Skip to main content
SpringerLink
Log in

Ischemic Stroke: Basic Pathophysiology and Neuroprotective Strategies

  • Chapter
  • First Online:
Acute Ischemic Stroke

Abstract

Over the last two decades, basic science research in the field of stroke has elucidated multiple pathways of cellular injury and repair after cerebral ischemia, resulting in the identification of several promising targets for neuroprotection [1]. A large number of neuroprotective agents have been shown to reduce stoke-related damage in animal models. To date, however, no single agent has achieved success in clinical trials. Nevertheless, analysis of the reasons behind the failure of recent drug trials, combined with the success of clot-lysing drugs in improving clinical outcome, has revealed new potential therapeutic opportunities and raised expectations that successful stroke treatment will be achieved in the near future. In this chapter, we first highlight the major mechanisms of neuronal injury, emphasizing those that are promising targets for stroke therapy. We then discuss the influence of these pathways on white matter injury, and briefly review the emerging concept of the neurovascular unit. Finally, we review emerging strategies for the treatment of acute ischemic stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Endres M, Dirnagl U, Moskowitz MA. Chapter 2: The ischemic cascade and mediators of ischemic injury. Handb Clin Neurol. 2008;92:31-41

    Article  Google Scholar 

  2. 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 

  3. Shimizu-Sasamata M, Bosque-Hamilton P, Huang PL, Moskowitz MA, Lo EH. Attenuated neurotransmitter release and spreading depression-like depolarizations after focal ischemia in mutant mice with disrupted type i nitric oxide synthase gene. J Neurosci. 1998;18:9564-9571

    PubMed  CAS  Google Scholar 

  4. Wang X, Shimizu-Sasamata M, Moskowitz MA, Newcomb R, Lo EH. Profiles of glutamate and gaba efflux in core versus peripheral zones of focal cerebral ischemia in mice. Neurosci Lett. 2001;313:121-124

    Article  PubMed  CAS  Google Scholar 

  5. Hossmann KA. Periinfarct depolarizations. Cerebrovasc Brain Metab Rev. 1996;8:195-208

    PubMed  CAS  Google Scholar 

  6. Bruno V, Battaglia G, Copani A, D’Onofrio M, Di Iorio P, De Blasi A, Melchiorri D, Flor PJ, Nicoletti F. Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J Cereb Blood Flow Metab. 2001;21:1013-1033

    Article  PubMed  CAS  Google Scholar 

  7. Michaelis EK. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol. 1998;54:369-415

    Article  PubMed  CAS  Google Scholar 

  8. Pellegrini-Giampietro DE, Zukin RS, Bennett MV, Cho S, Pulsinelli WA. Switch in glutamate receptor subunit gene expression in ca1 subfield of hippocampus following global ischemia in rats. Proc Natl Acad Sci U S A. 1992;89:10499-10503

    Article  PubMed  CAS  Google Scholar 

  9. Oguro K, Oguro N, Kojima T, Grooms SY, Calderone A, Zheng X, Bennett MV, Zukin RS. Knockdown of ampa receptor glur2 expression causes delayed neurodegeneration and increases damage by sublethal ischemia in hippocampal ca1 and ca3 neurons. J Neurosci. 1999;19:9218-9227

    PubMed  CAS  Google Scholar 

  10. Morikawa E, Mori H, Kiyama Y, Mishina M, Asano T, Kirino T. Attenuation of focal ischemic brain injury in mice deficient in the epsilon1 (nr2a) subunit of nmda receptor. J Neurosci. 1998;18:9727-9732

    PubMed  CAS  Google Scholar 

  11. Calabresi P, Centonze D, Gubellini P, Marfia GA, Pisani A, Sancesario G, Bernardi G. Synaptic transmission in the striatum: From plasticity to neurodegeneration. Prog Neurobiol. 2000;61:231-265

    Article  PubMed  CAS  Google Scholar 

  12. Horn J, Limburg M. Calcium antagonists for ischemic stroke: A systematic review. Stroke. 2001;32:570-576

    Article  PubMed  CAS  Google Scholar 

  13. Paschen W. Role of calcium in neuronal cell injury: Which subcellular compartment is involved? Brain Res Bull. 2000;53:409-413

    Article  PubMed  CAS  Google Scholar 

  14. Zipfel GJ, Lee JM, Choi DW. Reducing calcium overload in the ischemic brain. N Engl J Med. 1999;341:1543-1544

    Article  PubMed  CAS  Google Scholar 

  15. Weiss JH, Hartley DM, Koh JY, Choi DW. Ampa receptor activation potentiates zinc neurotoxicity. Neuron. 1993;10:43-49

    Article  PubMed  CAS  Google Scholar 

  16. Sorensen JC, Mattsson B, Andreasen A, Johansson BB. Rapid disappearance of zinc positive terminals in focal brain ischemia. Brain Res. 1998;812:265-269

    Article  PubMed  CAS  Google Scholar 

  17. Gribkoff VK, Starrett JE, Jr., Dworetzky SI, Hewawasam P, Boissard CG, Cook DA, Frantz SW, Heman K, Hibbard JR, Huston K, Johnson G, Krishnan BS, Kinney GG, Lombardo LA, Meanwell NA, Molinoff PB, Myers RA, Moon SL, Ortiz A, Pajor L, Pieschl RL, Post-Munson DJ, Signor LJ, Srinivas N, Taber MT, Thalody G, Trojnacki JT, Wiener H, Yeleswaram K, Yeola SW. Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-k potassium channels. Nat Med. 2001;7:471-477

    Article  PubMed  CAS  Google Scholar 

  18. Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab. 2001;21:2-14

    Article  PubMed  CAS  Google Scholar 

  19. Kroemer G, Reed JC. Mitochondrial control of cell death. Nat Med. 2000;6:513-519

    Article  PubMed  CAS  Google Scholar 

  20. Bernardi P, Petronilli V, Di Lisa F, Forte M. A mitochondrial perspective on cell death. Trends Biochem Sci. 2001;26:112-117

    Article  PubMed  CAS  Google Scholar 

  21. Kondo T, Reaume AG, Huang TT, Carlson E, Murakami K, Chen SF, Hoffman EK, Scott RW, Epstein CJ, Chan PH. 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 

  22. Kinouchi H, Epstein CJ, Mizui T, Carlson E, Chen SF, Chan PH. 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 

  23. Sheng H, Bart RD, Oury TD, Pearlstein RD, Crapo JD, Warner DS. Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia. Neuroscience. 1999;88:185-191

    Article  PubMed  CAS  Google Scholar 

  24. Kim GW, Kondo T, Noshita N, Chan PH. Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia/reperfusion in mice: Implications for the production and role of superoxide radicals. Stroke. 2002;33:809-815

    Article  PubMed  CAS  Google Scholar 

  25. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science. 1994;265:1883-1885

    Article  PubMed  CAS  Google Scholar 

  26. Iadecola C, Zhang F, Casey R, Nagayama M, Ross ME. 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 

  27. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA. 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 

  28. Zhang J, Dawson VL, Dawson TM, Snyder SH. Nitric oxide activation of poly(adp-ribose) synthetase in neurotoxicity. Science. 1994;263:687-689

    Article  PubMed  CAS  Google Scholar 

  29. Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH, Dawson VL. Poly(adp-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med. 1997;3:1089-1095

    Article  PubMed  CAS  Google Scholar 

  30. Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA. Ischemic brain injury is mediated by the activation of poly(adp-ribose)polymerase. J Cereb Blood Flow Metab. 1997;17:1143-1151

    Article  PubMed  CAS  Google Scholar 

  31. Yuan J, Yankner BA. Apoptosis in the nervous system. Nature. 2000;407:802-809

    Article  PubMed  CAS  Google Scholar 

  32. Nicotera P, Leist M, Fava E, Berliocchi L, Volbracht C. Energy requirement for caspase activation and neuronal cell death. Brain Pathol. 2000;10:276-282

    Article  PubMed  CAS  Google Scholar 

  33. Chopp M, Chan PH, Hsu CY, Cheung ME, Jacobs TP. DNA damage and repair in central nervous system injury: National institute of neurological disorders and stroke workshop summary. Stroke. 1996;27:363-369

    Article  PubMed  CAS  Google Scholar 

  34. Nicotera P, Lipton SA. Excitotoxins in neuronal apoptosis and necrosis. J Cereb Blood Flow Metab. 1999;19:583-591

    Article  PubMed  CAS  Google Scholar 

  35. Budd SL, Tenneti L, Lishnak T, Lipton SA. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons. Proc Natl Acad Sci U S A. 2000;97:6161-6166

    Article  PubMed  CAS  Google Scholar 

  36. Martin-Villalba A, Herr I, Jeremias I, Hahne M, Brandt R, Vogel J, Schenkel J, Herdegen T, Debatin KM. Cd95 ligand (fas-l/apo-1l) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J Neurosci. 1999;19:3809-3817

