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Experimental Neuroprotection: Translation to Human Stroke Trials

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Maturation Phenomenon in Cerebral Ischemia V

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Summary

For a drug to be effectivein vivo in-vitroprotection must be translated to studies of both global (transient forebrain ischemia) to discern “cellular” neuroprotection (cytoprotection) and focal ischemia to evaluate “parenchymal” neuroprotection (infarct reduction). Drug concentrations that suggest that the mechanism is activein vitromust translate to drug levels that achieve cytoprotection and infarct volume reductions which are not only significant but sustained (indefatigable). Initiation of experimental therapy should be delayed in order to have clinical relevance. Most importantly, the “effective dose” plasma level reached in rodents to achieve a neuroprotective effect must be matched in humans, in the absence of overt toxicity.

To date there are a number of shortcomings with “cytoprotective drugs” - in rats, in particular, their inability to protect white matter and striatum. The drugs have to be given early and the cytoprotective dose in rats has yet to be achieved in humans.

This review covers mechanisms of cell death following both focal and global ischemia such as excitotoxicity, acid and Ca’ overload, free radical-mediated injury, inflammation and apoptosis.

Drugs which block NMDA and AMPA receptors, as well as downstream events, have now made it to the clinic and they will be critically reviewed. Hypothermia following both global and focal ischemia is protective and at least for global ischemia has now been translated two successful clinical trials in patients resuscitated from cardiac arrest. For the first time neuroprotection has been demonstrated in patients who achieved better neurological outcomes. The review will finish with some rules for the translation of experimental work to clinical trials.

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References

  1. Adams JM, Cory S (1998) The Bd-2 protein family: arbiters of cell survival. Science 281:1322–1326

    PubMed  CAS  Google Scholar 

  2. Antonawich FJ (1999) Translocation of cytochrome C following transient global ischemia in the gerbil. Neurosci Lett 274:123–126

    PubMed  CAS  Google Scholar 

  3. Antonawich FJ, Krajewski S, Reed JC, Davis JN (1998) Bcl-x(1) Bax interaction after transient global ischemia. J Cereb Blood Flow Metab 18:882–886

    PubMed  CAS  Google Scholar 

  4. Barone FC, Hillegass ZM, Rzimas MN, Schmidt DB, Folley JJ, White RF, Price WJ, Feuerstein GZ, et al (1991) Polymorphonuclear leukocyte infiltration into cerebral focal ischemic tissue: myeloperoxidase activity and histologic verification. J Neurosci Res 29:336–345

    PubMed  CAS  Google Scholar 

  5. Barone FC, Hillegass ZM, Rzimas MN, Schmidt DB, Folley JJ, White RF, Price WJ, Feuerstein GZ, Clark RK, Griswald DE, Sarau HM (1995) Time related changes in myeloperoxidase activity and leukotriene B4 receptor binding reflect leukocyte influx in cerebral focal stroke. Mol Chem Neuropathol 24:13–30

    CAS  Google Scholar 

  6. Baudry M, Bundman MC, Smith EK, Lynch GS (1981) Micromolar calcium stimulates proteolysis and glutamate binding in rat brain synaptic membranes. Science 212:937–938

    PubMed  CAS  Google Scholar 

  7. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K (2002) Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 346:557–563

    PubMed  Google Scholar 

  8. Betz AL, Yang G-Y, Davidson BL (1995) Attenuation of stroke size in rats using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist in brain. J Cereb Blood Flow Metab 15:547–551

    PubMed  CAS  Google Scholar 

  9. Bruce AJ, Boling W, Kindy MS, Pesheni J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP (1996) Altered neuronal and microglial responses to excitotoxic and ischemic brain in mice lacking TNF receptors. Nature Med 2:788–794

    PubMed  CAS  Google Scholar 

  10. Buchan AM (1990) Do NMDA antagonists protect against cerebral ischemia: are clinical trials warranted? Cerebrovascular & Brain Metabolism Reviews 2:1–26

    CAS  Google Scholar 

  11. Buchan AM, Pulsinelli WA (1990) Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci 10:311–316

    PubMed  CAS  Google Scholar 

  12. Buchan AM, Li H, Cho SH, Pulsinelli WA (1991) Blockade of the AMPA receptor prevents CAIhippocampal injury following severe but transient forebrain ischemia in adult rats. Neurosci Let 132:255–258

