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What animal models have taught us about the treatment of acute stroke and brain protection

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Abstract

Stroke research has progressed in leaps and bounds in the past decades. A driving force is the increasing availability of new research tools in this field (eg, animal stroke models). Animal stroke models have been extensively applied to advance our understanding of the mechanisms of ischemic brain injury and to develop novel therapeutic strategies for reducing brain damage after a stroke. Animal stroke models have been useful in characterizing the molecular cascades of injury processes. These “injury pathways” are also the targets of therapeutic interventions. The major achievements made in the past 2 decades applying animal stroke models include 1) the identification of the mediator role of excitotoxin and oxygen free radicals in ischemic brain injury; 2) the confirmation of apoptosis as a major mechanism of ischemic cell death; 3) the characterization of postischemic gene expression; 4) the delineation of postischemic inflammatory reaction; 5) the application of transgenic mice to confirm the roles of purported mediators in ischemic brain injury; 6) development of novel magnetic resonance imaging sequences for early noninvasive detection of ischemic brain lesions; and, 7) the development of novel therapeutic strategies based on preclinical findings derived from animal stroke models.

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References and Recommended Reading

  1. Lee JM, Zipfel GJ, Choi DW: The changing landscape of ischaemic brain injury mechanisms. Nature 1999, 399(6738 Suppl):A7–14

    PubMed  CAS  Google Scholar 

  2. Fisher M, Bogousslavsky J: Further evolution toward effective therapy for acute ischemic stroke. JAMA 1998, 279:1298–1303.

    Article  PubMed  CAS  Google Scholar 

  3. Zivin JA, Fisher M, DeGirolami U, et al.: Tissue plasminogen activator reduces neurological damage after cerebral embolism. Science 1985, 230:1289–1292.

    Article  PubMed  CAS  Google Scholar 

  4. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995, 333:1581–1587.

    Article  Google Scholar 

  5. Kwiatkowski TG, Libman RB, Frankel M, et al.: Effects of tissue plasminogen activator for acute ischemic stroke at one year: National Institute of Neurological Disorders and Stroke Recombinant Tissue Plasminogen Activator Stroke Study Group. N Engl J Med 1999, 340:1781–1787.

    Article  PubMed  CAS  Google Scholar 

  6. Molinari GF: Why model strokes? Stroke 1988, 19:1195–1197.

    PubMed  CAS  Google Scholar 

  7. Hsu CY: Criteria for valid preclinical trials using animal stroke models. Stroke 1993, 24:633–636.

    PubMed  CAS  Google Scholar 

  8. Hossmann KA: Viability threshold and the penumbra of focal ischemia. Ann Neurol 1994, 36:557–565.

    Article  PubMed  CAS  Google Scholar 

  9. Du C, Hu R, Csernansky CA, et al.: Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab 1996, 16:195–201.

    Article  PubMed  CAS  Google Scholar 

  10. Hara H, Friedlander RM, Gagliardini V, et al.: Inhibition of interleukin 1 beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci USA 1997, 94:2007–2012.

    Article  PubMed  CAS  Google Scholar 

  11. Pulsinelli WA, Brierley JB, Plum F: Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 1982, 11:491–498.

    Article  PubMed  CAS  Google Scholar 

  12. Ginsberg MD, Busto R: Rodent models of cerebral ischemia. Stroke 1989,20:1627–1642.

    PubMed  CAS  Google Scholar 

  13. Hossmann KA: Experimental models for the investigation of brain ischemia. Cardiovasc Res 1998, 39:106–120.

    Article  PubMed  CAS  Google Scholar 

  14. Chan PH, Kawase M, Murakami K, et al.: Overexpression of SOD1 in transgenic rats protects vulnerable neurons against ischemic damage after global cerebral ischemia and reperfusion. J Neurosci 1998, 18:8292–8299.

    PubMed  CAS  Google Scholar 

  15. Guegan C, Onteniente B, Makiura Y, et al.: Reduction of cortical infarction and impairment of apoptosis in NGF-transgenic mice subjected to permanent focal ischemia. Mol Brain Res 1998, 55:133–140.

    Article  PubMed  Google Scholar 

  16. MacMillan V, Judge D, Wiseman A, et al.: Mice expressing a bovine basic fibroblast growth factor transgene in the brain show increased resistance to hypoxemic-ischemic cerebral damage. Stroke 1993, 24:1735–1739.