    PubMed  CAS  Google Scholar 

  37. Salvesen GS. A lysosomal protease enters the death scene. J Clin Invest. 2001;107:21-22

    Article  PubMed  CAS  Google Scholar 

  38. Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talk between jak2 and nf-kappab signalling cascades. Nature. 2001;412:641-647

    Article  PubMed  CAS  Google Scholar 

  39. Mannick JB, Hausladen A, Liu L, Hess DT, Zeng M, Miao QX, Kane LS, Gow AJ, Stamler JS. Fas-induced caspase denitrosylation. Science. 1999;284:651-654

    Article  PubMed  CAS  Google Scholar 

  40. Yamashima T. Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog Neurobiol. 2000;62:273-295

    Article  PubMed  CAS  Google Scholar 

  41. Mohr S, Stamler JS, Brune B. Mechanism of covalent modification of glyceraldehyde-3-phosphate dehydrogenase at its active site thiol by nitric oxide, peroxynitrite and related nitrosating agents. FEBS Lett. 1994;348:223-227

    Article  PubMed  CAS  Google Scholar 

  42. Elibol B, Soylemezoglu F, Unal I, Fujii M, Hirt L, Huang PL, Moskowitz MA, Dalkara T. Nitric oxide is involved in ischemia-induced apoptosis in brain: A study in neuronal nitric oxide synthase null mice. Neuroscience. 2001;105:79-86

    Article  PubMed  CAS  Google Scholar 

  43. Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL. Mediation of poly(adp-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science. 2002;297:259-263

    Article  PubMed  CAS  Google Scholar 

  44. Yu SP, Choi DW. Ions, cell volume, and apoptosis. Proc Natl Acad Sci U S A. 2000;97:9360-9362

    Article  PubMed  CAS  Google Scholar 

  45. Yu SP, Yeh C, Strasser U, Tian M, Choi DW. Nmda receptor-mediated k+ efflux and neuronal apoptosis. Science. 1999;284:336-339

    Article  PubMed  CAS  Google Scholar 

  46. Qiu J, Whalen MJ, Lowenstein P, Fiskum G, Fahy B, Darwish R, Aarabi B, Yuan J, Moskowitz MA. Upregulation of the fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J Neurosci. 2002;22:3504-3511

    PubMed  CAS  Google Scholar 

  47. Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA. Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci. 1998;18:3659-3668

    PubMed  CAS  Google Scholar 

  48. Fiskum G. Mitochondrial participation in ischemic and traumatic neural cell death. J Neurotrauma. 2000;17:843-855

    Article  PubMed  CAS  Google Scholar 

  49. Leist M, Jaattela M. Four deaths and a funeral: From caspases to alternative mechanisms. Nat Rev Mol Cell Biol. 2001;2:589-598

    Article  PubMed  CAS  Google Scholar 

  50. Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med. 2003;348:1365-1375

    Article  PubMed  CAS  Google Scholar 

  51. Graham SH, Chen J. Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab. 2001;21:99-109

    Article  PubMed  CAS  Google Scholar 

  52. Han BH, Xu D, Choi J, Han Y, Xanthoudakis S, Roy S, Tam J, Vaillancourt J, Colucci J, Siman R, Giroux A, Robertson GS, Zamboni R, Nicholson DW, Holtzman DM. Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury. J Biol Chem. 2002;277:30128-30136

    Article  PubMed  CAS  Google Scholar 

  53. Le DA, Wu Y, Huang Z, Matsushita K, Plesnila N, Augustinack JC, Hyman BT, Yuan J, Kuida K, Flavell RA, Moskowitz MA. Caspase activation and neuroprotection in caspase-3- deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci U S A. 2002;99:15188-15193

    Article  PubMed  CAS  Google Scholar 

  54. Chamorro A. Role of inflammation in stroke and atherothrombosis. Cerebrovasc Dis. 2004;17 Suppl 3:1-5

    Article  CAS  Google Scholar 

  55. Elkind MS, Cheng J, Boden-Albala B, Rundek T, Thomas J, Chen H, Rabbani LE, Sacco RL. Tumor necrosis factor receptor levels are associated with carotid atherosclerosis. Stroke. 2002;33:31-37

    Article  PubMed  CAS  Google Scholar 

  56. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836-843

    Article  PubMed  CAS  Google Scholar 

  57. Tanne D, Haim M, Boyko V, Goldbourt U, Reshef T, Matetzky S, Adler Y, Mekori YA, Behar S. Soluble intercellular adhesion molecule-1 and risk of future ischemic stroke: A nested case-control study from the bezafibrate infarction prevention (bip) study cohort. Stroke. 2002;33:2182-2186

    Article  PubMed  CAS  Google Scholar 

  58. Connolly ES, Jr., Winfree CJ, Springer TA, Naka Y, Liao H, Yan SD, Stern DM, Solomon RA, Gutierrez-Ramos JC, Pinsky DJ. Cerebral protection in homozygous null icam-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke. J Clin Invest. 1996;97:209-216

    Google Scholar 

  59. Connolly ES, Jr., Winfree CJ, Prestigiacomo CJ, Kim SC, Choudhri TF, Hoh BL, Naka Y, Solomon RA, Pinsky DJ. 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

    Article  PubMed  CAS  Google Scholar 

  60. del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ. Inflammation and stroke: Putative role for cytokines, adhesion molecules and inos in brain response to ischemia. Brain Pathol. 2000;10:95-112

    Article  PubMed  Google Scholar 

  61. Huang J, Kim LJ, Mealey R, Marsh HC, Jr., Zhang Y, Tenner AJ, Connolly ES, Jr., Pinsky DJ. Neuronal protection in stroke by an slex-glycosylated complement inhibitory protein. Science. 1999;285:595-599

    Article  PubMed  CAS  Google Scholar 

  62. Enlimomab Acute Stroke Trial Investigators. Use of anti-icam-1 therapy in ischemic stroke: Results of the enlimomab acute stroke trial. Neurology. 2001;57:1428-1434

    Google Scholar 

  63. Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C. Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab. 2002;22:308-317

    Article  PubMed  CAS  Google Scholar 

  64. Iadecola C, Niwa K, Nogawa S, Zhao X, Nagayama M, Araki E, Morham S, Ross ME. Reduced susceptibility to ischemic brain injury and n-methyl-d-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci U S A. 2001;98:1294-1299

    Article  PubMed  CAS  Google Scholar 

  65. Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ. Role of il-1alpha and il-1beta in ischemic brain damage. J Neurosci. 2001;21:5528-5534

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  67. Nawashiro H, Tasaki K, Ruetzler CA, Hallenbeck JM. Tnf-alpha pretreatment induces protective effects against focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 1997;17:483-490

    Article  PubMed  CAS  Google Scholar 

  68. Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP. 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 

  69. Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U. Neurodegenerative and neuroprotective effects of tumor necrosis factor (tnf) in retinal ischemia: Opposite roles of tnf receptor 1 and tnf receptor 2. J Neurosci. 2002;22:RC216

    Google Scholar 

  70. Zhang ZG, Zhang L, Jiang Q, Zhang R, Davies K, Powers C, Bruggen N, Chopp M. Vegf enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 2000;106:829-838

    Article  PubMed  CAS  Google Scholar 

  71. Jander S, Schroeter M, Peters O, Witte OW, Stoll G. Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. J Cereb Blood Flow Metab. 2001;21:218-225

    Article  PubMed  CAS  Google Scholar 

  72. Dreier JP, Major S, Manning A, Woitzik J, Drenckhahn C, Steinbrink J, Tolias C, Oliveira-Ferreira AI, Fabricius M, Hartings JA, Vajkoczy P, Lauritzen M, Dirnagl U, Bohner G, Strong AJ. Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage. Brain. 2009;132:1866-1881

    Article  PubMed  Google Scholar 

  73. Hansen AJ, Nedergaard M. Brain ion homeostasis in cerebral ischemia. Neurochem Pathol. 1988;9:195-209

    PubMed  CAS  Google Scholar 

  74. Strong AJ, Smith SE, Whittington DJ, Meldrum BS, Parsons AA, Krupinski J, Hunter AJ, Patel S, Robertson C. Factors influencing the frequency of fluorescence transients as markers of peri-infarct depolarizations in focal cerebral ischemia. Stroke. 2000;31:214-222

    Article  PubMed  CAS  Google Scholar 

  75. Gill R, Andine P, Hillered L, Persson L, Hagberg H. The effect of mk-801 on cortical spreading depression in the penumbral zone following focal ischaemia in the rat. J Cereb Blood Flow Metab. 1992;12:371-379