    CAS  Google Scholar 

  13. Buchan AM, Li H, Pulsinelli WA (1991) N-Methyl-D-Aspartate antagonists, MK801, fails to protect against neuronal damage caused by transient severe forebrain ischemia in adult rats. J Neuroscience 11:1049–1056

    CAS  Google Scholar 

  14. Buchan AM, Xue D, Huang ZG, Smith KE, Lesiuk H (1991) Delayed AMPA receptor blockade reduces cerebral infarction induced by focal ischemia. NeuroReport 2:473–476

    PubMed  CAS  Google Scholar 

  15. Buchan AM, Xue D, Slivka A (1992) A new model of temporary focal neocortical ischemia in the rat. Stroke 23:273–279

    PubMed  CAS  Google Scholar 

  16. Buchan AM (2001) “Neuroprotective stroke trials: a ten year dry season”. Update in Intensive Care and Emergency Medicine 37:236–251

    Google Scholar 

  17. Budd SL (1998) Mechanisms of neuronal damage in brain hypoxia/ischemia: focus on the role of mitochondrial calcium accumulation. Pharmacol Ther 80:203–229

    PubMed  CAS  Google Scholar 

  18. Charriaut-Marlangue C, Richard E, Ben-Ari Y (1999) DNA damage and DNA damage-inducible protein Gadd45 following ischemia in the P7 neonatal rat. Brain Res Dev Brain Res 116:133–140

    PubMed  CAS  Google Scholar 

  19. Chen H, Chopp M, Bodzin G (1992) Neutropenia reduces the volume of cerebral infarct after transient middle cerebral artery occlusion in the rat. Neurosci Res Comm 11:93–99

    Google Scholar 

  20. Chen J, Graham SH, Chan PH, Lan J, Zhou RL, Simon RP (1995) Bcl-2 is expressed in neurons that survive focal ischemia in the rat. NeuroReport 6:394–398

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  22. Chopp M, Li Y, Zhang ZG, Freytag SO (1992) P53 expression in brain after middle cerebral artery occlusion in the rat. Biochem Biophys Res Comm 182:1201–1207

    PubMed  CAS  Google Scholar 

  23. Clark RK, Lee EV, Fish CJ, White RF, Price WJ, Jonak GZ, Feuerstein GZ, Barone FC (1993) Development of tissue damage, inflammation and resolution following stroke: an immunohistochemical and quantitative planimetric study. Brain Res Bull 35:623–639

    Google Scholar 

  24. Colbourne F, Corbett D, Zhao Z, Yang J, Buchan AM (2000) Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. Cereb Blood Flow Metab 20:1702–1708

    CAS  Google Scholar 

  25. Colbourne F, Li H, Buchan AM (1999) Continuing post-ischemic neuronal death in CAl: Influence of ischemia duration, and cytoprotective doses of NBQX and SNX-111. Stroke 30:662–668

    PubMed  CAS  Google Scholar 

  26. Colbourne F, Li H, Buchan AM (1999) Indefatigable CAI sector neuroprotection with mild hypothermia induced 6 h after severe forebrain ischemia in rats. J Cereb Blood Flow Metab 19:742–749

    PubMed  CAS  Google Scholar 

  27. Crumrine RC, Thomas AL, Morgan PF (1994) Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J Cereb Blood Flow Metab 14:887–891

    PubMed  CAS  Google Scholar 

  28. Cryns V, Yuan J (1998) Proteases to die for. Genes Dev 12:1551–1570

    PubMed  CAS  Google Scholar 

  29. Davalos A, Fernandez-Real JM, Rilart M (1994) Iron related damage in acute ischemic stroke. Stroke 24:1543–1546

    Google Scholar 

  30. Del Zoppo GJ, Schmid-Schonbein GW, Mori E, Copeland BR, Chang CM (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22:1276–1283