    PubMed  CAS  Google Scholar 

  17. Martinou JC, Dubois-Dauphin M, et al.: Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 1994, 13:1017–1030.

    Article  PubMed  CAS  Google Scholar 

  18. Parsadanian AS, Cheng Y, Keller-Peck CR, et al.: Bcl-xL is an antiapoptotic regulator for postnatal CNS neurons. J Neurosci 1998, 18:1009–1019.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  20. Wang YF, Tsirka SE, Strickland S, et al.: Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 1998, 4:228–231.

    Article  PubMed  CAS  Google Scholar 

  21. Friedlander RM, Gagliardini V, Hara H, et al.: Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J Exp Med 1997, 185:933–940.

    Article  PubMed  CAS  Google Scholar 

  22. Soriano SG, Coxon A, Wang YF, et al.: Mice deficient in Mac-1 (CD11b/CD18) are less susceptible to cerebral ischemia/reperfusion injury. Stroke 1999, 30:134–139.

    PubMed  CAS  Google Scholar 

  23. Soriano SG, Lipton SA, Wang YF, et al.: Intercellular adhesion molecule-1-deficient mice are less susceptible to cerebral ischemia-reperfusion injury. Ann Neurol 1996, 39:618–624.

    Article  PubMed  CAS  Google Scholar 

  24. Connolly ES Jr, Winfree CJ, Prestigiacomo CJ, et al.: Exacerbation of cerebral injury in mice that express the P-selectin gene: identification of P-selectin blockade as a new target for the treatment of stroke. Circ Res 1997, 81:304–310.

    PubMed  CAS  Google Scholar 

  25. Bruce AJ, Boling W, Kindy MS, et al.: Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat Med 1996, 2:788–794.

    Article  PubMed  CAS  Google Scholar 

  26. Schneider A, Martin-Villalba A, Weih F, et al.: NF-kappaB is activated and promotes cell death in focal cerebral ischemia. Nat Med 1999, 5:554–559.

    Article  PubMed  CAS  Google Scholar 

  27. Panahian N, Yoshiura M, Maines MD: Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. J Neurochem 1999, 72:1187–1203.

    PubMed  CAS  Google Scholar 

  28. Takagi Y, Mitsui A, Nishiyama A, et al.: Overexpression of thioredoxin in transgenic mice attenuates focal ischemic brain damage. Proc Natl Acad Sci U S A 1999, 96:4131–4136.

    Article  PubMed  CAS  Google Scholar 

  29. Kinouchi H, Epstein CJ, Mizui T, et al.: Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc Natl Acad Sci U S A 1991, 88:11158–11162.

    Article  PubMed  CAS  Google Scholar 

  30. Kondo T, Reaume AG, Huang TT, et al.: Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J Neurosci 1997, 17:4180–4189.

    PubMed  CAS  Google Scholar 

  31. Keller JN, Kindy MS, Holtsberg FW, et al.: Mitochondrial manganese superoxide dismutase prevents neural apoptosis and reduces ischemic brain injury: suppression of peroxynitrite production, lipid peroxidation, and mitochondrial dysfunction. J Neurosci 1998, 18:687–697.

    PubMed  CAS  Google Scholar 

  32. Sheng H, Bart RD, Oury TD, et al.: Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia. Neuroscience 1999, 88:185–191.

    Article  PubMed  CAS  Google Scholar 

  33. Weisbrot-Lefkowitz M, Reuhl K, Perry B, et al.: Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage: Mol Brain Res 1998, 53:333–338.

    Article  PubMed  CAS  Google Scholar 

  34. Huang Z, Huang PL, Panahian N, et al.: Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 1994, 265:1883–1885.

    Article  PubMed  CAS  Google Scholar 

  35. Huang Z, Huang PL, Ma J, et al.: Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-L-arginine. J Cereb Blood Flow Metab 1996, 16:981–987.

    Article  PubMed  CAS  Google Scholar 

  36. Iadecola C, Zhang F, Casey R, et al.: Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci 1997, 17:9157–9164.

    PubMed  CAS  Google Scholar 

  37. Hata R, Gass P, Mies G, et al.: Attenuated c-fos mRNA induction after middle cerebral artery occlusion in CREB knockout mice does not modulate focal ischemic injury. J Cereb Blood Flow Metab 1998, 18:1325–1335.

    Article  PubMed  CAS  Google Scholar 

  38. Plumier JC, Krueger AM, Currie RW, et al.: Transgenic mice expressing the human inducible Hsp70 have hippocampal neurons resistant to ischemic injury. Cell Stress Chaperones 1997, 2:162–167.