    Article  PubMed  CAS  Google Scholar 

  76. Dohmen C, Sakowitz OW, Fabricius M, Bosche B, Reithmeier T, Ernestus RI, Brinker G, Dreier JP, Woitzik J, Strong AJ, Graf R. Spreading depolarizations occur in human ischemic stroke with high incidence. Ann Neurol. 2008;63:720-728

    Article  PubMed  Google Scholar 

  77. Iijima T, Mies G, Hossmann KA. Repeated negative dc deflections in rat cortex following middle cerebral artery occlusion are abolished by mk-801: Effect on volume of ischemic injury. J Cereb Blood Flow Metab. 1992;12:727-733

    Article  PubMed  CAS  Google Scholar 

  78. Busch E, Gyngell ML, Eis M, Hoehn-Berlage M, Hossmann KA. Potassium-induced cortical spreading depressions during focal cerebral ischemia in rats: Contribution to lesion growth assessed by diffusion-weighted nmr and biochemical imaging. J Cereb Blood Flow Metab. 1996;16:1090-1099

    Article  PubMed  CAS  Google Scholar 

  79. Dijkhuizen RM, Beekwilder JP, van der Worp HB, Berkelbach van der Sprenkel JW, Tulleken KA, Nicolay K. Correlation between tissue depolarizations and damage in focal ischemic rat brain. Brain Res. 1999;840:194-205

    Google Scholar 

  80. Hartings JA, Rolli ML, Lu XC, Tortella FC. Delayed secondary phase of peri-infarct depolarizations after focal cerebral ischemia: Relation to infarct growth and neuroprotection. J Neurosci. 2003;23:11602-11610

    PubMed  CAS  Google Scholar 

  81. Tatlisumak T, Takano K, Meiler MR, Fisher M. A glycine site antagonist, zd9379, reduces number of spreading depressions and infarct size in rats with permanent middle cerebral artery occlusion. Stroke. 1998;29:190-195

    Article  PubMed  CAS  Google Scholar 

  82. Chen Q, Chopp M, Bodzin G, Chen H. Temperature modulation of cerebral depolarization during focal cerebral ischemia in rats: Correlation with ischemic injury. J Cereb Blood Flow Metab. 1993;13:389-394

    Article  PubMed  CAS  Google Scholar 

  83. Petty MA, Wettstein JG. White matter ischaemia. Brain Res Brain Res Rev. 1999;31:58-64

    Article  PubMed  CAS  Google Scholar 

  84. Stys PK. Anoxic and ischemic injury of myelinated axons in cns white matter: From mechanistic concepts to therapeutics. J Cereb Blood Flow Metab. 1998;18:2-25

    Article  PubMed  CAS  Google Scholar 

  85. Li S, Mealing GA, Morley P, Stys PK. Novel injury mechanism in anoxia and trauma of spinal cord white matter: Glutamate release via reverse na+-dependent glutamate transport. J Neurosci. 1999;19:RC16

    Google Scholar 

  86. McDonald JW, Althomsons SP, Hyrc KL, Choi DW, Goldberg MP. Oligodendrocytes from forebrain are highly vulnerable to ampa/kainate receptor-mediated excitotoxicity. Nat Med. 1998;4:291-297

    Article  PubMed  CAS  Google Scholar 

  87. Gu C, Casaccia-Bonnefil P, Srinivasan A, Chao MV. Oligodendrocyte apoptosis mediated by caspase activation. J Neurosci. 1999;19:3043-3049

    PubMed  CAS  Google Scholar 

  88. Chandler S, Coates R, Gearing A, Lury J, Wells G, Bone E. Matrix metalloproteinases degrade myelin basic protein. Neurosci Lett. 1995;201:223-226

    Article  PubMed  CAS  Google Scholar 

  89. Rosenberg GA, Sullivan N, Esiri MM. White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke. 2001;32:1162-1168

    Article  PubMed  CAS  Google Scholar 

  90. Report of the stroke progress review group (sprg) to the director and the national advisory neurological disorders and stroke council of the national institute of neurological disorders and stroke (ninds). 2002:1-116

    Google Scholar 

  91. Grotta JC, Jacobs TP, Koroshetz WJ, Moskowitz MA. Stroke program review group: An interim report. Stroke. 2008;39:1364-1370

    Article  PubMed  Google Scholar 

  92. Lo EH. Experimental models, neurovascular mechanisms and translational issues in stroke research. Br J Pharmacol. 2008;153 Suppl 1:S396-405

    PubMed  CAS  Google Scholar 

  93. Petty MA, Lo EH. Junctional complexes of the blood-brain barrier: Permeability changes in neuroinflammation. Prog Neurobiol. 2002;68:311-323

    Article  PubMed  CAS  Google Scholar 

  94. Yong VW, Krekoski CA, Forsyth PA, Bell R, Edwards DR. Matrix metalloproteinases and diseases of the cns. Trends Neurosci. 1998;21:75-80

    Article  PubMed  CAS  Google Scholar 

  95. Cuzner ML, Opdenakker G. Plasminogen activators and matrix metalloproteases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system. J Neuroimmunol. 1999;94:1-14

    Article  PubMed  CAS  Google Scholar 

  96. Yong VW, Power C, Forsyth P, Edwards DR. Metallo­proteinases in biology and pathology of the nervous system. Nat Rev Neurosci. 2001;2:502-511

    Article  PubMed  CAS  Google Scholar 

  97. Wang X, Mori T, Jung JC, Fini ME, Lo EH. Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of map kinase. J Neurotrauma. 2002;19:615-625

    Article  PubMed  Google Scholar 

  98. Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001;21:1393-1400

    Article  PubMed  CAS  Google Scholar 

  99. Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, Smith JW, Liddington RC, Lipton SA. S-nitrosylation of matrix metalloproteinases: Signaling pathway to neuronal cell death. Science. 2002;297:1186-1190

    Article  PubMed  CAS  Google Scholar 

  100. Lee SR, Lo EH. Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation. J Cereb Blood Flow Metab. 2004;24:720-727

    Article  PubMed  CAS  Google Scholar 

  101. Justicia C, Panes J, Sole S, Cervera A, Deulofeu R, Chamorro A, Planas AM. Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlusion/reperfusion of the middle cerebral artery in rats. J Cereb Blood Flow Metab. 2003;23:1430-1440

    Article  PubMed  CAS  Google Scholar 

  102. Campbell SJ, Finlay M, Clements JM, Wells G, Miller KM, Perry VH, Anthony DC. Reduction of excitotoxicity and associated leukocyte recruitment by a broad-spectrum matrix metalloproteinase inhibitor. J Neurochem. 2004;89:1378-1386

    Article  PubMed  CAS  Google Scholar 

  103. Clark AW, Krekoski CA, Bou SS, Chapman KR, Edwards DR. Increased gelatinase a (mmp-2) and gelatinase b (mmp-9) activities in human brain after focal ischemia. Neurosci Lett. 1997;238:53-56

    Article  PubMed  CAS  Google Scholar 

  104. Gasche Y, Fujimura M, Morita-Fujimura Y, Copin JC, Kawase M, Massengale J, Chan PH. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: A possible role in blood-brain barrier dysfunction. J Cereb Blood Flow Metab. 1999;19:1020-1028

    Article  PubMed  CAS  Google Scholar 

  105. Heo JH, Lucero J, Abumiya T, Koziol JA, Copeland BR, del Zoppo GJ. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J Cereb Blood Flow Metab. 1999;19:624-633

    Article  PubMed  CAS  Google Scholar 

  106. Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: Effects of gene knockout and enzyme inhibition with bb-94. J Cereb Blood Flow Metab. 2000;20:1681-1689

    Article  PubMed  CAS  Google Scholar 

  107. Montaner J, Alvarez-Sabin J, Molina C, Angles A, Abilleira S, Arenillas J, Gonzalez MA, Monasterio J. Matrix metalloproteinase expression after human cardioembolic stroke: Temporal profile and relation to neurological impairment. Stroke. 2001;32:1759-1766

    Article  PubMed  CAS  Google Scholar 

  108. Sumii T, Lo EH. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke. 2002;33:831-836

    Article  PubMed  CAS  Google Scholar 

  109. Abilleira S, Montaner J, Molina CA, Monasterio J, Castillo J, Alvarez-Sabin J. Matrix metalloproteinase-9 concentration after spontaneous intracerebral hemorrhage. J Neurosurg. 2003;99:65-70

    Article  PubMed  CAS  Google Scholar 

  110. Fukuda S, Fini CA, Mabuchi T, Koziol JA, Eggleston LL, Jr., del Zoppo GJ. Focal cerebral ischemia induces active proteases that degrade microvascular matrix. Stroke. 2004;35:998-1004

    Article  PubMed  CAS  Google Scholar 

  111. Lo EH, Wang X, Cuzner ML. Extracellular proteolysis in brain injury and inflammation: Role for plasminogen activators and matrix metalloproteinases. J Neurosci Res. 2002;69:1-9