    PubMed  Google Scholar 

  31. Denner L (1999) Caspases in apoptic death. Exp Opin Invest Drugs 8:37–50

    CAS  Google Scholar 

  32. Dereski MO, Chopp M, Knight RA, Chen H, Garcia JH (1992) Focal cerebral ischemia in the rat: temporal profile of neutrophil responses. Neuroscience Res Comm 11:179–186

    Google Scholar 

  33. Dereski MO, Chopp M, Knight RA, Rodolosi LC, Garcia JH (1993) The heterogeneous temporal evolution of focal ischemic neuronal damage in the rat. Acta Neuropathol [Berl] 85:327–333

    CAS  Google Scholar 

  34. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397

    PubMed  CAS  Google Scholar 

  35. Dinarello CA (1996) Biology of interleukin-1. FASEB J 2:108–115

    Google Scholar 

  36. Dopp J, de Vellis J (1998) Strategies or therapeutic manipulation of cytokines and their receptors in inflammatory neurodegenerative diseases. Ment Retard Devel Disabil Res Rev 4:200–211

    Google Scholar 

  37. Dong H, Moody-Corbett F, Colbourne F, Pittman Q, Corbett D (2001) Electrophysiological properties of CAl neurons protected by postischemic hypothermia in gerbils. Stroke 32:788–795

    PubMed  CAS  Google Scholar 

  38. Dubai DB, Shughrue PJ, Wilson ME, Merchenthaler I, Wise PM (1999) Estradiol modulates bd-2 in cerebral ischemia: a potential role for estrogen receptors. J Neurosci 19:494–498

    Google Scholar 

  39. Dukta AJ, Kochanek PM, Hallenbeck JM (1989) Influence of granulocytopenia on canine cerebral ischemia induced by embolism. Stroke 20:390–395

    Google Scholar 

  40. Eldadah BA, Faden AI (2000) Caspase pathways, neuronal apoptosis and CNS injury. J Neurotrauma 17:811–829

    PubMed  CAS  Google Scholar 

  41. Ellison JA, Vellier JJ, Spera PA, Jonak ZL, Wang XK, Barone FC, Feuerstein GZ (1998) Osteopontin and its integrin receptor avb3 are upregulated during formation of the glial scar following focal stroke. Stroke 29:1698–1707

    PubMed  CAS  Google Scholar 

  42. Endes M, Namura S, Shimizu-Sasamota M, Waeber C, Zhang L, Gomez-Isla T, Hyman BT, Moskowitz MA (1998) Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab 18:238–247

    Google Scholar 

  43. Feuerstein GZ, Wang XK, Barone FC (1998) Inflammatory mediators of ischemic injury: cytokine gene regulation in stroke. In: Ginsberg MD, Bogousslowsky J (eds) Cerebrovascular disease: pathophysiology, diagnosis and management. Blackwell Science, pp 507–531

    Google Scholar 

  44. Friberg H, Connern C, Halestrap AP, Wieloch T (1999) Differences in the activation of the mitochondrial permeability transition among brain regions in the rat correlate with selective vulnerability. J Neurochem 72:2488–2497

    PubMed  CAS  Google Scholar 

  45. Fujimura M, Morita-Fujimura Y, Kawase M, Copin JC, Calagui B, Epstein CJ, Chan PH (1999) Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome C and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice. J Neurosci 19:3414–3422

    PubMed  CAS  Google Scholar 

  46. Garcia JE, Nonner D, Ross, Barrett JN (1992) Neurotoxic components in normal serum. Exp Neurol 118:309–316

    PubMed  CAS  Google Scholar 

  47. Gillardon F, Lenz C, Waschke KF, Krajewski S, Reed JC, Zimmermann M, Kuschinsky W (1996) Altered expression of Bel-2, Bel-X, and c-Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. Mol Brain Res 40:254–260

    PubMed  CAS  Google Scholar 

  48. Graham SH, Chen J, Clark RSB (2000) Bd-2 family gene products in cerebral ischemia and traumatic brain injury. J Neurotrauma 17:831–841

    PubMed  CAS  Google Scholar 

  49. Granger DN, Kvietys PR (1993) Leukocyte-endothelial adhesion induced by ischemia and re-perfusion. Can J Physiol Pharmacol 71:67–75