    Article  PubMed  CAS  Google Scholar 

  39. Lukkarinen JA, Kauppinen RA, Grohn OH, et al.: Neuroprotective role of ornithine decarboxylase activation in transient focal cerebral ischaemia: a study using ornithine decarboxylase-overexpressing transgenic rats. Eur J Neurosci 1998, 10:2046–2055.

    Article  PubMed  CAS  Google Scholar 

  40. Zhang F, Eckman C, Younkin S, et al.: Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein. J Neurosci 1997, 17:7655–7661.

    PubMed  CAS  Google Scholar 

  41. Sheng H, Laskowitz DT, Bennett E, et al.: Apolipoprotein E isoform-specific differences in outcome from focal ischemia in transgenic mice. J Cereb Blood Flow Metab 1998, 18:361–366.

    Article  PubMed  CAS  Google Scholar 

  42. Le D, Das S, Wang YF, et al.: Enhanced neuronal death from focal ischemia in AMPA-receptor transgenic mice. Mol Brain Res 1997, 52:235–241.

    Article  PubMed  CAS  Google Scholar 

  43. Endres M, Fink K, Zhu J, et al.: Neuroprotective effects of gelsolin during murine stroke. J Clin Invest 1999, 103:347–354.

    PubMed  CAS  Google Scholar 

  44. Liu PK, Hsu CY, Dizdaroglu M, et al.: Damage, repair, and mutagenesis in nuclear genes after mouse forebrain ischemia-reperfusion. J Neurosci 1996, 16:6795–6806.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  46. Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999, 79:1431–1568.

    PubMed  CAS  Google Scholar 

  47. Choi DW, Rothman SM: The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 1990, 13:171–182.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. Baker AJ, Zornow MH, Scheller MS, et al.: Changes in extracellular concentrations of glutamate, aspartate, glycine, dopamine, serotonin, and dopamine metabolites after transient global ischemia in the rabbit brain. J Neurochem 1991, 57:1370–1379.

    Article  PubMed  CAS  Google Scholar 

  50. Simon RP, Swan JH, Griffiths T, Meldrum BS: Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain. Science 1984, 226:850–852.

    Article  PubMed  CAS  Google Scholar 

  51. Bordi F, Pietra C, Ziviani L, et al.: The glycine antagonist GV150526 protects somatosensory evoked potentials and reduces the infarct area in the MCAO model of focal ischemia in the rat. Exp Neurol 1997, 145:425–433.

    Article  PubMed  CAS  Google Scholar 

  52. Schielke GP, Kupina NC, Boxer PA, et al.: The neuroprotective effect of the novel AMPA receptor antagonist PD152247 (PNQX) in temporary focal ischemia in the rat. Stroke 1999, 30:1472–1477.

    PubMed  CAS  Google Scholar 

  53. Choi DW, Koh JY: Zinc and brain injury. Annu Rev Neurosci 1998, 21:347–375.

    Article  PubMed  CAS  Google Scholar 

  54. Koh JY, Suh SW, Gwag BJ, et al.: The role of zinc in selective neuronal death after transient global cerebral ischemia. Science 1996, 272:1013–1016.

    Article  PubMed  CAS  Google Scholar 

  55. Chan PH: Role of oxidants in ischemic brain damage. Stroke 1996, 27:1124–1129.

    PubMed  CAS  Google Scholar 

  56. Iadecola C: Bright and dark sides of nitric oxide in ischemic brain injury. Trends Neurosci 1997, 20:132–139.

    Article  PubMed  CAS  Google Scholar 

  57. Dalkara T, Moskowitz MA: Nitric oxide in cerebrovascular regulation and ischemia. In Ischemic Stroke: From Basic Mechanisms to New Drug Development. Edited by Hsu CY. Switzerland: Karger; 1998:28–45.

    Google Scholar 

  58. Beckman JS, Beckman TW, Chen J, et al.: Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci U S A 1990, 87:1620–1624.

    Article  PubMed  CAS  Google Scholar 

  59. Charriaut-Marlangue C, Margaill I, Represa A, et al.: Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 1996, 16:186–194.

    Article  PubMed  CAS  Google Scholar 

  60. MacManus JP, Linnik MD: Gene expression induced by cerebral ischemia: an apoptotic perspective. J Cereb Blood Flow Metab 1997, 17:815–832.

    Article  PubMed  CAS  Google Scholar 

  61. Martin LJ, Al-Abdulla NA, Brambrink AM, et al.: Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis. Brain Res Bull 1998, 46:281–309.