    Article  PubMed  CAS  Google Scholar 

  112. Montaner J, Rovira A, Molina CA, Arenillas JF, Ribo M, Chacon P, Monasterio J, Alvarez-Sabin J. Plasmatic level of neuroinflammatory markers predict the extent of diffusion-weighted image lesions in hyperacute stroke. J Cereb Blood Flow Metab. 2003;23:1403-1407

    Article  PubMed  CAS  Google Scholar 

  113. Nagai N, Yamamoto S, Tsuboi T, Ihara H, Urano T, Takada Y, Terakawa S, Takada A. Tissue-type plasminogen activator is involved in the process of neuronal death induced by oxygen-glucose deprivation in culture. J Cereb Blood Flow Metab. 2001;21:631-634

    Article  PubMed  CAS  Google Scholar 

  114. Nicole O, Docagne F, Ali C, Margaill I, Carmeliet P, MacKenzie ET, Vivien D, Buisson A. The proteolytic activity of tissue-plasminogen activator enhances nmda receptor-mediated signaling. Nat Med. 2001;7:59-64

    Article  PubMed  CAS  Google Scholar 

  115. Yepes M, Sandkvist M, Wong MK, Coleman TA, Smith E, Cohan SL, Lawrence DA. Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood. 2000;96:569-576

    PubMed  CAS  Google Scholar 

  116. Wang YF, Tsirka SE, Strickland S, Stieg PE, Soriano SG, Lipton SA. 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 

  117. Tabrizi P, Wang L, Seeds N, McComb JG, Yamada S, Griffin JH, Carmeliet P, Weiss MH, Zlokovic BV. Tissue plasminogen activator (tpa) deficiency exacerbates cerebrovascular fibrin deposition and brain injury in a murine stroke model: Studies in tpa-deficient mice and wild-type mice on a matched genetic background. Arterioscler Thromb Vasc Biol. 1999;19:2801-2806

    Article  PubMed  CAS  Google Scholar 

  118. Ginsberg MD. On ischemic brain injury in genetically altered mice. Arterioscler Thromb Vasc Biol. 1999;19:2581-2583

    Article  PubMed  CAS  Google Scholar 

  119. Wang X, Lee SR, Arai K, Tsuji K, Rebeck GW, Lo EH. Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med. 2003;9:1313-1317

    Article  PubMed  CAS  Google Scholar 

  120. Anon. Tissue plasminogen activator for acute ischemic stroke. The national institute of neurological disorders and stroke rt-pa stroke study group. N Engl J Med. 1995;333:1581-1587

    Article  Google Scholar 

  121. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Diener HC, Ashwood T, Wasiewski WW, Emeribe U. Nxy-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357:562-571

    Article  PubMed  CAS  Google Scholar 

  122. Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener HC, Grotta J, Lyden P, Shuaib A, Hardemark HG, Wasiewski WW. Nxy-059 for acute ischemic stroke. N Engl J Med. 2006;354:588-600

    Article  PubMed  CAS  Google Scholar 

  123. Ehrenreich H, Weissenborn K, Prange H, Schneider D, Weimar C, Wartenberg K, Schellinger PD, Bohn M, Becker H, Wegrzyn M, Jahnig P, Herrmann M, Knauth M, Bahr M, Heide W, Wagner A, Schwab S, Reichmann H, Schwendemann G, Dengler R, Kastrup A, Bartels C. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40:e647-e656

    Article  PubMed  CAS  Google Scholar 

  124. Anon. A randomized trial of tirilazad mesylate in patients with acute stroke (ranttas). The ranttas investigators. Stroke. 1996;27:1453-1458

    Google Scholar 

  125. Anon. Clinical trial of nimodipine in acute ischemic stroke. The American Nimodipine Study Group. Stroke. 1992;23:3-8

    Article  Google Scholar 

  126. Wahlgren NG, Ranasinha KW, Rosolacci T, Franke CL, van Erven PM, Ashwood T, Claesson L. 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

    Article  PubMed  CAS  Google Scholar 

  127. Lyden P, Shuaib A, Ng K, Levin K, Atkinson RP, Rajput A, Wechsler L, Ashwood T, Claesson L, Odergren T, Salazar-Grueso E. Clomethiazole acute stroke study in ischemic stroke (class-i): Final results. Stroke. 2002;33:122-128

    Article  PubMed  CAS  Google Scholar 

  128. Diener HC, Cortens M, Ford G, Grotta J, Hacke W, Kaste M, Koudstaal PJ, Wessel T. Lubeluzole in acute ischemic stroke treatment: A double-blind study with an 8-hour inclusion window comparing a 10-mg daily dose of lubeluzole with placebo. Stroke. 2000;31:2543-2551

    Article  PubMed  CAS  Google Scholar 

  129. Davis SM, Lees KR, Albers GW, Diener HC, Markabi S, Karlsson G, Norris J. Selfotel in acute ischemic stroke : Possible neurotoxic effects of an nmda antagonist. Stroke. 2000;31:347-354

    Article  PubMed  CAS  Google Scholar 

  130. Albers GW, Goldstein LB, Hall D, Lesko LM. Aptiganel hydrochloride in acute ischemic stroke: A randomized controlled trial. JAMA. 2001;286:2673-2682

    Article  PubMed  CAS  Google Scholar 

  131. Lees KR, Asplund K, Carolei A, Davis SM, Diener HC, Kaste M, Orgogozo JM, Whitehead J. Glycine antagonist (gavestinel) in neuroprotection (gain international) in patients with acute stroke: A randomised controlled trial. Gain international investigators. Lancet. 2000;355:1949-1954

    Article  CAS  Google Scholar 

  132. Sacco RL, DeRosa JT, Haley EC, Jr., Levin B, Ordronneau P, Phillips SJ, Rundek T, Snipes RG, Thompson JL. Glycine antagonist in neuroprotection for patients with acute stroke: Gain americas: A randomized controlled trial. JAMA. 2001;285:1719-1728

    Article  PubMed  CAS  Google Scholar 

  133. Del Zoppo GJ. Why do all drugs work in animals but none in stroke patients? 1. Drugs promoting cerebral blood flow. J Intern Med. 1995;237:79-88

    Google Scholar 

  134. Grotta J. Why do all drugs work in animals but none in stroke patients? 2. Neuroprotective therapy. J Intern Med. 1995;237:89-94

    Article  CAS  Google Scholar 

  135. Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, Lo EH. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40:2244-2250

    Article  PubMed  Google Scholar 

  136. Kidwell CS, Liebeskind DS, Starkman S, Saver JL. Trends in acute ischemic stroke trials through the 20th century. Stroke. 2001;32:1349-1359

    Article  PubMed  CAS  Google Scholar 

  137. Lo EH, Singhal AB, Torchilin VP, Abbott NJ. Drug delivery to damaged brain. Brain Res Brain Res Rev. 2001;38:140-148

    Article  PubMed  CAS  Google Scholar 

  138. Sorensen AG, Copen WA, Ostergaard L, Buonanno FS, Gonzalez RG, Rordorf G, Rosen BR, Schwamm LH, Weisskoff RM, Koroshetz WJ. Hyperacute stroke: Simultaneous measurement of relative cerebral blood volume, relative cerebral blood flow, and mean tissue transit time. Radiology. 1999;210:519-527

    PubMed  CAS  Google Scholar 

  139. Saver JL, Albers GW, Dunn B, Johnston KC, Fisher M. Stroke therapy academic industry roundtable (stair) recommendations for extended window acute stroke therapy trials. Stroke. 2009;40:2594-2600

    Article  PubMed  Google Scholar 

  140. Saver JL, Kidwell C, Eckstein M, Ovbiagele B, Starkman S. Physician-investigator phone elicitation of consent in the field: A novel method to obtain explicit informed consent for prehospital clinical research. Prehosp Emerg Care. 2006;10:182-185

    Article  PubMed  Google Scholar 

  141. Hossmann KA. Viability thresholds and the penumbra of focal ischemia. Ann Neurol. 1994;36:557-565

    Article  PubMed  CAS  Google Scholar 

  142. Baron JC. Perfusion thresholds in human cerebral ischemia: Historical perspective and therapeutic implications. Cerebrovasc Dis. 2001;11 Suppl 1:2-8

    Article  PubMed  Google Scholar 

  143. Ginsberg MD, Pulsinelli WA. The ischemic penumbra, injury thresholds, and the therapeutic window for acute stroke. Ann Neurol. 1994;36:553-554

    Article  PubMed  CAS  Google Scholar 

  144. Markus R, Reutens DC, Kazui S, Read S, Wright P, Pearce DC, Tochon-Danguy HJ, Sachinidis JI, Donnan GA. Hypoxic tissue in ischaemic stroke: Persistence and clinical consequences of spontaneous survival. Brain. 2004;127:1427-1436

