417, 1–13 (2009).

    CAS  PubMed  Article  Google Scholar 

  165. Turrens, J. F. Superoxide production by the mitochondrial respiratory chain. Biosci. Rep. 17, 3–8 (1997).

    CAS  PubMed  Article  Google Scholar 

  166. Sugawara, T. & Chan, P. H. Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid. Redox Signal. 5, 597–607 (2003).

    CAS  PubMed  Article  Google Scholar 

  167. Namba, K., Takeda, Y., Sunami, K. & Hirakawa, M. Temporal profiles of the levels of endogenous antioxidants after four-vessel occlusion in rats. J. Neurosurg. Anesthesiol. 13, 131–137 (2001).

    CAS  PubMed  Article  Google Scholar 

  168. Pryor, W. A. & Squadrito, G. L. The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide. Am. J. Physiol. 268, L699–L722 (1995).

    CAS  PubMed  Google Scholar 

  169. Kawase, M. et al. Exacerbation of delayed cell injury after transient global ischemia in mutant mice with CuZn superoxide dismutase deficiency. Stroke 30, 1962–1968 (1999).

    CAS  PubMed  Article  Google Scholar 

  170. Chan, P. H. et al. Overexpression of SOD1 in transgenic rats protects vulnerable neurons against ischemic damage after global cerebral ischemia and reperfusion. J. Neurosci. 18, 8292–8299 (1998). This important article demonstrates the protective effects of endogenous antioxidant overexpression following global ischaemia, supporting the importance of oxidative stress in ischaemic injury.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. Kurinami, H. et al. Prohibitin viral gene transfer protects hippocampal CA1 neurons from ischemia and ameliorates postischemic hippocampal dysfunction. Stroke 45, 1131–1138 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. Chouchani, E. T. et al. A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury. Cell Metab. 23, 254–263 (2016).

    CAS  PubMed  Article  Google Scholar 

  173. Stepanova, A. et al. Reverse electron transfer results in a loss of flavin from mitochondrial complex I: Potential mechanism for brain ischemia reperfusion injury. J. Cereb. Blood Flow. Metab. 37, 3649–3658 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. Kahl, A. et al. Critical role of flavin and glutathione in complex I-mediated bioenergetic failure in brain ischemia/reperfusion injury. Stroke 49, 1223–1231 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. Galkin, A. Brain ischemia/reperfusion injury and mitochondrial complex I damage. Biochemistry 84, 1411–1423 (2019). This is an excellent review of oxidative stress, mitochondrial dysfunction and reverse electron transfer following IRI.

    CAS  PubMed  Google Scholar 

  177. Tam, J. et al. The role of decreased cardiolipin and impaired electron transport chain in brain damage due to cardiac arrest. Neurochem. Int. 120, 200–205 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. Chan, P. H. Role of oxidants in ischemic brain damage. Stroke 27, 1124–1129 (1996).

    CAS  PubMed  Article  Google Scholar 

  179. Chan, P. H. Mitochondria and neuronal death/survival signaling pathways in cerebral ischemia. Neurochem. Res. 29, 1943–1949 (2004).

    CAS  PubMed  Article  Google Scholar 

  180. Brustovetsky, N., Brustovetsky, T., Jemmerson, R. & Dubinsky, J. M. Calcium-induced cytochrome c release from CNS mitochondria is associated with the permeability transition and rupture of the outer membrane. J. Neurochem. 80, 207–218 (2002).

    CAS  PubMed  Article  Google Scholar 

  181. Starkov, A. A., Chinopoulos, C. & Fiskum, G. Mitochondrial calcium and oxidative stress as mediators of ischemic brain injury. Cell Calcium 36, 257–264 (2004).

    CAS  PubMed  Article  Google Scholar 

  182. Bernardi, P. et al. The mitochondrial permeability transition from in vitro artifact to disease target. FEBS J. 273, 2077–2099 (2006).