    Article  PubMed  CAS  Google Scholar 

  62. Linnik MD, Zobrist RH, Hatfield MD: Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 1993, 24:2002–2009.

    PubMed  CAS  Google Scholar 

  63. Nitatori T, Sato N, Waguri S, et al.: Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 1995, 15:1001–1011.

    PubMed  CAS  Google Scholar 

  64. Li Y, Sharov VG, Jiang N, et al.: Ultrastructural and light microscopic evidence of apoptosis after middle cerebral artery occlusion in the rat. Am J Pathol 1995, 146:1045–1051.

    PubMed  CAS  Google Scholar 

  65. Cheng Y, Deshmukh M, D’Costa A, et al.: Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury. J Clin Invest 1998, 101:1992–1999.

    PubMed  CAS  Google Scholar 

  66. Endres M, Namura S, Shimizu-Sasamata M, et al.: Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab 1998, 18:238–247.

    Article  PubMed  CAS  Google Scholar 

  67. Himi T, Ishizaki Y, Murota S: A caspase inhibitor blocks ischaemia-induced delayed neuronal death in the gerbil. Eur J Neurosci 1998, 10:777–781.

    Article  PubMed  CAS  Google Scholar 

  68. Green DR, Reed JC: Mitochondria and apoptosis. Science 1998, 281:1309–1312.

    Article  PubMed  CAS  Google Scholar 

  69. Kroemer G, Dallaporta B, Resche-Rigon M: The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 1998, 60:619–642.

    Article  PubMed  CAS  Google Scholar 

  70. Krajewski S, Krajewska M, Ellerby LM, et al.: Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci USA 1999, 96:5752–5757.

    Article  PubMed  CAS  Google Scholar 

  71. Ouyang YB, Tan Y, Comb M, et al.: Survival-and death-promoting events after transient cerebral ischemia: phosphorylation of Akt, release of cytochrome C and activation of caspase-like proteases. J Cereb Blood Flow Metab 1999, 19:1126–1135.

    Article  PubMed  CAS  Google Scholar 

  72. Velier JJ, Ellison JA, Kikly KK, et al.: Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. J Neurosci 1999, 19:5932–5941.

    PubMed  CAS  Google Scholar 

  73. Hsu CY, An G, Liu JS, et al.: Expression of immediate early gene and growth factor mRNAs in a focal cerebral ischemia model in the rat. Stroke 1993, 24(12 Suppl):I78–8.

    PubMed  CAS  Google Scholar 

  74. An G, Lin TN, Liu JS, et al.: Expression of c-fos and c-jun family genes after focal cerebral ischemia. Ann Neurol 1993, 33:457–464.

    Article  PubMed  CAS  Google Scholar 

  75. Akins PT, Liu PK, Hsu CY: Immediate early gene expression in response to cerebral ischemia: friend or foe? Stroke 1996, 27:1682–1687.

    PubMed  CAS  Google Scholar 

  76. Jaattela M, Wissing D, Kokholm K, et al.: Hsp70 exerts its anti-apoptotic function downstream of caspase-3-like proteases. EMBO J 1998, 17:6124–6134.

    Article  PubMed  CAS  Google Scholar 

  77. Chen J, Graham SH, Nakayama M, et al.: Apoptosis repressor genes Bcl-2 and Bcl-x-long are expressed in the rat brain following global ischemia. J Cereb Blood Flow Metab 1997, 17:2–10.

    Article  PubMed  CAS  Google Scholar 

  78. Gillardon F, Lenz C, Waschke KF, et al.: Altered expression of Bcl-2, Bcl-X, Bax, and c-Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. Mol Brain Res 1996, 40:254–260.

    Article  PubMed  CAS  Google Scholar 

  79. Barone FC, Feuerstein GZ: Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 1999, 19:819–834.

    Article  PubMed  CAS  Google Scholar 

  80. Minami M, Kuraishi Y, Yabuuchi K, et al.: Induction of interleukin-1 beta mRNA in rat brain after transient forebrain ischemia. J Neurochem 1992, 58:390–392.

    Article  PubMed  CAS  Google Scholar 

  81. Kochanek PM, Hallenbeck JM: Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke. Stroke 1991, 23:1367–1379.

    Google Scholar 

  82. Hayward NJ, Elliott PJ, Sawyer SD, et al.: Lack of evidence for neutrophil participation during infarct formation. Exp Neurol 1996, 139:188–202.

    Article  PubMed  CAS  Google Scholar 

  83. Ahmed S-H, He YY, Nassief A, et al.: Effects of lipopolysaccharide priming on acute ischemic brain injury. Stroke 2000, 31:193–199.

    PubMed  CAS  Google Scholar 

  84. Miettinen S, Fusco FR, Yrjanheikki J, et al.: Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-D-aspartic acid-receptors and phospholipase A2. Proc Natl Acad Sci USA 1997, 94:6500–6505.

    Article  PubMed  CAS  Google Scholar 

  85. Nogawa S, Zhang F, Ross ME, Iadecola C: Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci 1997, 17:2746–2755.

    PubMed  CAS  Google Scholar 

  86. Moseley ME, Kucharczyk J, Mintorovitch J, et al.: Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats. AJNR Am J Neuroradiol 1990, 11:423–429.

    PubMed  CAS  Google Scholar 

  87. Busza AL, Allen KL, King MD, et al.: Diffusion-weighted imaging studies of cerebral ischemia in gerbils: potential relevance to energy failure. Stroke 1992, 23:1602–1612.

    PubMed  CAS  Google Scholar 

  88. Engelhorn T, Doerfler A, Kastrup A, et al.: Decompressive craniectomy, reperfusion, or a combination for early treatment of acute “malignant” cerebral hemispheric stroke in rats? potential mechanisms studied by MRI. Stroke 1999, 30:1456–1463.

    PubMed  CAS  Google Scholar 

  89. Lutsep HL, Albers GW, DeCrespigny A, et al.: Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke. Ann Neurol 1997, 41:574–580.

    Article  PubMed  CAS  Google Scholar 

  90. Marks MP, Tong DC, Beaulieu C, et al.: Evaluation of early reperfusion and i.v. tPA therapy using diffusion- and perfusion-weighted MRI. Neurology 1999, 52:1792–1798.

    PubMed  CAS  Google Scholar 

  91. Fisher M, Warach S: New magnetic resonance imaging techniques for stroke diagnosis and treatment. In Ischemic Stroke: From Basic Mechanisms to New Drug Development. Edited by Hsu CY. Switzerland: Karger; 1998:139–150.

    Google Scholar 

  92. Lin W, Paczynski RP, Venkatesan R, et al.: Quantitative regional brain water measurement with magnetic resonance imaging in a focal ischemia model. Magn Reson Med 1997, 38:303–310.

    Article  PubMed  CAS  Google Scholar 

  93. Lin W, Paczynski RP, Celik A, et al.: Experimental hypoxemic hypoxia: changes in R2• of brain parenchyma accurately reflect the combined effects of changes in arterial and cerebral venous oxygen saturation. Magn Reson Med 1998, 39:474–481.

    Article  PubMed  CAS  Google Scholar 

  94. Lin W, Paczynski RP, Celik A, et al.: Experimental hypoxemic hypoxia: effects of variation in hematocrit on magnetic resonance T2•-weighted brain images. J Cereb Blood Flow Metab 1998, 18:1018–1021.

    Article  PubMed  CAS  Google Scholar 

  95. Lin W, Celik A, Paczynski RP, et al.: Quantitative magnetic resonance imaging in experimental hypercapnia: improvement in the relation between changes in brain R2 and the oxygen saturation of venous blood after correction for changes in cerebral blood volume. J Cereb Blood Flow Metab 1999, 19:853–862.

    Article  PubMed  CAS  Google Scholar 

  96. Busto R, Dietrich WD, Globus MY, et al.: Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987, 7:729–738.

    PubMed  CAS  Google Scholar 

  97. Ginsberg MD: Temperature influences on ischemic brain injury. In Ischemic Stroke: From Basic Mechanisms to New Drug Development. Edited by Hsu CY. Switzerland: Karger, 1998:65–88.

    Google Scholar 

  98. Minamisawa H, Smith ML, Siesjo BK: The effect of mild hyperthermia and hypothermia on brain damage following 5, 10, and 15 minutes of forebrain ischemia. Ann Neurol 1990, 28:26–33.

    Article  PubMed  CAS  Google Scholar 

  99. Reith J, Jorgensen HS, Pedersen PM, et al.: Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 1996, 347:422–425.

    Article  PubMed  CAS  Google Scholar 

  100. Park CK, Nehls DG, Graham DI, et al.: The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol 1988, 24:543–551.

    Article  PubMed  CAS  Google Scholar 

  101. Goldberg MP: Stroke trials database. Internet Stoke Center at Washington University (cited 17 Dec, 1999) {http://www.neuro.wustl.edu/stroke/stroke-trials.htm}

  102. Olney JW: Neurotoxicity of NMDA receptor antagonists: An overview. Psychopharmacol Bull 1994, 30:533–540.

    PubMed  CAS  Google Scholar 

  103. Dyker AG, Lees KR: Safety and tolerability of GV150526 (a glycine site antagonist at the N-methyl-D-aspartate receptor) in patients with acute stroke. Stroke 1999, 30:986–992.