    Google Scholar 

  145. Reed SD, Cramer SC, Blough DK, Meyer K, Jarvik JG. Treatment with tissue plasminogen activator and inpatient mortality rates for patients with ischemic stroke treated in community hospitals. Stroke. 2001;32:1832-1840

    Article  PubMed  CAS  Google Scholar 

  146. Baron JC. Mapping the ischaemic penumbra with pet: A new approach. Brain. 2001;124:2-4

    Article  PubMed  CAS  Google Scholar 

  147. Heiss WD, Kracht LW, Thiel A, Grond M, Pawlik G. Penumbral probability thresholds of cortical flumazenil binding and blood flow predicting tissue outcome in patients with cerebral ischaemia. Brain. 2001;124:20-29

    Article  PubMed  CAS  Google Scholar 

  148. Baird AE, Warach S. Magnetic resonance imaging of acute stroke. J Cereb Blood Flow Metab. 1998;18:583-609

    Article  PubMed  CAS  Google Scholar 

  149. Kidwell CS, Alger JR, Saver JL. Beyond mismatch: Evolving paradigms in imaging the ischemic penumbra with multimodal magnetic resonance imaging. Stroke. 2003;34:2729-2735

    Article  PubMed  Google Scholar 

  150. Schlaug G, Benfield A, Baird AE, Siewert B, Lovblad KO, Parker RA, Edelman RR, Warach S. The ischemic penumbra: Operationally defined by diffusion and perfusion mri. Neurology. 1999;53:1528-1537

    Google Scholar 

  151. Schaefer PW, Ozsunar Y, He J, Hamberg LM, Hunter GJ, Sorensen AG, Koroshetz WJ, Gonzalez RG. Assessing tissue viability with mr diffusion and perfusion imaging. AJNR Am J Neuroradiol. 2003;24:436-443

    PubMed  Google Scholar 

  152. Gonzalez RG, Hakimelahi R, Schaefer PW, Roccatagliata L, Sorensen AG, Singhal AB. Stability of large diffusion/perfusion mismatch in anterior circulation strokes for 4 or more hours. BMC Neurol. 2010;10:13

    Article  PubMed  Google Scholar 

  153. Lev MH, Segal AZ, Farkas J, Hossain ST, Putman C, Hunter GJ, Budzik R, Harris GJ, Buonanno FS, Ezzeddine MA, Chang Y, Koroshetz WJ, Gonzalez RG, Schwamm LH. Utility of perfusion-weighted ct imaging in acute middle cerebral artery stroke treated with intra-arterial thrombolysis: Prediction of final infarct volume and clinical outcome. Stroke. 2001;32:2021-2028

    Article  PubMed  CAS  Google Scholar 

  154. Wintermark M, Reichhart M, Thiran JP, Maeder P, Chalaron M, Schnyder P, Bogousslavsky J, Meuli R. Prognostic accuracy of cerebral blood flow measurement by perfusion computed tomography, at the time of emergency room admission, in acute stroke patients. Ann Neurol. 2002;51:417-432

    Article  PubMed  Google Scholar 

  155. Wintermark M, Reichhart M, Cuisenaire O, Maeder P, Thiran JP, Schnyder P, Bogousslavsky J, Meuli R. Comparison of admission perfusion computed tomography and qualitative diffusion- and perfusion-weighted magnetic resonance imaging in acute stroke patients. Stroke. 2002;33:2025-2031

    Article  PubMed  CAS  Google Scholar 

  156. Hunter GJ, Hamberg LM, Ponzo JA, Huang-Hellinger FR, Morris PP, Rabinov J, Farkas J, Lev MH, Schaefer PW, Ogilvy CS, Schwamm L, Buonanno FS, Koroshetz WJ, Wolf GL, Gonzalez RG. Assessment of cerebral perfusion and arterial anatomy in hyperacute stroke with three-dimensional functional ct: Early clinical results. AJNR Am J Neuroradiol. 1998;19:29-37

    PubMed  CAS  Google Scholar 

  157. Jovin TG, Yonas H, Gebel JM, Kanal E, Chang YF, Grahovac SZ, Goldstein S, Wechsler LR. The cortical ischemic core and not the consistently present penumbra is a determinant of clinical outcome in acute middle cerebral artery occlusion. Stroke. 2003;34:2426-2433

    Article  PubMed  Google Scholar 

  158. Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, Fischer M, Furlan A, Kaste M, Lees KR, Soehngen M, Warach S. The desmoteplase in acute ischemic stroke trial (dias). A phase ii mri-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36:66

    Google Scholar 

  159. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, Bammer R, Kakuda W, Lansberg MG, Shuaib A, Coplin W, Hamilton S, Moseley M, Marks MP. Magnetic resonance imaging profiles predict clinical response to early reperfusion: The diffusion and perfusion imaging evaluation for understanding stroke evolution (defuse) study. Ann Neurol. 2006;60:508-517

    Article  PubMed  Google Scholar 

  160. Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, Barber PA, Bladin C, De Silva DA, Byrnes G, Chalk JB, Fink JN, Kimber TE, Schultz D, Hand PJ, Frayne J, Hankey G, Muir K, Gerraty R, Tress BM, Desmond PM. Effects of alteplase beyond 3 h after stroke in the echoplanar imaging thrombolytic evaluation trial (epithet): A placebo-controlled randomised trial. Lancet Neurol. 2008;7:299-309

    Article  PubMed  Google Scholar 

  161. Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F, Kaste M, Lipka LJ, Pedraza S, Ringleb PA, Rowley HA, Schneider D, Schwamm LH, Leal JS, Sohngen M, Teal PA, Wilhelm-Ogunbiyi K, Wintermark M, Warach S. Intravenous desmoteplase in patients with acute ischaemic stroke selected by mri perfusion-diffusion weighted imaging or perfusion ct (dias-2): A prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8:141-150

    Article  PubMed  CAS  Google Scholar 

  162. Wintermark M, Albers GW, Alexandrov AV, Alger JR, Bammer R, Baron JC, Davis S, Demaerschalk BM, Derdeyn CP, Donnan GA, Eastwood JD, Fiebach JB, Fisher M, Furie KL, Goldmakher GV, Hacke W, Kidwell CS, Kloska SP, Kohrmann M, Koroshetz W, Lee TY, Lees KR, Lev MH, Liebeskind DS, Ostergaard L, Powers WJ, Provenzale J, Schellinger P, Silbergleit R, Sorensen AG, Wardlaw J, Wu O, Warach S. Acute stroke imaging research roadmap. Stroke. 2008;39:1621-1628

    Article  PubMed  Google Scholar 

  163. Lansberg MG, Thijs VN, Bammer R, Olivot JM, Marks MP, Wechsler LR, Kemp S, Albers GW. The mra-dwi mismatch identifies patients with stroke who are likely to benefit from reperfusion. Stroke. 2008;39:2491-2496

    Article  PubMed  Google Scholar 

  164. Liebeskind DS. Reversing stroke in the 2010s: Lessons from desmoteplase in acute ischemic stroke-2 (dias-2). Stroke. 2009;40:3156-3158

    Article  PubMed  Google Scholar 

  165. Nogawa S, Forster C, Zhang F, Nagayama M, Ross ME, Iadecola C. Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia. Proc Natl Acad Sci U S A. 1998;95:10966-10971

    Article  PubMed  CAS  Google Scholar 

  166. Lyden PD, Jackson-Friedman C, Shin C, Hassid S. Synergistic combinatorial stroke therapy: A quantal bioassay of a gaba agonist and a glutamate antagonist. Exp Neurol. 2000;163:477-489

    Article  PubMed  CAS  Google Scholar 

  167. Barth A, Barth L, Newell DW. Combination therapy with mk-801 and alpha-phenyl-tert-butyl-nitrone enhances protection against ischemic neuronal damage in organotypic hippocampal slice cultures. Exp Neurol. 1996;141:330-336

    Article  PubMed  CAS  Google Scholar 

  168. Onal MZ, Li F, Tatlisumak T, Locke KW, Sandage BW, Jr., Fisher M. Synergistic effects of citicoline and mk-801 in temporary experimental focal ischemia in rats. Stroke. 1997;28:1060-1065

    Article  PubMed  CAS  Google Scholar 

  169. Du C, Hu R, Csernansky CA, Liu XZ, Hsu CY, Choi DW. 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 

  170. 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 

  171. Barth A, Barth L, Morrison RS, Newell DW. Bfgf enhances the protective effects of mk-801 against ischemic neuronal injury in vitro. Neuroreport. 1996;7:1461-1464

    Article  PubMed  CAS  Google Scholar 

  172. Schmid-Elsaesser R, Hungerhuber E, Zausinger S, Baethmann A, Reulen HJ. 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 