    CAS  PubMed  Article  Google Scholar 

  183. Schinzel, A. C. et al. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc. Natl Acad. Sci. USA 102, 12005–12010 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  184. Sugawara, T., Fujimura, M., Morita-Fujimura, Y., Kawase, M. & Chan, P. H. Mitochondrial release of cytochrome c corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia. J. Neurosci. 19, RC39 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. Vaseva, A. V. et al. p53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149, 1536–1548 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. Kirsch, J. R., Helfaer, M. A., Haun, S. E., Koehler, R. C. & Traystman, R. J. Polyethylene glycol-conjugated superoxide dismutase improves recovery of postischemic hypercapnic cerebral blood flow in piglets. Pediatr. Res. 34, 530–537 (1993).

    CAS  PubMed  Article  Google Scholar 

  187. Stanimirovic, D. B., Markovic, M., Micic, D. V., Spatz, M. & Mrsulja, B. B. Liposome-entrapped superoxide dismutase reduces ischemia/reperfusion ‘oxidative stress’ in gerbil brain. Neurochem. Res. 19, 1473–1478 (1994).

    CAS  PubMed  Article  Google Scholar 

  188. Cuzzocrea, S. et al. Effects of tempol, a membrane-permeable radical scavenger, in a gerbil model of brain injury. Brain Res. 875, 96–106 (2000).

    CAS  PubMed  Article  Google Scholar 

  189. Hall, E. D., Pazara, K. E. & Braughler, J. M. 21-Aminosteroid lipid peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils. Stroke 19, 997–1002 (1988).

    CAS  PubMed  Article  Google Scholar 

  190. Hall, E. D. & Yonkers, P. A. Attenuation of postischemic cerebral hypoperfusion by the 21-aminosteroid U74006F. Stroke 19, 340–344 (1988).

    CAS  PubMed  Article  Google Scholar 

  191. Cerchiari, E. L., Hoel, T. M., Safar, P. & Sclabassi, R. J. Protective effects of combined superoxide dismutase and deferoxamine on recovery of cerebral blood flow and function after cardiac arrest in dogs. Stroke 18, 869–878 (1987).

    CAS  PubMed  Article  Google Scholar 

  192. Uchino, H. et al. Differential neuroprotection by cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition. Neurobiol. Dis. 10, 219–233 (2002).

    CAS  PubMed  Article  Google Scholar 

  193. Uchino, H. et al. Amelioration by cyclosporin A of brain damage in transient forebrain ischemia in the rat. Brain Res. 812, 216–226 (1998).

    CAS  PubMed  Article  Google Scholar 

  194. Knapp, J., Roewer, J., Bruckner, T., Bottiger, B. W. & Popp, E. Evaluation of cyclosporine a as a cardio- and neuroprotective agent after cardiopulmonary resuscitation in a rat model. Shock 43, 576–581 (2015).

    CAS  PubMed  Article  Google Scholar 

  195. Cour, M. et al. Ubiquitous protective effects of cyclosporine A in preventing cardiac arrest-induced multiple organ failure. J. Appl. Physiol. 117, 930–936 (2014).

    CAS  PubMed  Article  Google Scholar 

  196. Argaud, L. et al. Effect of cyclosporine in nonshockable out-of-hospital cardiac arrest: the CYRUS randomized clinical trial. JAMA Cardiol. 1, 557–565 (2016).

    PubMed  Article  Google Scholar 

  197. Nighoghossian, N. et al. Cyclosporine in acute ischemic stroke. Neurology 84, 2216–2223 (2015).

    CAS  PubMed  Article  Google Scholar 

  198. Iqbal, K. & Tellez-Nagel, I. Isolation of neurons and glial cells from normal and pathological human brains. Brain Res. 45, 296–301 (1972).

    CAS  PubMed  Article  Google Scholar 

  199. Gilden, D. H. et al. Human brain in tissue culture. I. Acquisition, initial processing, and establishment of brain cell cultures. J. Comp. Neurol. 161, 295–306 (1975).

    CAS  PubMed  Article  Google Scholar 

  200. Konishi, Y., Lindholm, K., Yang, L. B., Li, R. & Shen, Y. Isolation of living neurons from human elderly brains using the immunomagnetic sorting DNA-linker system. Am. J. Pathol. 161, 1567–1576 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  201. Charpak, S. & Audinat, E. Cardiac arrest in rodents: maximal duration compatible with a recovery of neuronal activity. Proc. Natl Acad. Sci. USA 95, 4748–4753 (1998). This is an important study investigating the maximum amount of ischaemic time compatible with electrophysiological function of neurons in acute brain slice cultures.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. Barksdale, K. A. et al. Mitochondrial viability in mouse and human postmortem brain. FASEB J. 24, 3590–3599 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  203. Verwer, R. W. et al. Cells in human postmortem brain tissue slices remain alive for several weeks in culture. FASEB J. 16, 54–60 (2002). This article demonstrates that organotypic slice cultures can be harvested up to 8h after death in the post-mortem human brain and can be maintained for prolonged periods.

    CAS  PubMed  Article  Google Scholar 

  204. Onorati, M. et al. Zika virus disrupts phospho-TBK1 localization and mitosis in human neuroepithelial stem cells and radial glia. Cell Rep. 16, 2576–2592 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. Sousa, A. M. M. et al. Molecular and cellular reorganization of neural circuits in the human lineage. Science 358, 1027–1032 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  206. Brockman, S. K. & Jude, J. R. The tolerance of the dog brain to total arrest of circulation. Bull. Johns. Hopkins Hosp. 106, 74–80 (1960).

    CAS  PubMed  Google Scholar 

  207. Neely, W. A. & Youmans, J. R. Anoxia of canine brain without damage. JAMA 183, 1085–1087 (1963).

    CAS  PubMed  Article  Google Scholar 

  208. Kleihues, P., Hossmann, K. A., Pegg, A. E., Kobayashi, K. & Zimmermann, V. Resuscitation of the monkey brain after one hour complete ischemia. III. Indications of metabolic recovery. Brain Res. 95, 61–73 (1975).

    CAS  PubMed  Article  Google Scholar 

  209. 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. Neurol. Sci. 77, 305–320 (1987). This article describes the almost full neurological recovery following 1h of global cerebral ischaemia in the normothermic cat.

    CAS  PubMed  Article  Google Scholar 

  210. Trummer, G. et al. Superior neurologic recovery after 15 minutes of normothermic cardiac arrest using an extracorporeal life support system for optimized blood pressure and flow. Perfusion 29, 130–138 (2014).

    CAS  PubMed  Article  Google Scholar 

  211. Fischer, E. G., Ames, A. III & Lorenzo, A. V. Cerebral blood flow immediately following brief circulatory stasis. Stroke 10, 423–427 (1979).

    CAS  PubMed  Article  Google Scholar 

  212. Kreibich, M. et al. Improved outcome in an animal model of prolonged cardiac arrest through pulsatile high pressure controlled automated reperfusion of the whole body. Artif. Organs 42, 992–1000 (2018).

    CAS  PubMed  Article  Google Scholar 

  213. Anstadt, M. P. et al. Pulsatile versus nonpulsatile reperfusion improves cerebral blood flow after cardiac arrest. Ann. Thorac. Surg. 56, 453–461 (1993).

    CAS  PubMed  Article  Google Scholar 

  214. Bowen, D. M., Smith, C. B., White, P. & Davison, A. N. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 99, 459–496 (1976).

    CAS  PubMed  Article  Google Scholar 

  215. Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002).

    CAS  PubMed  Article  Google Scholar 

  216. Laub, G. W., Banaszak, D., Kupferschmid, J., Magovern, G. J. & Young, J. C. Percutaneous cardiopulmonary bypass for the treatment of hypothermic circulatory collapse. Ann. Thorac. Surg. 47, 608–611 (1989).

    CAS  PubMed  Article  Google Scholar 

  217. Letsou, G. V. et al. Is cardiopulmonary bypass effective for treatment of hypothermic arrest due to drowning or exposure? Arch. Surg. 127, 525–528 (1992).

    CAS  PubMed  Article  Google Scholar 

  218. Hughes, A., Riou, P. & Day, C. Full neurological recovery from profound (18.0 degrees C) acute accidental hypothermia: successful resuscitation using active invasive rewarming techniques. Emerg. Med. J. 24, 511–512 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  219. Walpoth, B. H. et al. Outcome of survivors of accidental deep hypothermia and circulatory arrest treated with extracorporeal blood warming. N. Engl. J. Med. 337, 1500–1505 (1997). This is an important clinical study demonstrating positive outcomes for individuals who experienced accidental deep hypothermia and CA and were treated with extracorporeal warming.

    CAS  PubMed  Article  Google Scholar 

  220. Allen, B. S., Veluz, J. S., Buckberg, G. D., Aeberhard, E. & Ignarro, L. J. Deep hypothermic circulatory arrest and global reperfusion injury: avoidance by making a pump prime reperfusate - a new concept. J. Thorac. Cardiovasc. Surg. 125, 625–32 (2003).

    PubMed  Article  Google Scholar 

  221. Griepp, R. B. & Di Luozzo, G. Hypothermia for aortic surgery. J. Thorac. Cardiovasc. Surg. 145, S56–58 (2013).

    PubMed  Article  Google Scholar 

  222. Benson, D. W., Williams, G. R. Jr., Spencer, F. C. & Yates, A. J. The use of hypothermia after cardiac arrest. Anesth. Analg. 38, 423–428 (1959).

    CAS  PubMed  Article  Google Scholar 

  223. Williams, G. R. Jr. & Spencer, F. C. The clinical use of hypothermia following cardiac arrest. Ann. Surg. 148, 462–468 (1958).

    PubMed  PubMed Central  Article  Google Scholar 

  224. Bernard, S. A. et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J. Med. 346, 557–563 (2002).

    PubMed  Article  Google Scholar 

  225. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N. Engl. J. Med. 346, 549–556 (2002).

    Article  Google Scholar 

  226. Donnino, M. W. et al. Temperature management after cardiac arrest: an advisory statement by the Advanced Life Support Task Force of the International Liaison Committee on Resuscitation and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical care, Perioperative and Resuscitation. Circulation 132, 2448–2456 (2015).

    CAS  PubMed  Article  Google Scholar 

  227. Bougouin, W. et al. Extracorporeal cardiopulmonary resuscitation in out-of-hospital cardiac arrest: a registry study. Eur. Heart J. https://doi.org/10.1093/eurheartj/ehz753 (2019).

    Article  Google Scholar 

  228. Holmberg, M. J. et al. Extracorporeal cardiopulmonary resuscitation for cardiac arrest: A systematic review. Resuscitation 131, 91–100 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  229. Stub, D. et al. Refractory cardiac arrest treated with mechanical CPR, hypothermia, ECMO and early reperfusion (the CHEER trial). Resuscitation 86, 88–94 (2015).

    PubMed  Article  Google Scholar 

  230. Bartos, J. A. et al. Improved survival with extracorporeal cardiopulmonary resuscitation despite progressive metabolic derangement associated with prolonged resuscitation. Circulation 141, 877–886 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  231. Lascarrou, J. B. et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N. Engl. J. Med. 381, 2327–2337 (2019).

    PubMed  Article  Google Scholar 

  232. Berg, K. M. et al. Adult advanced life support: 2020 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations. Circulation 142, S92–S139 (2020).

    PubMed  Article  Google Scholar 

  233. Nolan, J. P. et al. European resuscitation council and european society of intensive care medicine 2015 guidelines for post-resuscitation care. Intensive Care Med. 41, 2039–2056 (2015).

    PubMed  Article  Google Scholar 

  234. Hifumi, T. et al. Association between rewarming duration and neurological outcome in out-of-hospital cardiac arrest patients receiving therapeutic hypothermia. Resuscitation 146, 170–177 (2020).

    PubMed  Article  Google Scholar 

  235. Safar, P. et al. Improved cerebral resuscitation from cardiac arrest in dogs with mild hypothermia plus blood flow promotion. Stroke 27, 105–113 (1996).

    CAS  PubMed  Article  Google Scholar 

  236. Tisherman, S. A. et al. Therapeutic deep hypothermic circulatory arrest in dogs: a resuscitation modality for hemorrhagic shock with ‘irreparable’ injury. J. Trauma. 30, 836–847 (1990). This is a seminal study showing the protective effects of deep hypothermic circulatory arrest for haemorrhagic shock.

    CAS  PubMed  Article  Google Scholar 

  237. Tisherman, S. A. et al. Profound hypothermia (less than 10 degrees C) compared with deep hypothermia (15 degrees C) improves neurologic outcome in dogs after two hours’ circulatory arrest induced to enable resuscitative surgery. J. Trauma. 31, 1051–1061 (1991).

    CAS  PubMed  Article  Google Scholar 

  238. Alam, H. B. et al. The rate of induction of hypothermic arrest determines the outcome in a Swine model of lethal hemorrhage. J. Trauma. 57, 961–969 (2004).

    PubMed  Article  Google Scholar 

  239. Alam, H. B. et al. Does the rate of rewarming from profound hypothermic arrest influence the outcome in a swine model of lethal hemorrhage? J. Trauma. 60, 134–146 (2006).

    PubMed  Article  Google Scholar 

  240. Yenari, M., Kitagawa, K., Lyden, P. & Perez-Pinzon, M. Metabolic downregulation: a key to successful neuroprotection? Stroke 39, 2910–2917 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  241. Erecinska, M., Thoresen, M. & Silver, I. A. Effects of hypothermia on energy metabolism in Mammalian central nervous system. J. Cereb. Blood Flow. Metab. 23, 513–530 (2003).

    CAS  PubMed  Article  Google Scholar 

  242. Hagerdal, M., Harp, J. & Siesjo, B. K. Effect of hypothermia upon organic phosphates, glycolytic metabolites, citric acid cycle intermediates and associated amino acids in rat cerebral cortex. J. Neurochem. 24, 743–748 (1975).

    CAS  PubMed  Article  Google Scholar 

  243. Colbourne, F., Grooms, S. Y., Zukin, R. S., Buchan, A. M. & Bennett, M. V. Hypothermia rescues hippocampal CA1 neurons and attenuates down-regulation of the AMPA receptor GluR2 subunit after forebrain ischemia. Proc. Natl Acad. Sci. USA 100, 2906–2910 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  244. Xu, L., Yenari, M. A., Steinberg, G. K. & Giffard, R. G. Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J. Cereb. Blood Flow. Metab. 22, 21–28 (2002).

    PubMed  Article  Google Scholar 

  245. Perrone, S. et al. Whole body hypothermia and oxidative stress in babies with hypoxic-ischemic brain injury. Pediatr. Neurol. 43, 236–240 (2010).

    PubMed  Article  Google Scholar 

  246. D’Cruz, B. J. et al. Hypothermic reperfusion after cardiac arrest augments brain-derived neurotrophic factor activation. J. Cereb. Blood Flow. Metab. 22, 843–851 (2002).

    PubMed  Article  Google Scholar 

  247. Schmidt, K. M., Repine, M. J., Hicks, S. D., DeFranco, D. B. & Callaway, C. W. Regional changes in glial cell line-derived neurotrophic factor after cardiac arrest and hypothermia in rats. Neurosci. Lett. 368, 135–139 (2004).

    CAS  PubMed  Article  Google Scholar 

  248. Zhao, H. et al. Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J. Neurosci. 25, 9794–9806 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  249. Spahn, D. R. Blood substitutes. Artificial oxygen carriers: perfluorocarbon emulsions. Crit. Care 3, R93–97 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  250. Winslow, R. M., Vandegriff, K. D. & Intaglietta, M. Blood Substitutes: New Challenges (Birkhäuser, 1996).

  251. Manning, J. E. et al. Selective aortic arch perfusion with hemoglobin-based oxygen carrier-201 for resuscitation from exsanguinating cardiac arrest in swine. Crit. Care Med. 29, 2067–2074 (2001).

    CAS  PubMed  Article  Google Scholar 

  252. Paradis, N. A. Dose-response relationship between aortic infusions of polymerized bovine hemoglobin and return of circulation in a canine model of ventricular fibrillation and advanced cardiac life support. Crit. Care Med. 25, 476–483 (1997).

    CAS  PubMed  Article  Google Scholar 

  253. Del Zoppo, G. J. Why do all drugs work in animals but none in stroke patients? 1. Drugs promoting cerebral blood flow. J. Intern. Med. 237, 79–88 (1995).

    PubMed  Article  Google Scholar 

  254. Gladstone, D. J., Black, S. E. & Hakim, A. M. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33, 2123–2136 (2002).

    PubMed  Article  Google Scholar 

  255. Richard Green, A., Odergren, T. & Ashwood, T. Animal models of stroke: do they have value for discovering neuroprotective agents? Trends Pharmacol. Sci. 24, 402–408 (2003).

    CAS  PubMed  Article  Google Scholar 

  256. Suzuki, J., Fujimoto, S., Mizoi, K. & Oba, M. The protective effect of combined administration of anti-oxidants and perfluorochemicals on cerebral ischemia. Stroke 15, 672–679 (1984).

    CAS  PubMed  Article  Google Scholar 

  257. Schabitz, W. R. et al. Synergistic effects of a combination of low-dose basic fibroblast growth factor and citicoline after temporary experimental focal ischemia. Stroke 30, 427–431 (1999).

    CAS  PubMed  Article  Google Scholar 

  258. Gwag, B. J., Lobner, D., Koh, J. Y., Wie, M. B. & Choi, D. W. Blockade of glutamate receptors unmasks neuronal apoptosis after oxygen-glucose deprivation in vitro. Neuroscience 68, 615–619 (1995).

    CAS  PubMed  Article  Google Scholar 

  259. Du, C. et al. Additive neuroprotective effects of dextrorphan and cycloheximide in rats subjected to transient focal cerebral ischemia. Brain Res. 718, 233–236 (1996).

    CAS  PubMed  Article  Google Scholar 

  260. Schulz, J. B. et al. Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia. Cell Death Differ. 5, 847–857 (1998).

    CAS  PubMed  Article  Google Scholar 

  261. Spinelli, E. et al. Thrombolytic-enhanced extracorporeal cardiopulmonary resuscitation after prolonged cardiac arrest. Crit. Care Med. 44, e58–e69 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  262. Xanthos, T. et al. Combination pharmacotherapy in the treatment of experimental cardiac arrest. Am. J. Emerg. Med. 27, 651–659 (2009).

    PubMed  Article  Google Scholar 

  263. Safar, P., Stezoski, W. & Nemoto, E. M. Amelioration of brain damage after 12 minutes’ cardiac arrest in dogs. Arch. Neurol. 33, 91–95 (1976).

    CAS  PubMed  Article  Google Scholar 

  264. Banks, P., Franks, N. P. & Dickinson, R. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia. Anesthesiology 112, 614–622 (2010).

    CAS  PubMed  Article  Google Scholar 

  265. Fries, M. et al. Combining xenon and mild therapeutic hypothermia preserves neurological function after prolonged cardiac arrest in pigs. Crit. Care Med. 40, 1297–1303 (2012).

    CAS  PubMed  Article  Google Scholar 

  266. Fries, M. et al. Early administration of xenon or isoflurane may not improve functional outcome and cerebral alterations in a porcine model of cardiac arrest. Resuscitation 80, 584–590 (2009).

    CAS  PubMed  Article  Google Scholar 

  267. Laitio, R. et al. Effect of inhaled xenon on cerebral white matter damage in comatose survivors of out-of-hospital cardiac arrest: a randomized clinical trial. JAMA 315, 1120–1128 (2016).

    CAS  PubMed  Article  Google Scholar 

  268. Abe, K. et al. α-Tocopherol and ubiquinones in rat brain subjected to decapitation ischemia. Brain Res. 273, 166–169 (1983).

    CAS  PubMed  Article  Google Scholar 

  269. Ikeda, M., Yoshida, S., Busto, R., Santiso, M. & Ginsberg, M. D. Polyphosphoinositides as a probable source of brain free fatty acids accumulated at the onset of ischemia. J. Neurochem. 47, 123–132 (1986).

    CAS  PubMed  Article  Google Scholar 

  270. Kabat, H., Dennis, C. & Baker, A. B. Recovery of function following arrest of the brain circulation. Am. J. Physiol. 132, 0737–0747 (1941).

    Article  Google Scholar 

  271. Rossen, R., Kabat, H. & Anderson, J. P. Acute arrest of cerebral circulation in man. Arch. Neurol. Pyschiatry 50, 510–528 (1943).

    Article  Google Scholar 

  272. Nemoto, E. M. et al. Global brain ischemia: a reproducible monkey model. Stroke 8, 558–564 (1977).

    CAS  PubMed  Article  Google Scholar 

  273. Safar, P. et al. Emergency cardiopulmonary bypass for resuscitation from prolonged cardiac arrest. Am. J. Emerg. Med. 8, 55–67 (1990). This is an important investigation demonstrating the efficacy of cardiopulmonary bypass in treating postresuscitation syndrome.

    CAS  PubMed  Article  Google Scholar 

  274. Schleien, C. L. et al. Effect of epinephrine on cerebral and myocardial perfusion in an infant animal preparation of cardiopulmonary resuscitation. Circulation 73, 809–817 (1986).

    CAS  PubMed  Article  Google Scholar 

  275. Foerster, K. et al. Twenty minutes of normothermic cardiac arrest in a pig model: the role of short-term hypothermia for neurological outcome. Perfusion 33, 270–277 (2018).

    PubMed  Article  Google Scholar 

  276. Foerster, K. et al. Prolonged cardiac arrest and resuscitation by extracorporeal life support: favourable outcome without preceding anticoagulation in an experimental setting. Perfusion 28, 520–528 (2013).

    CAS  PubMed  Article  Google Scholar 

  277. Niemann, J. T., Rosborough, J. P., Youngquist, S., Thomas, J. & Lewis, R. J. Is all ventricular fibrillation the same? A comparison of ischemically induced with electrically induced ventricular fibrillation in a porcine cardiac arrest and resuscitation model. Crit. Care Med. 35, 1356–1361 (2007).

    PubMed  Article  Google Scholar 

  278. Bergey, J. L., Nocella, K. & McCallum, J. D. Acute coronary artery occlusion-reperfusion-induced arrhythmias in rats, dogs and pigs: antiarrhythmic evaluation of quinidine, procainamide and lidocaine. Eur. J. Pharmacol. 81, 205–216 (1982).

    CAS  PubMed  Article  Google Scholar 

  279. Gildea, E. F. C. S. The effects of anemia on the cerebral cortex of the cat. Arch. Neurol. Psychiatry 23, 876–903 (1930).

    Article  Google Scholar 

  280. Blomqvist, P., Mabe, H., Ingvar, M. & Siesjo, B. K. Models for studying long-term recovery following forebrain ischemia in the rat. 1. Circulatory and functional effects of 4-vessel occlusion. Acta Neurol. Scand. 69, 376–384 (1984).

    CAS  PubMed  Article  Google Scholar 

  281. Pulsinelli, W. A. & Brierley, J. B. A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10, 267–272 (1979).

    CAS  PubMed  Article  Google Scholar 

  282. Pulsinelli, W. A., Levy, D. E. & Duffy, T. E. Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia. Ann. Neurol. 11, 499–502 (1982).

    CAS  PubMed  Article  Google Scholar 

  283. Hossmann, K. A. Experimental models for the investigation of brain ischemia. Cardiovasc. Res. 39, 106–120 (1998).

    CAS  PubMed  Article  Google Scholar 

  284. Han, F. et al. A rodent model of emergency cardiopulmonary bypass resuscitation with different temperatures after asphyxial cardiac arrest. Resuscitation 81, 93–99 (2010).

    PubMed  Article  Google Scholar 

  285. Fink, E. L. et al. Experimental model of pediatric asphyxial cardiopulmonary arrest in rats. Pediatr. Crit. Care Med. 5, 139–144 (2004).

    PubMed  PubMed Central  Article  Google Scholar 

  286. Martin, L. J. et al. Hypoxia-ischemia causes abnormalities in glutamate transporters and death of astroglia and neurons in newborn striatum. Ann. Neurol. 42, 335–348 (1997).

    CAS  PubMed  Article  Google Scholar 

  287. Zhang, K. & Sejnowski, T. J. A universal scaling law between gray matter and white matter of cerebral cortex. Proc. Natl Acad. Sci. USA 97, 5621–5626 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  288. Koehler, R. C., Yang, Z. J., Lee, J. K. & Martin, L. J. Perinatal hypoxic-ischemic brain injury in large animal models: Relevance to human neonatal encephalopathy. J. Cereb. Blood Flow. Metab. 38, 2092–2111 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  289. Diedler, J. et al. Quantitative EEG correlates of low cerebral perfusion in severe stroke. Neurocrit Care 11, 210–216 (2009).

    PubMed  Article  Google Scholar 

  290. Nagata, K., Tagawa, K., Hiroi, S., Shishido, F. & Uemura, K. Electroencephalographic correlates of blood flow and oxygen metabolism provided by positron emission tomography in patients with cerebral infarction. Electroencephalogr. Clin. Neurophysiol. 72, 16–30 (1989).

    CAS  PubMed  Article  Google Scholar 

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Authors and Affiliations

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Contributions

S.G.D., G.T., K.A.H., Z.V., K.T.G., F.B. and N.S. researched data for the article. S.G.D., G.T., K.A.H., F.B. and N.S. wrote the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Friedhelm Beyersdorf or Nenad Sestan.

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Competing interests

S.G.D., Z.V. and N.S. are listed with J. Silbereis as inventors on a patent held by Yale University entitled “Methods, systems and compositions for normothermic ex vivo restoration and preservation of intact organs” (WO2019157277A1). F.B., C.B., and G.T. are shareholders in Resuscitec GmbH, a company originating from the University of Freiburg. K.A.H., K.T.G., D.A., D. Damjanovic, J-S.P. and D. Dellal declare no competing interests.

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Glossary

Delayed neuronal death

Morphological and histological features associated with neuronal cell damage and death that become apparent multiple days following an injury or insult.

Rational polytherapy

Combination therapy that is rationally designed to target multiple deleterious mechanisms simultaneously or in a deliberate sequence.

Extracorporeal perfusion

The use of a mechanical pump device with auxiliary components that circulates either a patient’s blood or a specialized solution to provide circulatory support.

Electroencephalogram flattening

The absence of synchronous electrical activity in the brain, also known as a flat line or isoelectric reading.

Acidosis

The condition in which cellular or tissue pH decreases below the normal homeostatic range owing to the accumulation of protons.

Anoxic depolarization

An acute neuronal event involving the loss of cell membrane potentials caused by energy failure secondary to oxygen deprivation.

‘No-reflow’ phenomenon

The persistence of microvascular perfusion deficits despite the successful re-establishment of global circulation following ischaemia.

Haemodilution

The act of reducing the concentration of cells and components in the blood through the introduction of a fluid.

Erythrocyte

A red blood cell.

Haemoconcentration

The process of concentrating cells and components in the blood through the removal of fluid.

Neurovascular unit

A specialized functional and structural unit in the brain composed of endothelial, glial and neuronal cells that facilitate coupling between neuronal activity and blood flow.

Blood–brain barrier

(BBB). A specialized barrier within the vasculature of the brain that limits the non-selective movement of peripheral blood components into the brain.

Glycocalyx

A network of biomolecules that line the luminal surface of the cerebrovascular endothelium.

Weibel–Palade bodies

Storage granules in endothelial cells that contain multiple biomolecules, such as P-selectin.

Excitotoxicity

A pathological process by which neurons are damaged and killed through the overactivation of cellular receptors by the excitatory neurotransmitter glutamate.

Simulated in vitro ischaemia

An experimental method through which cultured cells and tissues are subjected to conditions similar to in vivo ischaemia by the combination of hypoxia and hypoglycaemia.

Necrosis

A form of cell death that results from unregulated digestion or autolysis of the cell.

Reverse electron transfer

The process by which electrons are transferred in the reverse order in the electron transport chain, leading to the reduction of NAD+.

Non-shockable

Describing cardiac rhythms that are incompatible with electrical defibrillation, such as pulseless electrical activity and asystole.

Proximal occlusions

Clots or blockages in the proximal parts of large vessels (for example, of the neck or base of the brain).

Perfluorocarbon

A class of organic molecules that form the basis of solvents with high oxygen-carrying capacities.

Histotoxic hypoxia

A chemically induced form of hypoxia in which cells are unable to utilize oxygen despite adequate delivery or concentration of oxygen.

Ventricular fibrillation

An abnormal cardiac rhythm in which the ventricles display erratic and uncoordinated contractions (fibrillation) owing to aberrant electrical conduction.

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Daniele, S.G., Trummer, G., Hossmann, K.A. et al. Brain vulnerability and viability after ischaemia. Nat Rev Neurosci 22, 553–572 (2021). https://doi.org/10.1038/s41583-021-00488-y

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