    PubMed  CAS  Google Scholar 

  104. Muir KW, Lees KR: A randomized, double-blind, placebo-controlled pilot trial of intravenous magnesium sulfate in acute stroke. Stroke 1995, 26:1183–1188.

    PubMed  CAS  Google Scholar 

  105. Smith SE, Meldrum BS: Cerebroprotective effect of lamotrigine after focal ischemia in rats. Stroke 1995, 26:117–121.

    PubMed  CAS  Google Scholar 

  106. Culmsee C, Junker V, Wolz P, et al.: Lubeluzole protects hippocampal neurons from excitotoxicity in vitro and reduces brain damage caused by ischemia. Eur J Pharmacol 1998, 342:193–201.

    Article  PubMed  CAS  Google Scholar 

  107. Lazarewicz JW, Pluta R, Puka M, Salinska E: Diverse mechanisms of neuronal protection by nimodipine in experimental rabbit brain ischemia. Stroke 1990, 21(12 Suppl):IV108-IV110.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  109. Gotti B, Duverger D, Bertin J, et al.: Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents: I. evidence for efficacy in models of focal cerebral ischemia. J Pharmacol Exp Ther 1988, 247:1211–1221.

    PubMed  CAS  Google Scholar 

  110. Chan SA, Reid KH, Schurr A, et al.: Fosphenytoin reduces hippocampal neuronal damage in rat following transient global ischemia. Acta Neurochir (Wien) 1998, 140:175–180.

    Article  CAS  Google Scholar 

  111. Marshall JW, Cross AJ, Ridley RM: Functional benefit from clomethiazole treatment after focal cerebral ischemia in a nonhuman primate species. Exp Neurol 1999, 156:121–129.

    Article  PubMed  CAS  Google Scholar 

  112. Wahlgren NG, Ranasinha KW, Rosolacci T, et al.: Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients. Stroke 1999, 30:21–28.

    PubMed  CAS  Google Scholar 

  113. Chen K, Finklestein SP: Neurotrophic factors. In Ischemic Stroke: From Basic Mechanisms to New Drug Development. Edited by Hsu CY. Switzerland: Karger; 1998:116–126.

    Google Scholar 

  114. Jiang N, Finklestein SP, Do T, et al.: Delayed intravenous administration of basic fibroblast growth factor reduces infarct volume in a model of focal cerebral ischemia/reperfusion in the rat. J Neurol Sci 1996, 139:173–179.

    Article  PubMed  CAS  Google Scholar 

  115. Stroemer RP, Kent TA, Hulsebosch CE: Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke 1995, 26:2135–2144.

    PubMed  CAS  Google Scholar 

  116. Lesiuk H, Sutherland G, Peeling J, et al.: Effect of U74006F on forebrain ischemia in rats. Stroke 1991, 22:896–901.

    PubMed  CAS  Google Scholar 

  117. Liu TH, Beckman JS, Freeman BA, et al.: Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury. Am J Physiol 1989, 256:H589-H593.

    PubMed  CAS  Google Scholar 

  118. He YY, Hsu CY, Ezrin AM, Miller MS: Polyethylene glycol-conjugated superoxide dismutase in focal cerebral ischemia-reperfusion. Am J Physiol 1993, 265:H252-H256.

    PubMed  CAS  Google Scholar 

  119. Yamaguchi T, Sano K, Takakura K, et al.: Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Stroke 1998, 29:12–17.

    PubMed  CAS  Google Scholar 

  120. Matsuo Y, Onodera H, Shiga Y, et al.: Correlation between myeloperoxidase-quantified neutrophil accumulation and ischemic brain injury in the rat. Effects of neutrophil depletion. Stroke 1994, 25:1469–1475.

    PubMed  CAS  Google Scholar 

  121. Jiang N, Moyle M, Soule HR, et al.: Neutrophil inhibitory factor is neuroprotective after focal ischemia in rats. Ann Neurol 1995, 38:935–942.

    Article  PubMed  CAS  Google Scholar 

  122. Chen H, Chopp M, Zhang RL, et al.: Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 1994, 35:458–463.

    Article  PubMed  Google Scholar 

  123. Zhang RL, Chopp M, Li Y, et al.: Anti-ICAM-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Neurology 1994, 44:1747–1751.

    PubMed  CAS  Google Scholar 

  124. Stroemer RP, Rothwell NJ: Cortical protection by localized striatal injection of IL-1ra following cerebral ischemia in the rat. J Cereb Blood Flow Metab 1997, 17:597–604.

    Article  PubMed  CAS  Google Scholar 

  125. Sherman DG: The Enlimomab acute stroke trial: final results [abstract]. Neurology 1997, 48:S33.001, A270.

    Google Scholar 

  126. D’Orlando KJ, Sandage BW Jr: Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury. Neurol Res 1995, 17:281–284.

    PubMed  CAS  Google Scholar 

  127. Chen ST, Hsu CY, Hogan EL, et al.: Thromboxane, prostacyclin, and leukotrienes in cerebral ischemia. Neurology 1986, 36:466–470.

    PubMed  CAS  Google Scholar 

  128. Kakihana M, Fukuda N, Suno M, Nagaoka A: Effects of CDP-choline on neurologic deficits and cerebral glucose metabolism in a rat model of cerebral ischemia. Stroke 1988, 19:217–222.

    PubMed  CAS  Google Scholar 

  129. Andersen M, Overgaard K, Meden P, et al.: Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model. Stroke 1999, 30:1464–1471.

    PubMed  CAS  Google Scholar 

  130. Clark WM, Williams BJ, Selzer KA, et al.: A randomized efficacy trial of citicoline in patients with acute ischemic stroke. Stroke 1999, 30:2592–2597.

    PubMed  CAS  Google Scholar 

  131. Yrjanheikki J, Tikka T, Keinanen R, et al.: A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A 1999, 96:13496–13500.

    Article  PubMed  CAS  Google Scholar 

  132. van Bruggen N, Thibodeaux H, Palmer JT, et al.: VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 1999, 104:1613–1620.

    Article  PubMed  Google Scholar 

  133. Moore PK, Wallace P, Gaffen Z, et al.: Characterization of a novel nitric oxide synthase inhibitor 7-nitroindazole and related indazoles: antinociceptive and cardiovascular effects. Br J Pharmacol 1993, 110:219–224.

    PubMed  CAS  Google Scholar 

  134. Coert BA, Anderson RE, Meyer FB: A comparative study of the effects of two nitric oxide synthase inhibitors and two nitric oxide donors on temporary focal cerebral ischemia in the Wistar rat. J Neurosurg 1999, 90:332–338.

    Article  PubMed  CAS  Google Scholar 

  135. Nagayama M, Zhang F, Iadecola C: Delayed treatment with aminoguanidine decreases focal cerebral ischemic damage and enhances neurologic recovery in rats. J Cereb Blood Flow Metab 1998, 18:1107–1113.

    Article  PubMed  CAS  Google Scholar 

  136. Thornberry NA, Lazebnik Y: Caspases: enemies within. Science 1998, 281:1312–1316.

    Article  PubMed  CAS  Google Scholar 

  137. Schulz JB, Weller M, Moskowitz MA: Caspases as treatment targets in stroke and neurodegenerative diseases. Ann Neurol 1999, 45:421–429.

    Article  PubMed  CAS  Google Scholar 

  138. Bartus RT, Dean RL, Cavanaugh K, et al.: Time-related neuronal changes following middle cerebral artery occlusion: implications for therapeutic intervention and the role of calpain. J Cereb Blood Flow Metab 1995, 15:969–979.

    PubMed  CAS  Google Scholar 

  139. Lee KS, Frank S, Vanderklish P, et al.: Inhibition of proteolysis protects hippocampal neurons from ischemia. Proc Natl Acad Sci U S A 1991, 88:7233–7237.

    Article  PubMed  CAS  Google Scholar 

  140. Markgraf CG, Velayo NL, Johnson MP, et al.: Six-hour window of opportunity for calpain inhibition in focal cerebral ischemia in rats. Stroke 1998, 29:152–158.

    PubMed  CAS  Google Scholar 

  141. Lekieffre D, Benavides J, Scatton B, et al.: Neuroprotection afforded by a combination of eliprodil and a thrombolytic agent, rt-PA, in a rat thromboembolic stroke model. Brain Res 1997, 776:88–95.

    Article  PubMed  CAS  Google Scholar 

  142. Bowes MP, Rothlein R, Fagan SC, Zivin JA: Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurology 1995, 45:815–819.

    PubMed  CAS  Google Scholar 

  143. Schabitz WR, Li F, Irie K, et al.: Synergistic effects of a combination of low-dose basic fibroblast growth factor and citicoline after temporary experimental focal ischemia. Stroke 1999, 30:427–431.

    PubMed  CAS  Google Scholar 

  144. Schmid-Elsaesser R, Zausinger S, Hungerhuber E, et al.: Neuroprotective effects of combination therapy with tirilazad and magnesium in rats subjected to reversible focal cerebral ischemia. Neurosurgery 1999, 44:163–171.

    Article  PubMed  CAS  Google Scholar 

  145. Du C, Hu R, Csernansky CA, et al.: Additive neuroprotective effects of dextrorphan and cycloheximide in rats subjected to transient focal cerebral ischemia. Brain Res 1996, 718:233–236.

    Article  PubMed  CAS  Google Scholar 

  146. Chabrier PE, Auguet M, Spinnewyn B, et al.: BN 80933, a dual inhibitor of neuronal nitric oxide synthase and lipid peroxidation: a promising neuroprotective strategy. Proc Natl Acad Sci U S A 1999, 96:10824–10829.

    Article  PubMed  CAS  Google Scholar 

  147. Pazos AJ, Green EJ, Busto R, et al.: Effects of combined postischemic hypothermia and delayed N-tert-butyl-a-pheylnitrone (PBN) administration on histopathological and behavioral deficits associated with transient global ischemia in rats. Brain Res 1999, 846:186–195.

    Article  PubMed  CAS  Google Scholar 

  148. Schmid-Elsaesser R, Hungerhuber E, Zausinger S, et al.: Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia. Stroke 1999, 30:1891–1819.

    PubMed  CAS  Google Scholar 

  149. Lee YS, Yoon BW, Roh JK: Neuroprotective effects of lamotrigine enhanced by flunarizine in gerbil global ischemia. Neurosci Lett 1999, 265:215–217.

    Article  PubMed  CAS  Google Scholar 

  150. Schmid-Elsaesser R, Hungerhuber E, Zausinger S, et al.: Neuroprotective efficacy of combination therapy with two different antioxidants in rats subjected to transient focal ischemia. Brain Res 1999, 816:471–479.

    Article  PubMed  CAS  Google Scholar 

  151. Schmid-Elsaesser R, Zausinger S, Hungerhuber E, et al.: Monotherapy with dextromethorphan or tirilazad—but not a combination of both—improves outcome after transient focal cerebral ischemia in rats. Exp Brain Res 1998, 122:121–127.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  153. Onal MZ, Li F, Tatlisumak T, et al.: Synergistic effects of citicoline and MK-801 in temporary experimental focal ischemia in rats. Stroke 1997, 28:1060–1065.

    PubMed  CAS  Google Scholar 

  154. Davis S, Helfaer MA, Traystman RJ, et al.: Parallel antioxidant and antiexcitotoxic therapy improves outcome after incomplete global cerebral ischemia in dogs. Stroke 1997, 28:198–205.

    PubMed  CAS  Google Scholar 

  155. Dietrich WD, Lin B, Globus MY, et al.: Effect of delayed MK-801 (dizocilpine) treatment with or without immediate postischemic hypothermia on chronic neuronal survival after global forebrain ischemia in rats. J Cereb Blood Flow Metab 1995, 15:960–968.

    PubMed  CAS  Google Scholar 

  156. Auer RN: Combination therapy with U74006F (tirilazad mesylate), MK-801, insulin and diazepam in transient forebrain ischaemia. Neurol Res 1995, 17:132–136.

    PubMed  CAS  Google Scholar 

  157. Lippert K, Welsch M, Krieglstein J: Over-additive protective effect of dizocilpine and NBQX against neuronal damage. Eur J Pharmacol 1994, 253:207–213.

    Article  PubMed  CAS  Google Scholar 

  158. Lyden PD, Lonzo L: Combination therapy protects ischemic brain in rats: a glutamate antagonist plus a gamma-aminobutyric acid agonist. Stroke 1994, 25:189–196.

    PubMed  CAS  Google Scholar 

  159. Hewitt K, Corbett D: Combined treatment with MK-801 and nicardipine reduces global ischemic damage in the gerbil. Stroke 1992, 23:82–86.

    PubMed  CAS  Google Scholar 

  160. Uematsu D, Araki N, Greenberg JH, et al.: Combined therapy with MK-801 and nimodipine for protection of ischemic brain damage. Neurology 1991, 41:88–94.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  162. Stroke Therapy Academic Industry Roundtable (STAIR): Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999, 30:2752–2758.

    Google Scholar 

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Ahmed, SH., Shaikh, A.Y., Shaikh, Z.Y. et al. What animal models have taught us about the treatment of acute stroke and brain protection. Curr Atheroscler Rep 2, 167–180 (2000). https://doi.org/10.1007/s11883-000-0112-2

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