  173. Schabitz WR, Li F, Irie K, Sandage BW, Jr., Locke KW, Fisher M. Synergistic effects of a combination of low-dose basic fibroblast growth factor and citicoline after temporary experimental focal ischemia. Stroke. 1999;30:427-431; discussion 431-422

    Google Scholar 

  174. Ma J, Qiu J, Hirt L, Dalkara T, Moskowitz MA. Synergistic protective effect of caspase inhibitors and bfgf against brain injury induced by transient focal ischaemia. Br J Pharmacol. 2001;133:345-350

    Article  PubMed  CAS  Google Scholar 

  175. Hacke W, Brott T, Caplan L, Meier D, Fieschi C, von Kummer R, Donnan G, Heiss WD, Wahlgren NG, Spranger M, Boysen G, Marler JR. Thrombolysis in acute ischemic stroke: Controlled trials and clinical experience. Neurology. 1999;53:S3-S14

    Article  PubMed  CAS  Google Scholar 

  176. Garcia JH, Liu KF, Ho KL. Neuronal necrosis after middle cerebral artery occlusion in wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke. 1995;26:636-642; discussion 643

    Google Scholar 

  177. Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC, Jr., Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G. Association of outcome with early stroke treatment: Pooled analysis of atlantis, ecass, and ninds rt-pa stroke trials. Lancet. 2004;363:768-774

    Article  PubMed  Google Scholar 

  178. Asahi M, Asahi K, Wang X, Lo EH. Reduction of tissue plasminogen activator-induced hemorrhage and brain injury by free radical spin trapping after embolic focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2000;20:452-457

    Article  PubMed  CAS  Google Scholar 

  179. Meden P, Overgaard K, Sereghy T, Boysen G. Enhancing the efficacy of thrombolysis by ampa receptor blockade with nbqx in a rat embolic stroke model. J Neurol Sci. 1993;119:209-216

    Article  PubMed  CAS  Google Scholar 

  180. Zivin JA, Mazzarella V. Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke. Arch Neurol. 1991;48:1235-1238

    Article  PubMed  CAS  Google Scholar 

  181. Andersen M, Overgaard K, Meden P, Boysen G, Choi SC. Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model. Stroke. 1999;30:1464-1471

    Article  PubMed  CAS  Google Scholar 

  182. Yang Y, Li Q, Shuaib A. Enhanced neuroprotection and reduced hemorrhagic incidence in focal cerebral ischemia of rat by low dose combination therapy of urokinase and topiramate. Neuropharmacology. 2000;39:881-888

    Article  PubMed  CAS  Google Scholar 

  183. 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

    Article  PubMed  CAS  Google Scholar 

  184. Shuaib A, Yang Y, Nakada MT, Li Q, Yang T. Glycoprotein iib/iiia antagonist, murine 7e3 f(ab’) 2, and tissue plasminogen activator in focal ischemia: Evaluation of efficacy and risk of hemorrhage with combination therapy. J Cereb Blood Flow Metab. 2002;22:215-222

    Article  PubMed  CAS  Google Scholar 

  185. Lyden P, Jacoby M, Schim J, Albers G, Mazzeo P, Ashwood T, Nordlund A, Odergren T. The clomethiazole acute stroke study in tissue-type plasminogen activator-treated stroke (class-t): Final results. Neurology. 2001;57:1199-1205

    Article  PubMed  CAS  Google Scholar 

  186. Grotta J. Combination therapy stroke trial: Recombinant tissue-type plasminogen activator with/without lubeluzole. Cerebrovasc Dis. 2001;12:258-263

    Article  PubMed  CAS  Google Scholar 

  187. Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N, Fukunaga R, Kimura K, Mikoshiba K. ‘Ischemic tolerance’ phenomenon found in the brain. Brain Res. 1990;528:21-24

    Article  PubMed  CAS  Google Scholar 

  188. Kawahara N, Wang Y, Mukasa A, Furuya K, Shimizu T, Hamakubo T, Aburatani H, Kodama T, Kirino T. Genome-wide gene expression analysis for induced ischemic tolerance and delayed neuronal death following transient global ischemia in rats. J Cereb Blood Flow Metab. 2004;24:212-223

    Article  PubMed  CAS  Google Scholar 

  189. Kirino T. Ischemic tolerance. J Cereb Blood Flow Metab. 2002;22:1283-1296

    Article  PubMed  Google Scholar 

  190. Wegener S, Gottschalk B, Jovanovic V, Knab R, Fiebach JB, Schellinger PD, Kucinski T, Jungehulsing GJ, Brunecker P, Muller B, Banasik A, Amberger N, Wernecke KD, Siebler M, Rother J, Villringer A, Weih M. Transient ischemic attacks before ischemic stroke: Preconditioning the human brain? A multicenter magnetic resonance imaging study. Stroke. 2004;35:616-621

    Article  PubMed  Google Scholar 

  191. Weih M, Kallenberg K, Bergk A, Dirnagl U, Harms L, Wernecke KD, Einhaupl KM. Attenuated stroke severity after prodromal tia: A role for ischemic tolerance in the brain? Stroke. 1999;30:1851-1854

    Article  PubMed  CAS  Google Scholar 

  192. Moncayo J, de Freitas GR, Bogousslavsky J, Altieri M, van Melle G. Do transient ischemic attacks have a neuroprotective effect? Neurology. 2000;54:2089-2094

    Article  PubMed  CAS  Google Scholar 

  193. Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26:248-254

    Article  PubMed  CAS  Google Scholar 

  194. Lin JY, Chung SY, Lin MC, Cheng FC. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique. Life Sci. 2002;71:803-811

    Article  PubMed  CAS  Google Scholar 

  195. Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature. 1984;307:462-465

    Article  PubMed  CAS  Google Scholar 

  196. Chi OZ, Pollak P, Weiss HR. Effects of magnesium sulfate and nifedipine on regional cerebral blood flow during middle cerebral artery ligation in the rat. Arch Int Pharmacodyn Ther. 1990;304:196-205

    PubMed  CAS  Google Scholar 

  197. Izumi Y, Roussel S, Pinard E, Seylaz J. Reduction of infarct volume by magnesium after middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 1991;11:1025-1030

    Article  PubMed  CAS  Google Scholar 

  198. Marinov MB, Harbaugh KS, Hoopes PJ, Pikus HJ, Harbaugh RE. Neuroprotective effects of preischemia intraarterial magnesium sulfate in reversible focal cerebral ischemia. J Neurosurg. 1996;85:117-124

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  200. Muir KW, Lees KR, Ford I, Davis S. Magnesium for acute stroke (intravenous magnesium efficacy in stroke trial): Randomised controlled trial. Lancet. 2004;363:439-445

    Article  PubMed  CAS  Google Scholar 

  201. Saver JL, Kidwell C, Eckstein M, Starkman S. Prehospital neuroprotective therapy for acute stroke: Results of the field administration of stroke therapy-magnesium (fast-mag) pilot trial. Stroke. 2004;35:e106-108

    Article  PubMed  CAS  Google Scholar 

  202. Belayev L, Pinard E, Nallet H, Seylaz J, Liu Y, Riyamongkol P, Zhao W, Busto R, Ginsberg MD. Albumin therapy of transient focal cerebral ischemia: In vivo analysis of dynamic microvascular responses. Stroke. 2002;33:1077-1084

    Article  PubMed  Google Scholar 

  203. Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD. Human albumin therapy of acute ischemic stroke: Marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke. 2001;32:553-560

    Article  PubMed  CAS  Google Scholar 

  204. Hill MD, Moy CS, Palesch YY, Martin R, Dillon CR, Waldman BD, Patterson L, Mendez IM, Ryckborst KJ, Tamariz D, Ginsberg MD. The albumin in acute stroke trial (alias); design and methodology. Int J Stroke. 2007;2:214-219

    Article  PubMed  Google Scholar 

  205. Astrup J, Sorensen PM, Sorensen HR. Inhibition of cerebral oxygen and glucose consumption in the dog by hypothermia, pentobarbital, and lidocaine. Anesthesiology. 1981;55:263-268

    Article  PubMed  CAS  Google Scholar 

  206. Cardell M, Boris-Moller F, Wieloch T. Hypothermia prevents the ischemia-induced translocation and inhibition of protein kinase c in the rat striatum. J Neurochem. 1991;57:1814-1817

    Article  PubMed  CAS  Google Scholar 

  207. Globus MY, Busto R, Lin B, Schnippering H, Ginsberg MD. Detection of free radical activity during transient global ischemia and recirculation: Effects of intraischemic brain temperature modulation. J Neurochem. 1995;65:1250-1256

    Article  PubMed  CAS  Google Scholar 

  208. Krieger DW, Yenari MA. Therapeutic hypothermia for acute ischemic stroke: What do laboratory studies teach us? Stroke. 2004;35:1482-1489

    Article  PubMed  Google Scholar 

  209. Han HS, Karabiyikoglu M, Kelly S, Sobel RA, Yenari MA. Mild hypothermia inhibits nuclear factor-kappab translocation in experimental stroke. J Cereb Blood Flow Metab. 2003;23:589-598

    Article  PubMed  CAS  Google Scholar 

  210. Wang GJ, Deng HY, Maier CM, Sun GH, Yenari MA. Mild hypothermia reduces icam-1 expression, neutrophil infiltration and microglia/monocyte accumulation following experimental stroke. Neuroscience. 2002;114:1081-1090

    Article  PubMed  CAS  Google Scholar 

  211. Yenari MA, Iwayama S, Cheng D, Sun GH, Fujimura M, Morita-Fujimura Y, Chan PH, Steinberg GK. Mild ­hypothermia attenuates cytochrome c release but does not alter bcl-2 expression or caspase activation after experimental stroke. J Cereb Blood Flow Metab. 2002;22:29-38

    Article  PubMed  CAS  Google Scholar 

  212. Prosser CL. Temperature. In: Prosser CL, ed. Comparative animal physiology. Philadelphia: WB Saunders; 1973:362-428.