    PubMed  CAS  Google Scholar 

  50. Guillian D, Chen J, Ingman JE, George JK, Noponen M (1989) The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain. J Neurosci 9:4410–4429

    Google Scholar 

  51. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Dounan G, Schneider D, Diez-Tejedor E, Trouillas P (1998) Randomised double blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke [ECASS II]. Lancet 352:1245–1251

    PubMed  CAS  Google Scholar 

  52. Hallenbeck JM, Dutka AJ, Tanishima T, Kochanek PM, Kumaroo KK, Thompson CB, Obrenovitch TP, Contreras TJ (1986) Polymorphonuclear leukocyte accumulation in brain regions with low blood flow during the early postischemic period. Stroke 17:246–253

    PubMed  CAS  Google Scholar 

  53. Hara H, Fink K, Endres M, Friedlander RM, Gaglardini V, Juan J, Moskowitz MA (1997a) Attenuation of transient focal cerebral ischemia injury in transgenic mice expressing a mutant ICE inhibitory protein. J Cereb Blood Flow Metab 17:370–375

    CAS  Google Scholar 

  54. Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z, Shimizu-Sasamata, Ayata C, Fink K, Huang Z, Shimizu-Sasamata M, Yuan J, Moskowitz MA (1997b) Inhibition of interleukin 1: Converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA 94:2007–2012

    CAS  Google Scholar 

  55. Hata R, Maeda K, Hermann D, Mies G, Hossmann K-A (2000) Evolution of brain infarction after transient focal cerebral ischemia in mice. Cereb Blood Flow Metab 20:937–946

    CAS  Google Scholar 

  56. Huang ZG, Xue D, Preston E, Karbalai H, Buchan AM (1999) Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. The Cana Neurol Sci 26:4, 298–304

    CAS  Google Scholar 

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

    Google Scholar 

  58. Hirschberg DL, Yoles E, Belkin M, Shwartz M (1994) Inflammation after axonal injury has conflicting consequences for recovery of function: rescue of spared axons is impaired but regeneration is supported. J Neuroimmunol 50:9–16

    PubMed  CAS  Google Scholar 

  59. Hossman KA, Hata R, Maeda K, Trapp T, Mies G (2003) Transgenic Mutants for the Investigation of Molecular Stroke Mechanisms. Maturation Phenomenon in Cerebral Ischemia, Vol V

    Google Scholar 

  60. Hou ST, Tu Y, Buchan AM, Huang Z, Preston E, Rasquinha I, Robertson GS, MacManus JP (1997) Increases in DNA lesions and the DNA damage indicator Gadd45 following transient cerebral ischemia. Biochem Cell Biol 75:383–392

    PubMed  CAS  Google Scholar 

  61. Hsu CY, An G, Liu JS, Xue JJ, He YY, Lin TN (1993) Expression of immediate early gene and growth factor mRNAs in a focal cerebral ischemia model in the rat. Stroke 24:178

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  63. Kaplan B, Brint S, Tanabe J, Jacewicz M, Wang XJ, Pulsinelli W (1991) Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke 22:1032–1039

    PubMed  CAS  Google Scholar 

  64. Kochanek PM, Hallenback JM (1992) Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke. Stroke 23:1367–1379

    PubMed  CAS  Google Scholar 

  65. Kogure K, Yamasaki Y, Matsuo Y, Kato H, Onodera H (1996) Inflammation of the brain after ischemia. Acta Neurochir 66 (suppl):40–45

    CAS  Google Scholar 

  66. Krajewski S, Mai JK, Krajewska M, Sikorska M, Mossakowski MJ, Reed JC (1995) Upregulation of box protein levels in neurons following cerebral ischemia. J Neurosci 15:6364–6376

    PubMed  CAS  Google Scholar 

  67. Krajewski S, Krajewska M, Ellerby LM, Welsh K, Xie Z, Deveraux QL, Salvesen GS, Bredesen DE, Rosenthal RE, Fiskum G, Reed JC (1999) Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci USA 11:5752–5757

    Google Scholar 

  68. Kuida K, Loppke JA, Ku G, Harding MW, Livingston DJ, Su MSS, Flavell RA (1995) Altered cytokine export and apoptosis in mice deficient in interleukin 1/! converting enzyme. Science 217:2000–2002

    Google Scholar 

  69. Lazarov-Spiegler O, Rapalino O, Agranov G, Schwartz M (1998) Restricted inflammatory reaction in CNS: A key impediment to axonal regeneration? Molec Med Today 4:337–342

    CAS  Google Scholar 

  70. Lee JL, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399 (suppl):A7–A14

    PubMed  CAS  Google Scholar 

  71. Lemasters JJ, Qian T, Elmore SP, Trost LC, Nishimura Y, Herman B, Bradham CA, Brenner DA, Nieminen AL (1998) Confocal microscopy of the mitochondrial permeability transition in necrotic cell killing, apoptosis and autophagy. Biofactors 8:283–285

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  73. Li H, Colbourne F, Sun P, Zhao Z, Buchan AM (2000) Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats. Stroke 31:176–182

    PubMed  CAS  Google Scholar 

  74. Li Y, Chopp M, Zhang ZG, Zaloga C, Niewenhuis L, Gantam S (1994) P53-immunoreactive protein and P53 mRNA expression after transient middle cerebral artery occlusion in rats. Stroke 25:849–856

    PubMed  CAS  Google Scholar 

  75. Liu T, Young PR, McDonnell PC, White RF, Barone FC, Feuerstein GZ (1993) Cytokine-induced neutrophil chemoattractant mRNA expressed in cerebral ischemia. Neurosci Lett 164:125–128

    PubMed  CAS  Google Scholar 

  76. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ (1994) Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25:1481–1488

    PubMed  CAS  Google Scholar 

  77. Loddick SA, Rothwell NJ (1996) Neuroprotective effects of human recombinant interleukin-1 receptor. J Cereb Blood Flow Metab 16:932–940

    PubMed  CAS  Google Scholar 

  78. Loddick SA, MacKenzie A, Rothwell NJ (1996) An ICE inhibitor z-VAD-dbc attenuates ischaemic brain damage in the rat. NeuroReport 7:1465–1468

    PubMed  CAS  Google Scholar 

  79. Ma J, Endes M, Moskowitz MA (1998) Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischemia in mice. Br J Pharmacol 124:756–762

    PubMed  CAS  Google Scholar 

  80. MacManus JP, Buchan AM (2000) Apoptosis after experimental stroke: fact or fashion? J Neurotrauma 17:899–913

    PubMed  CAS  Google Scholar 

  81. Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, Alberti-ni P, Talabot D, Catsicas S, Pietra C, et al (1994) Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017–1030

    PubMed  CAS  Google Scholar 

  82. Matsushita K, Matsuyama T, Kitagawa K, Matsumoto M, Yanagihara T, Sugita M (1998) Alterations of Bd-2 family proteins precede cytoskeletal proteolysis in the penumbra, but not in infarct centres following focal cerebral ischemia in mice. Neuroscience 83:439–448

    PubMed  CAS  Google Scholar 

  83. Miller RJ (1987) Multiple calcium channels and neuronal function. Science 235:46–53

    PubMed  CAS  Google Scholar 

  84. Minami M, Kyraishi Y, Yabunchi K, Yamazaki A, Satoh M (1992) Induction of interleukin-1ß mRNA in rat brain after transient forebrain ischemia. J Neurochem 58:390–392

    PubMed  CAS  Google Scholar 

  85. Murphy AN, Fiskum G, Beal MF (1999) Mitochondria in neurodegeneration: bioenergetic function in cell life and death. J Cereb Blood Flow Metab 19:231–245

    PubMed  CAS  Google Scholar 

  86. Nakatsuka H, Ohta S, Tanaka J, Toku K, Kumon Y, Maeda N, Sakanaka M, Sakaki S (1999) Release of cytochrome C from mitochondria to cytosol in gerbil hippocampal CAl neurons after transient forebrain ischemia. Brain Res 849:216–219

    PubMed  CAS  Google Scholar 

  87. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. New Engl J Med 333:1581–1587

    Google Scholar 

  88. Nawashiro H, Tasaki K, Ruetzlav CA, Hallenbeck JM (1997) TNF-alpha pretreatment induces protective effects against focal cerebral ischemia in mice. J Cereb Blood Flow Metab 17:483–490

    PubMed  CAS  Google Scholar 

  89. Okada Y, Copeland BR, Mori E, Tung MM, Thomas WS, del Zoppo GJ (1994) P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion. Stroke 25:202–211

    PubMed  CAS  Google Scholar 

  90. Okutsuki T, Reutzler CA, Tasaki K, Hallenbeck JM (1996) Induction of tolerance to ischemia by preconditioned interleukin-la in gerbil hippocampal neurons. J Cereb Blood Flow Metab 16:1137–1142

    Google Scholar 

  91. Ouyang YB, Kuroda S, Kristian T, Siesjo BK (1997) Release of mitochondrial aspartate aminotransferase (mast) following transient focal cerebral ischemia suggests the opening of a mitochondrial permeability transition pore. Neurosci Res Commun 20:167–173

    CAS  Google Scholar 

  92. Park SW, Kim YB, Hwang SN, Choi DY, Kwon JT, Min BK, Suk JS (2000) The effects of Nmethyl-N-nitrosourea and azoxymethane on focal cerebral infarction and the expression of p53, p21 proteins. Brain Res 855:298–306

    PubMed  CAS  Google Scholar 

  93. Pellegrini-Giampietro DE, Zukin RS, Bennett MVL, Cho S, Pulsinelli WA (1992) Switch in glutamate receptor subunit gene expression in CAIsubfield of hippocampus following global ischemia in rats. Proc Natl Acad Sci USA 89:10499–10503

    PubMed  CAS  Google Scholar 

  94. Piani D, Spranger M, Frei K, Schaffner A, Fontana A (1992) Macrophage-induced cytotoxicity of N-methyl-D-aspartate receptor positive neurons involves excitatory amino acids rather than reactive oxygen intermediates and cytokines. Eur J Immunol 22:2429–2436

    PubMed  CAS  Google Scholar 

  95. Pozzilli C, Lenzi GL, Argentino C, Carolei A, Raura M, Signor A, Bozzao L, Pozzilli P (1985) Imaging of leukocyte infiltration in lumen cerebral infarcts. Stroke 16:251–255

    PubMed  CAS  Google Scholar 

  96. Pulsinelli WA, Brierly JB (1979) A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke 10:267–272

    PubMed  CAS  Google Scholar 

  97. Pulsinelli WA, Buchan AM (1988) The four-vessel occlusion rat model: method for complete occlusion of vertebral arteries and control of collateral circulation. Stroke 19:913–914

    PubMed  CAS  Google Scholar 

  98. Pulsinelli WA, Duffy TE (1983) Regional energy balance in rat brain after transient forebrain ischemia. J Neurochem 40:1500–1503

    PubMed  CAS  Google Scholar 

  99. Relton JK, Martin D, Thompson RC, Russell DA (1996) Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol 138:206–213

    PubMed  CAS  Google Scholar 

  100. Ritter L, Coull B, Davisgomen G, McDonough P (1998) Leukocytes accumulate in the cerebral microcirculation during the first hour of reperfusion following stroke. FASEB J 12:188

    Google Scholar 

  101. Romanic AM, White RF, Arleth AJ, Ohlstein EO, Barone FC (1998) Matrix metalloproteinase expression increases following cerebral ischemia: inhibition of MMP-9 reduces infarct size. Stroke 29:1020–1030

    PubMed  CAS  Google Scholar 

  102. Rosenberg GA, Navratil M, Barone F, Feuerstein G (1996) Proteolytic cascade enzymes increase in focal cerebral ischemia in rat. J Cereb Blood Flow Metab 16:360–366

    PubMed  CAS  Google Scholar 

  103. Rothwell NJ (1991) Functions and mechanisms of interleukin-1 in the brain. Trends Pharmacol Sci 12:430–435

    PubMed  CAS  Google Scholar 

  104. Rothwell NJ (1997) Cytokines and acute neurodegeneration. Mol Psych 2:120–121

    CAS  Google Scholar 

  105. Rothwell NJ, Luheshi GN (1996) Brain TNF: damage limitation or damaged reputation? Nature Med 2:746–747

    PubMed  CAS  Google Scholar 

  106. Schielke GP, Yang GY, Shivers BD, Betz AL (1998) Reduced ischemic brain injury in interleukin-1 beta converting enzyme-deficient mice. J Cereb Blood Flow Metab 18:180–185

    PubMed  CAS  Google Scholar 

  107. Sheardown MJ, Nielson EO, Hansen AJ, Jacobsen P, Honre T (1990) 2,3-Dihydroxy-6-nitro-7sulfamoyl-benzo[F] quinoxaline: a neuroprotectant for cerebral ischemia. Science 247:571–574

    PubMed  CAS  Google Scholar 

  108. Siesjö BK (1992a) Pathophysiology and treatment of focal cerebral ischemia. Part I: Pathophysiology. J Neurosurg 77:169–184

    Google Scholar 

  109. Siesjö BK (1992b) Pathophysiology and treatment of focal cerebral ischemia. Part II: Pathophysiology. J Neurosurg 77:351–354

    Google Scholar 

  110. Siesjö BK, Kristian T, Katsura K (1998) Overview of bioenergetic failure and metabolic cascades in brain ischemia. In: Ginsberg MD, Bogousslaysky J (eds) Cerebrovascular disease. Blackwell Science, pp 3–13

    Google Scholar 

  111. Sionov RV, Haupt Y (1999) The cellular response to p53: the decision between life and death. Oncogene 18:6145–6157

    PubMed  CAS  Google Scholar 

  112. Smith ML, Bendek G, Dahlgren N, Rosen I, Wieloch T, Siesjö BK (1984) Models for studying long-term recovery following forebrain ischemia in the rat: a 2-vessel occlusion model. Acta Neurol Scand 69:385–401

    CAS  Google Scholar 

  113. Sugawara T, Fujimura M, Morita-Fujimura Y, Kawase M, Chan PH (1999) Mitochondrial release of cytochrome C corresponds to the selective vulnerability of hippocampal CAI neurons in rats after transient global cerebral ischemia. J Neurosci 19:RC39:1–6

    Google Scholar 

  114. Takao T, Tracey DE, Mitchel WM, De Souza EB (1990) Interleukin-1 receptors in mouse brain: characterisation and neuronal localisation. Endocrinology 127:3070–3078

    PubMed  CAS  Google Scholar 

  115. Tomasevic G, Kamme F, Stubberod P, Wieloch M, Wieloch T (1999) The tumor suppressor p53 and its response gene p21 WAFI/Cipl are not markers of neuronal death following transient global cerebral ischemia. Neuroscience 90:781–792

    PubMed  CAS  Google Scholar 

  116. Tu Y, Hou ST, Huang Z, Robertson GS, MacManus JP (1998) Increased Mdm2 expression in rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 18:658–669

    PubMed  CAS  Google Scholar 

  117. van Lookeren Campagne M, Gill R (1998) Increased expression of cyclin G1 and p21WAF1/ CIP1 in neurons following transient forebrain ischemia: comparison with early DNA damage. J Neurosci Res 53:279–296

    PubMed  Google Scholar 

  118. Wang X, Siren AL, Liu Y, Yue TL, Barone FC, Feuerstein GZ (1994b) Upregulation of intracellular adhesion molecule-1 (ICAM-1) on brain microvascular endothelial cells in rat ischemic cortex. Mol Brain Res 26:61–68

    CAS  Google Scholar 

  119. Wang X, Yue T-L, Barone FC, White RF, Gagnon RC, Feuerstein GZ (1994) Concomitant cortical expression of TNFa and IL-lß mRNA follows early response gene expression in transient focal ischemia. Mol Chem Neuropathol 23:103–114

    PubMed  CAS  Google Scholar 

  120. Wang X, Yue TL, Barone FC, Feuerstein GZ (1995a) Demonstration of increased endothelial-leukocyte adhesion molecule-1 mRNA expression in rat ischemic cortex. Stroke 26:1665–1669

    CAS  Google Scholar 

  121. Wang X, Yue TL, Barone FC, Feuerstein GZ (1995b) Monocyte chemoattractant protein-1 (MCP-1) mRNA expression in rat ischemic cortex. Stroke 26:661–666

    CAS  Google Scholar 

  122. Wang X, Yue TL, Young PR, Barone FC, Feuerstein GZ (1995) Expression of interleukin-6, cfos, and zif268 mRNA in rat ischemic cortex. J Cereb Blood Flow Metab 15:166–171

    PubMed  CAS  Google Scholar 

  123. Wang X, Barone FC, Aiyar NV, Feuerstein GZ (1997) Interleukin-1 receptor and receptor antagonist gene expression after focal stroke in rats. Stroke 28:155–162

    PubMed  CAS  Google Scholar 

  124. Wang X, Ellison JA, Siren AL, Lysko PG, Yue TL, Barone FC, Shatzman A, Feuerstein GZ (1998) Prolonged expression of interferon inducible protein 10 in ischemic cortex after permanent occlusion of the middle cerebral artery in rat. J Neurochem 71:1194–1204

    PubMed  CAS  Google Scholar 

  125. Wardlaw JM, Yamaguchi T, del Zoppo G (1999) Thrombolytic therapy versus control in acute ischaemic stroke. Stroke module of the Cochrane Database of Systematic Reviews. Available in the Cochrane Library (database on disk and CDROM). Oxford: Update software

    Google Scholar 

  126. Watanabe H, Ohta S, Kumon Y, Sakaki S, Sakanaka M (1999) Increase in p53 protein expression following cortical infarction in the spontaneously hypertensive rat. Brain Res 837:38–45

    PubMed  CAS  Google Scholar 

  127. Xue D, Huang ZG, Smith KE, Buchan AM (1992) Immediate or delayed mild hypothermia prevents focal cerebral infarction. Brain Research 587:66–72

    PubMed  CAS  Google Scholar 

  128. Xue D, Huang ZG, Barnes K, Lesiuk HJ, Smith KE, Buchan AM (1994) Delayed treatment with AMPA, but not NMDA, antagonists reduces neocortical infarction. J Cereb Blood Flow Metab 14:251–261

    PubMed  CAS  Google Scholar 

  129. Yabucchi K, Minami M, Katsumata S, Yamazaki A, Satoh M (1994) An in situ hybridization study on interleukin-lß mRNA induced by transient forebrain ischemia in the rat brain. Mol Brain Res 26:135–142

    Google Scholar 

  130. Yao H, Ibayashi S, Nakane H, Cai H, Uchimura H, Fujishima M (1997) AMPA receptor antagonist, YM90K, reduces infarct volume in thrombotic distal middle cerebral artery occlusion in spontaneously hypertensive rats. Brain Res 753:80–85

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Professor of Neurology, Department of Clinical Neurosciences, University of Calgary, Rm 1162, 1403-29 Street N.W., Calgary, Alberta, Canada, T2N 2T9

    A. M. Buchan

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  1. P. A. Barber
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  2. B. Bruederlin
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  3. A. M. Buchan
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Editors and Affiliations

  1. Office of Stroke Research, Foothills Medical Centre, Rm 1162, 1403-29 Street N.W., Calgary, Alberta, T2N 2T9, Canada

    Alastair M. Buchan

  2. Department of Neurosurgery, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shu, Tokyo, 180-0023, Japan

    Umeo Ito

  3. Department of Psychology, University of Alberta, Edmonton, Alberta, T6G 2E9, Canada

    Fred Colbourne

  4. Department of Neuropathology Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku 113, Tokyo, Japan

    Toshihiko Kuroiwa

  5. Laboratory of Neuropathology and Neuroanatomical Sciences, NINDS, National Institutes of Health, Bethesda, Maryland, 20892-4128, USA

    Igor Klatzo

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© 2004 Springer-Verlag Berlin Heidelberg

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Barber, P.A., Bruederlin, B., Buchan, A.M. (2004). Experimental Neuroprotection: Translation to Human Stroke Trials. In: Buchan, A.M., Ito, U., Colbourne, F., Kuroiwa, T., Klatzo, I. (eds) Maturation Phenomenon in Cerebral Ischemia V. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18713-1_14

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  • DOI: https://doi.org/10.1007/978-3-642-18713-1_14

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-40874-1

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