    Google Scholar 

  213. Markarian GZ, Lee JH, Stein DJ, Hong SC. Mild hypothermia: Therapeutic window after experimental cerebral ischemia. Neurosurgery. 1996;38:542-550; discussion 551

    Google Scholar 

  214. Welsh FA, Harris VA. Postischemic hypothermia fails to reduce ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab. 1991;11:617-620

    Article  PubMed  CAS  Google Scholar 

  215. Ginsberg MD. Hypothermic neuroprotection in cerebral ischemia. In: Welch KMA, Caplan LR, Reis DJ, Siesjo BK, Weir B, eds. Primer on cerebrovascular diseases. San Diego: Academic Press; 1997:272-275.

    Chapter  Google Scholar 

  216. Corbett D, Hamilton M, Colbourne F. Persistent neuroprotection with prolonged postischemic hypothermia in adult rats subjected to transient middle cerebral artery occlusion. Exp Neurol. 2000;163:200-206

    Article  PubMed  CAS  Google Scholar 

  217. The hypothermia after cardiac arrest study group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  219. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke. 1998;29:2461-2466

    Article  PubMed  CAS  Google Scholar 

  220. Krieger DW, De Georgia MA, Abou-Chebl A, Andrefsky JC, Sila CA, Katzan IL, Mayberg MR, Furlan AJ. Cooling for acute ischemic brain damage (cool aid): An open pilot study of induced hypothermia in acute ischemic stroke. Stroke. 2001;32:1847-1854

    Article  PubMed  CAS  Google Scholar 

  221. Kammersgaard LP, Rasmussen BH, Jorgensen HS, Reith J, Weber U, Olsen TS. Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling: A case-control study: The copenhagen stroke study. Stroke. 2000;31:2251-2256

    Article  PubMed  CAS  Google Scholar 

  222. Hayashi S, Nehls DG, Kieck CF, Vielma J, DeGirolami U, Crowell RM. Beneficial effects of induced hypertension on experimental stroke in awake monkeys. J Neurosurg. 1984;60:151-157

    Article  PubMed  CAS  Google Scholar 

  223. Cole DJ, Matsumura JS, Drummond JC, Schell RM. Focal cerebral ischemia in rats: Effects of induced hypertension, during reperfusion, on cbf. J Cereb Blood Flow Metab. 1992;12:64-69

    Article  PubMed  CAS  Google Scholar 

  224. Shin HK, Nishimura M, Jones PB, Ay H, Boas DA, Moskowitz MA, Ayata C. Mild induced hypertension improves blood flow and oxygen metabolism in transient focal cerebral ischemia. Stroke. 2008;39:1548-1555

    Article  PubMed  CAS  Google Scholar 

  225. Fischberg GM, Lozano E, Rajamani K, Ameriso S, Fisher MJ. Stroke precipitated by moderate blood pressure reduction. J Emerg Med. 2000;19:339-346

    Article  PubMed  CAS  Google Scholar 

  226. Kassell NF, Peerless SJ, Durward QJ, Beck DW, Drake CG, Adams HP. Treatment of ischemic deficits from vasospasm with intravascular volume expansion and induced arterial hypertension. Neurosurgery. 1982;11:337-343

    Article  PubMed  CAS  Google Scholar 

  227. Rordorf G, Cramer SC, Efird JT, Schwamm LH, Buonanno F, Koroshetz WJ. Pharmacological elevation of blood ­pressure in acute stroke. Clinical effects and safety. Stroke. 1997;28:2133-2138

    CAS  Google Scholar 

  228. Rordorf G, Koroshetz WJ, Ezzeddine MA, Segal AZ, Buonanno FS. A pilot study of drug-induced hypertension for treatment of acute stroke. Neurology. 2001;56:1210-1213

    Article  PubMed  CAS  Google Scholar 

  229. Hillis AE, Ulatowski JA, Barker PB, Torbey M, Ziai W, Beauchamp NJ, Oh S, Wityk RJ. A pilot randomized trial of induced blood pressure elevation: Effects on function and focal perfusion in acute and subacute stroke. Cerebrovasc Dis. 2003;16:236-246

    Article  PubMed  CAS  Google Scholar 

  230. Hillis AE, Wityk RJ, Beauchamp NJ, Ulatowski JA, Jacobs MA, Barker PB. Perfusion-weighted mri as a marker of response to treatment in acute and subacute stroke. Neuroradiology. 2004;46:31-39

    Article  PubMed  CAS  Google Scholar 

  231. Hillis AE, Barker PB, Beauchamp NJ, Winters BD, Mirski M, Wityk RJ. Restoring blood pressure reperfused wernicke’s area and improved language. Neurology. 2001;56:670-672

    Article  PubMed  CAS  Google Scholar 

  232. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4:399-415

    Article  PubMed  CAS  Google Scholar 

  233. Yin W, Badr AE, Mychaskiw G, Zhang JH. Down regulation of cox-2 is involved in hyperbaric oxygen treatment in a rat transient focal cerebral ischemia model. Brain Res. 2002;926:165-171

    Article  PubMed  CAS  Google Scholar 

  234. Yin D, Zhou C, Kusaka I, Calvert JW, Parent AD, Nanda A, Zhang JH. Inhibition of apoptosis by hyperbaric oxygen in a rat focal cerebral ischemic model. J Cereb Blood Flow Metab. 2003;23:855-864

    Article  PubMed  CAS  Google Scholar 

  235. Wada K, Miyazawa T, Nomura N, Tsuzuki N, Nawashiro H, Shima K. Preferential conditions for and possible mechanisms of induction of ischemic tolerance by repeated hyperbaric oxygenation in gerbil hippocampus. Neurosurgery. 2001;49:160-166; discussion 166-167

    Google Scholar 

  236. Menzel M, Doppenberg EM, Zauner A, Soukup J, Reinert MM, Bullock R. Increased inspired oxygen concentration as a factor in improved brain tissue oxygenation and tissue lactate levels after severe human head injury. J Neurosurg. 1999;91:1-10

    Article  PubMed  CAS  Google Scholar 

  237. Rockswold SB, Rockswold GL, Vargo JM, Erickson CA, Sutton RL, Bergman TA, Biros MH. Effects of hyperbaric oxygenation therapy on cerebral metabolism and intracranial pressure in severely brain injured patients. J Neurosurg. 2001;94:403-411

    Article  PubMed  CAS  Google Scholar 

  238. Zhang JH, Singhal AB, Toole JF. Oxygen therapy in ischemic stroke. Stroke. 2003;34:e152-e153; author reply e153-e155

    Google Scholar 

  239. Badr AE, Yin W, Mychaskiw G, Zhang JH. Effect of hyperbaric oxygen on striatal metabolites: A microdialysis study in awake freely moving rats after mca occlusion. Brain Res. 2001;916:85-90

    Article  PubMed  CAS  Google Scholar 

  240. Shin HK, Dunn AK, Jones PB, Boas DA, Lo EH, Moskowitz MA, Ayata C. Normobaric hyperoxia improves cerebral blood flow and oxygenation, and inhibits peri-infarct depolarizations in experimental focal ischaemia. Brain. 2007;130:1631-1642

    Article  PubMed  Google Scholar 

  241. Ingvar HD, Lassen NA. Treatment of focal cerebral ischemia with hyperbaric oxygen. Acta Neurol Scand. 1965;41:92-95

    Article  PubMed  CAS  Google Scholar 

  242. Badr AE, Yin W, Mychaskiw G, Zhang JH. Dual effect of hbo on cerebral infarction in mcao rats. Am J Physiol Regul Integr Comp Physiol. 2001;280:R766-R770

    PubMed  CAS  Google Scholar 

  243. Burt JT, Kapp JP, Smith RR. Hyperbaric oxygen and cerebral infarction in the gerbil. Surg Neurol. 1987;28:265-268

    Article  PubMed  CAS  Google Scholar 

  244. Lou M, Eschenfelder CC, Herdegen T, Brecht S, Deuschl G. Therapeutic window for use of hyperbaric oxygenation in focal transient ischemia in rats. Stroke. 2004;35:578-583

    Article  PubMed  Google Scholar 

  245. Veltkamp R, Warner DS, Domoki F, Brinkhous AD, Toole JF, Busija DW. Hyperbaric oxygen decreases infarct size and behavioral deficit after transient focal cerebral ischemia in rats. Brain Res. 2000;853:68-73

    Article  PubMed  CAS  Google Scholar 

  246. Sunami K, Takeda Y, Hashimoto M, Hirakawa M. Hyperbaric oxygen reduces infarct volume in rats by increasing oxygen supply to the ischemic periphery. Crit Care Med. 2000;28:2831-2836

    Article  PubMed  CAS  Google Scholar 

  247. Schabitz WR, Schade H, Heiland S, Kollmar R, Bardutzky J, Henninger N, Muller H, Carl U, Toyokuni S, Sommer C, Schwab S. Neuroprotection by hyperbaric oxygenation after experimental focal cerebral ischemia monitored by mr-imaging. Stroke. 2004;35:1175-1179

    Google Scholar 

  248. Roos JA, Jackson-Friedman C, Lyden P. Effects of hyperbaric oxygen on neurologic outcome for cerebral ischemia in rats. Acad Emerg Med. 1998;5:18-24

    Article  PubMed  CAS  Google Scholar 

  249. Kawamura S, Yasui N, Shirasawa M, Fukasawa H. Therapeutic effects of hyperbaric oxygenation on acute focal cerebral ischemia in rats. Surg Neurol. 1990;34:101-106

    Article  PubMed  CAS  Google Scholar 

  250. Weinstein PR, Anderson GG, Telles DA. Results of hyperbaric oxygen therapy during temporary middle cerebral artery occlusion in unanesthetized cats. Neurosurgery. 1987;20:518-524

    Article  PubMed  CAS  Google Scholar 

  251. Anderson DC, Bottini AG, Jagiella WM, Westphal B, Ford S, Rockswold GL, Loewenson RB. A pilot study of hyperbaric oxygen in the treatment of human stroke. Stroke. 1991;22:1137-1142

    Article  PubMed  CAS  Google Scholar 

  252. Nighoghossian N, Trouillas P, Adeleine P, Salord F. Hyperbaric oxygen in the treatment of acute ischemic stroke. A double-blind pilot study. Stroke. 1995;26:1369-1372

    CAS  Google Scholar 

  253. Rusyniak DE, Kirk MA, May JD, Kao LW, Brizendine EJ, Welch JL, Cordell WH, Alonso RJ. Hyperbaric oxygen therapy in acute ischemic stroke: Results of the hyperbaric oxygen in acute ischemic stroke trial pilot study. Stroke. 2003;34:571-574

    Article  PubMed  Google Scholar 

  254. Flynn EP, Auer RN. Eubaric hyperoxemia and experimental cerebral infarction. Ann Neurol. 2002;52:566-572

    Article  PubMed  Google Scholar 

  255. Singhal AB, Wang X, Sumii T, Mori T, Lo EH. Effects of normobaric hyperoxia in a rat model of focal cerebral ischemia-reperfusion. J Cereb Blood Flow Metab. 2002;22:861-868

    Article  PubMed  Google Scholar 

  256. Singhal AB, Dijkhuizen RM, Rosen BR, Lo EH. Normobaric hyperoxia reduces mri diffusion abnormalities and infarct size in experimental stroke. Neurology. 2002;58:945-952

    Article  PubMed  Google Scholar 

  257. Singhal AB, Benner T, Roccatagliata L, Schaefer PW, Koroshetz WJ, Buonanno FS, Lo EH, Gonzalez RG, Sorensen AG. Normobaric hyperoxia therapy in hyperacute human stroke: Attenuation of dwi abnormalities and improved nihss scores (abstract). Stroke. 2004;35:293

    Google Scholar 

  258. Singhal AB, Ratai E, Benner T, Koroshetz WJ, Roccatagliata L, Lopez C, Schaefer P, Lo EH, Gonzalez RG, Sorensen AG. Normobaric hyperoxia in hyperacute stroke: Serial nihss scores, diffusion-perfusion mri and mr-spectroscopy (abstract). Neurology. 2004;62:464

    Google Scholar 

  259. Liu S, Shi H, Liu W, Furuichi T, Timmins GS, Liu KJ. Interstitial po2 in ischemic penumbra and core are ­differentially affected following transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab. 2004;24:343-349

    Article  PubMed  CAS  Google Scholar 

  260. Watson BD, Busto R, Goldberg WJ, Santiso M, Yoshida S, Ginsberg MD. Lipid peroxidation in vivo induced by reversible global ischemia in rat brain. J Neurochem. 1984;42:268-274

    Article  PubMed  CAS  Google Scholar 

  261. Mickel HS, Vaishnav YN, Kempski O, von Lubitz D, Weiss JF, Feuerstein G. Breathing 100% oxygen after global brain ischemia in mongolian gerbils results in increased lipid peroxidation and increased mortality. Stroke. 1987;18:426-430

    Article  PubMed  CAS  Google Scholar 

  262. Dubinsky JM, Kristal BS, Elizondo-Fournier M. An obligate role for oxygen in the early stages of glutamate-induced, delayed neuronal death. J Neurosci. 1995;15:7071-7078

    PubMed  CAS  Google Scholar 

  263. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033-1041

    Google Scholar 

  264. Chapman N, Huxley R, Anderson C, Bousser MG, Chalmers J, Colman S, Davis S, Donnan G, MacMahon S, Neal B, Warlow C, Woodward M. Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: The progress trial. Stroke. 2004;35:116-121

    Article  PubMed  CAS  Google Scholar 

  265. Heart protection study collaborative group. Mrc/bhf heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet. 2002;360:7-22

    Article  Google Scholar 

  266. Anon. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the hope study and micro-hope substudy. Heart outcomes prevention evaluation study investigators. Lancet. 2000;355:253-259

    Google Scholar 

  267. Laufs U, La Fata V, Plutzky J, Liao JK. Upregulation of endothelial nitric oxide synthase by hmg coa reductase inhibitors. Circulation. 1998;97:1129-1135

    Article  PubMed  CAS  Google Scholar 

  268. Yamada M, Huang Z, Dalkara T, Endres M, Laufs U, Waeber C, Huang PL, Liao JK, Moskowitz MA. Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by l-arginine after chronic statin treatment. J Cereb Blood Flow Metab. 2000;20:709-717

    Article  PubMed  CAS  Google Scholar 

  269. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke protection by 3-hydroxy-3-methylglutaryl (hmg)-coa reductase inhibitors mediated by endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 1998;95:8880-8885

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Stroke Service and Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Aneesh B. Singhal

  2. Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Eng H. Lo

  3. Department of Neurology, Hacettepe University, Ankara, Turkey

    Turgay Dalkara

  4. Departments of Radiology and Neurology, Stroke and Neurovascular Regulation Laboratory, Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA

    Michael A. Moskowitz

Authors
  1. Aneesh B. Singhal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eng H. Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Turgay Dalkara
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael A. Moskowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aneesh B. Singhal .

Editor information

Editors and Affiliations

  1. Massachusetts General Hospital, Dept. Neuroradiology, Harvard Medical School, Fruit St., Boston, 02114, Massachusetts, USA

    R. Gilberto González

  2. Massachusetts General Hospital, Dept. Neuroradiology, Harvard Medical School, Fruit St. 55, Boston, 02114, Massachusetts, USA

    Joshua A. Hirsch

  3. Massachusetts General Hospital, Dept. Neuroradiology, Harvard Medical School, Fruit St. 55, Boston, 02114, Massachusetts, USA

    Michael H. Lev

  4. Massachusetts General Hospital, Dept. Neuroradiology, Harvard Medical School, Fruit St. 55, Boston, 02114, Massachusetts, USA

    Pamela W. Schaefer

  5. , Department of Neurology, Massachusetts General Hospital, Fruit Street 55, Boston, 02114, Massachusetts, USA

    Lee H. Schwamm

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Berlin Heidelberg

About this chapter

Cite this chapter

Singhal, A.B., Lo, E.H., Dalkara, T., Moskowitz, M.A. (2011). Ischemic Stroke: Basic Pathophysiology and Neuroprotective Strategies. In: González, R., Hirsch, J., Lev, M., Schaefer, P., Schwamm, L. (eds) Acute Ischemic Stroke. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-12751-9_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-12751-9_1

  • Published:

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-12750-2

  • Online ISBN: 978-3-642-12751-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation