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  • Review Article
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Neurological diseases

Mechanisms, challenges and opportunities in stroke

Nature Reviews Neuroscience volume 4, pages 399–414 (2003)Cite this article

Key Points

  • 'Stroke' refers to an umbrella of conditions caused by the occlusion or haemorrhage of blood vessels that supply the brain. Risk factors include elevated blood pressure and homocysteine levels, diabetes, atherosclerosis and genetic factors.

  • In the core of the affected brain region, blood flow deficits, low ATP levels and energy stores, ionic disruption and metabolic failure are most severe, and cell death progresses within minutes. The ischaemic penumbra that surrounds the anoxic core suffers milder insults, and cells in this region can be rescued by rapid treatment.

  • Three main mechanisms contribute to cell death during stroke — excitotoxicity and ionic imbalance, oxidative/nitrosative stress and apoptotic-like cell death.

  • Proteolysis of the neurovascular matrix by plasminogen activator and metalloproteinases is linked with stroke-related haemorrhage and oedema, and anoikis. Therapeutic modulation of these proteases might ameliorate these indications.

  • Inflammatory cascades are triggered by ischaemic injury, in both the occluded blood vessels and brain parenchyma. Effects of inflammation are both detrimental (for example, exacerbation of oedema) and potentially beneficial.

  • Thrombolytic therapy — lysing of clots in the occluded blood vessels to reperfuse affected brain regions — is the current standard for treatment of stroke. Reperfusion injury and cell death might be minimized through co-administration of neuroprotectants.

  • The neurovascular unit — a conceptual model comprised of cerebral endothelial cells, astrocytes, neurons and the extracellular matrix — provides a framework for developing treatments based on an integrative and dynamic view of evolving tissue damage.

  • Targeting more than one mechanism/cellular pathway to develop combination therapies might prove more effective than current treatments. Potentially useful variables include preconditioning with non-damaging hypoxic/ischaemic challenges and hypothermia.

Abstract

Over the past two decades, research has heavily emphasized basic mechanisms that irreversibly damage brain cells after stroke. Much attention has focused on what makes neurons die easily and what strategies render neurons resistant to ischaemic injury. In the past few years, clinical experience with clot-lysing drugs has confirmed expectations that early reperfusion improves clinical outcome. With recent research emphasizing ways to reduce tissue damage by both vascular and cell-based mechanisms, the spotlight is now shifting towards the study of how blood vessels and brain cells communicate with each other. This new research focus addresses an important need in stroke research, and provides challenges and opportunities that can be used to therapeutic advantage.

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Figure 1: Major pathways implicated in ischaemic cell death: excitotoxicity, ionic imbalance, oxidative and nitrosative stresses and apoptotic-like mechanisms.
Figure 2: Interactions between pathways that generate oxygen and nitrogen radicals.
Figure 3: Cell death pathways that are relevant to an apoptotic-like mechanism in cerebral ischaemia.
Figure 4: Schematic view of the neurovascular unit or module, and some of its components.
Figure 5: Summary of a protease cascade involving members of the matrix metalloproteinase (MMP) family of endopeptidases.

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References

  1. Report of the Stroke Progress Review Group. (National Institute of Neurological Disorders and Stroke, Maryland) 1–116 (2002). This report from an expert panel convened by the National Institute of Neurological Disorders and Stroke (NINDS) assessed progress in stroke research and provided recommendations for priorities and directions to be emphasized for the next decade.

  2. Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N. Engl. J. Med. 342, 145–153 (2000).

  3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 7–22 (2002).

  4. Yusuf, S. Two decades of progress in preventing vascular disease. Lancet 360, 2–3 (2002).

    Article  PubMed  Google Scholar 

  5. Hassan, A. & Markus, H. S. Genetics and ischaemic stroke. Brain 123, 1784–1812 (2000).

    Article  PubMed  Google Scholar 

  6. Ginsberg, M. D., Belayev, L., Zhao, W., Huh, P. W. & Busto, R. The acute ischemic penumbra: topography, life span, and therapeutic response. Acta Neurochir. Suppl. (Wien) 73, 45–50 (1999).

    CAS  Google Scholar 

  7. Garcia, J. H. et al. Ischemic stroke and incomplete infarction. Stroke 27, 761–765 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Shimizu-Sasamata, M., Bosque-Hamilton, P., Huang, P. L., Moskowitz, M. A. & Lo, E. H. Attenuated neurotransmitter release and spreading depression-like depolarizations after focal ischemia in mutant mice with disrupted type I nitric oxide synthase gene. J. Neurosci. 18, 9564–9571 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cao, G. et al. In vivo delivery of a Bcl-xL fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J. Neurosci. 22, 5423–5431 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hossmann, K. A. Periinfarct depolarizations. Cerebrovasc. Brain Metab. Rev. 8, 195–208 (1996). A comprehensive review of penumbral blood flow and metabolic dynamics in focal cerebral ischaemia.

    CAS  PubMed  Google Scholar 

  12. Bruno, V. et al. Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J. Cereb. Blood Flow Metab. 21, 1013–1033 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Michaelis, E. K. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog. Neurobiol. 54, 369–415 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Pellegrini-Giampietro, D. E., Zukin, R. S., Bennett, M. V., Cho, S. & Pulsinelli, W. A. Switch in glutamate receptor subunit gene expression in CA1 subfield of hippocampus following global ischemia in rats. Proc. Natl Acad. Sci. USA 89, 10499–10503 (1992). One of the earliest demonstrations that post-ischaemic modifications in neurotransmitter receptor structure influence excitotoxic neuronal death.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Oguro, K. et al. Knockdown of AMPA receptor GluR2 expression causes delayed neurodegeneration and increases damage by sublethal ischemia in hippocampal CA1 and CA3 neurons. J. Neurosci. 19, 9218–9227 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Morikawa, E. et al. Attenuation of focal ischemic brain injury in mice deficient in the ε1 (NR2A) subunit of NMDA receptor. J. Neurosci. 18, 9727–9732 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Calabresi, P. et al. Synaptic transmission in the striatum: from plasticity to neurodegeneration. Prog. Neurobiol. 61, 231–265 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Horn, J. & Limburg, M. Calcium antagonists for ischemic stroke: a systematic review. Stroke 32, 570–576 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Paschen, W. Role of calcium in neuronal injury. Brain Res. Bull. 53, 409–413 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Frederickson, C. J. Neurobiology of zinc and zinc-containing neurons. Int. Rev. Neurobiol. 31, 145–238 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Weiss, J. H., Hartley, D. M., Koh, J. Y. & Choi, D. W. AMPA receptor activation potentiates zinc neurotoxicity. Neuron 10, 43–49 (1993).

    Article  CAS  PubMed  Google Scholar 

  23. Sorensen, J. C., Mattsson, B., Andreasen, A. & Johansson, B. B. Rapid disappearance of zinc positive terminals in focal brain ischemia. Brain Res. 812, 265–269 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Gribkoff, V. K. et al. Targeting acute ischemic stroke with a calcium-sensitive opener of maxi-K potassium channels. Nature Med. 7, 471–477 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Fiskum, G., Murphy, A. N. & Beal, M. F. Mitochondria in neurodegeneration: acute ischemia and chronic neurodegenerative diseases. J. Cereb. Blood Flow Metab. 19, 351–369 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Murphy, A. N., Fiskum, G. & Beal, M. F. Mitochondria in neurodegeneration: Bioenergetic function in cell life and death. J. Cereb. Blood Flow Metab. 19, 231–245 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Makar, T. K. et al. Vitamin E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: evidence that astrocytes play an important role in antioxidative processes in the brain. J. Neurochem. 62, 45–53 (1994).

    Article  CAS  PubMed  Google Scholar 

  29. Kroemer, G. & Reed, J. C. Mitochondrial control of cell death. Nature Med. 6, 513–519 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Bernardi, P., Petronilli, V., DiLisa, F. & Forte, M. A mitochondrial perspective on cell death. Trends Biochem. Sci. 26, 112–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Fujimura, M. et al. Manganese superoxide dismutase mediates the early release of mitochondrial cytochrome C and subsequent DNA fragmentation after permanent focal cerebral ischemia in mice. J. Neurosci. 19, 3414–3422 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kondo, T. et al. Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edema formation after transient focal cerebral ischemia. J. Neurosci. 17, 4180–4189 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kinouchi, H. et al. Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc. Natl Acad. Sci. USA 88, 11158–11162 (1991). The first study that used transgenic mice to demonstrate the importance of oxidative stress in ischaemic brain injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sheng, H. et al. Mice overexpressing extracellular superoxide dismutase have increased resistance to focal cerebral ischemia. Neuroscience 88, 185–191 (1999).

    Article  CAS  PubMed  Google Scholar 

  35. Beckman, J. S., Beckman, T. W., Chen, J., Marshall, P. A. & Freeman, B. A. Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc. Natl Acad. Sci. USA 87, 1620–1624 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Huang, Z. et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265, 1883–1885 (1994). The first study using knockout mouse technology to show that the neuronal isoform of nitric oxide synthase has a detrimental role in focal stroke.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhang, J., Dawson, V. L., Dawson, T. M. & Snyder, S. H. Nitric oxide activation of poly(ADP-ribose) synthetase in neurotoxicity. Science 263, 687–689 (1994).

    Article  CAS  PubMed  Google Scholar 

  39. Eliasson, M. J. et al. Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nature Med. 3, 1089–1095 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Endres, M., Wang, Z. -Q., Namura, S., Waeber, C. & Moskowitz, M. A. Ischemic brain injury is mediated by the activation of poly(ADP-ribose) polymerase. J. Cereb. Blood Flow Metab. 17, 1143–1151 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Yuan, J. & Yanker, B. Y. Apoptosis in the nervous system. Nature 407, 802–809 (2000). A succinct summary of apoptotic cascades of cell death in neurological diseases.

    Article  CAS  PubMed  Google Scholar 

  42. Nicotera, P., Leist, M., Fava, E., Berliocchi, L. & Volbracht, C. Energy requirement for caspase activation and neuronal cell death. Brain Pathol. 10, 276–282 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Yu, S. P. & Choi, D. W. Ions, cell volume, and apoptosis. Proc. Natl Acad. Sci. USA 97, 9360–9362 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yu, S. P., Yeh, C., Strasser, U., Tian, M. & Choi, D. W. NMDA receptor-mediated K+ efflux and neuronal apoptosis. Science 284, 336–339 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Nicotera, P. & Lipton, S. A. Excitotoxins in neuronal apoptosis and necrosis. J. Cereb. Blood Flow Metab. 19, 583–591 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Budd, S. L., Tenneti, L., Lishnak, T. & Lipton, S. A. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons. Proc. Natl Acad. Sci. USA 97, 6161–6666 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Martin-Villalba, A. et al. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons. J. Neurosci. 19, 3809–3817 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chopp, M., Chan, P. H., Hsu, C. Y., Cheung, M. E. & Jacobs, T. P. DNA damage and repair in central nervous system injury. Stroke 27, 363–369 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Salvesen, G. S. A lysosomal protease enters the death scene. J. Clin. Invest. 107, 21–22 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yamashina, T. Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog. Neurobiol. 62, 273–295 (2000).

    Article  Google Scholar 

  51. Digicaylioglu, M. & Lipton, S. A. Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-κB signalling cascades. Nature 412, 641–647 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Mohr, S., Stamler, J. S. & 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. 348, 223–227 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. Mannick, J. B. et al. Fas-induced caspase denitrosylation. Science 284, 651–654 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Elibol, B. et al. Nitric oxide is involved in ischemia-induced apoptosis in brain: a study in neuronal nitric oxide synthase null mice. Neuroscience 105, 79–86 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Yu, S. -W. et al. Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297, 259–263 (2002). This study shows important organelle cross-talk linking mitochondrial dysfunction, energy deficits related to PARP activation and caspase-independent cell death mediated by AIF.

    Article  CAS  PubMed  Google Scholar 

  56. Schulz, J. B., Weller, M. & Moskowitz, M. A. Caspases as treatment targets in stroke and neurodegenerative diseases. Ann. Neurol. 45, 421–429 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Namura, S. et al. Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J. Neurosci. 18, 3659–3668 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wei, M. C. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hara, H. et al. Inhibition of interleukin 1β converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc. Natl Acad. Sci. USA 94, 2007–2012 (1997). The first study demonstrating proof-of-concept that pharmacological inhibition of caspases protects brain in experimental stroke models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Han, B. H. et al. Selective, reversible caspase-3 inhibitor is neuroprotective and reveals distinct pathways of cell death after neonatal hypoxic-ischemic brain injury. J. Biol. Chem. 277, 30128–30136 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Fink, K. et al. Prolonged therapeutic window for ischemic brain damage caused by delayed caspase activation. J. Cereb. Blood Flow Metab. 18, 1071–1076 (1998).

    Article  CAS  PubMed  Google Scholar 

  62. Le, D. A. et al. Caspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc. Natl Acad. Sci. USA 99, 15188–15193 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Graham, S. H. & Chen, J. Programmed cell death in cerebral ischemia. J. Cereb. Blood Flow Metab. 21, 99–109 (2001). A comprehensive review surveying the evidence for multiple pathways of apoptotic-like cell death in stroke.

    Article  CAS  PubMed  Google Scholar 

  64. Qiu, J. et al. Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J. Neurosci. 22, 3504–3511 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Susin, S. A. et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441–446 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Asoh, S. et al. Protection against ischemic brain injury by protein therapeutics. Proc. Natl Acad. Sci. USA 99, 17107–17112 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Fiskum, G. Mitochondrial participation in ischemic and traumatic neural cell death. J. Neurotrauma 17, 843–854 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Leist, M. & Jäättelä, M. Four deaths and a funeral: from caspases to alternative mechanisms. Nature Rev. Mol. Cell Biol. 2, 1–10 (2001).

    Article  CAS  Google Scholar 

  69. Petty, M. A. & Lo, E. H. Junctional complexes of the blood–brain barrier: permeability changes in neuroinflammation. Prog. Neurobiol. 68, 311–323 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Cuzner, M. L. & Opdenakker, G. Plasminogen activators and matrix metalloproteinases, mediators of extracellular proteolysis in inflammatory demyelination of the central nervous system. J. Neuroimmunol. 94, 1–14 (1999).

    Article  CAS  PubMed  Google Scholar 

  71. Yong, V. W., Krekoski, C. A., Forsyth, P. A., Bell, R. & Edwards, D. R. Matrix metalloproteinases and disease of the CNS. Trends Neurosci. 21, 75–80 (1998).

    Article  CAS  PubMed  Google Scholar 

  72. Yong, V. W., Power, C., Forsyth, P. & Edwards, D. R. Metalloproteinases in biology and pathology of the nervous system. Nature Rev. Neurosci. 2, 502–511 (2001). An authoritative review describing the pathophysiologic roles of MMPs in CNS disorders.

    Article  CAS  Google Scholar 

  73. Szklarczyk, A., Lapinska, J., Rylski, M., McKay, R. D. & Kaczmarek, L. Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. J. Neurosci. 22, 920–930 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Asahi, M. et al. Role of matrix metalloproteinase 9 in focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J. Cereb. Blood Flow Metab. 20, 1681–1690 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Gasche, Y. et al. Early appearance of activated MMP-9 after focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 19, 1020–1028 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Heo, J. H. et al. Matrix metalloproteinases increase very early during experimental focal cerebral ischemia. J. Cereb. Blood Flow Metab. 19, 624–633 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Rosenberg, G. A. & Navratil, M. Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology 48, 921–927 (1997).

    Article  CAS  PubMed  Google Scholar 

  78. Wang, X. et al. Effects of matrix metalloproteinase 9 gene knockout on morphological and motor outcomes after traumatic brain injury. J. Neurosci. 20, 7037–7043 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Clark, A. W., Krekoski, C. A., Bou, S. S., Chapman, K. R. & Edwards, D. R. Increased gelatinase A (MMP-2) and gelatinase B (MMP-9) activities in human brain after focal ischemia. Neurosci. Lett. 238, 53–56 (1997).

    Article  CAS  PubMed  Google Scholar 

  80. Montaner, J. et al. Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke 32, 1759–1766 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Wang, X., Mori, T., Jung, J. C., Fini, M. E. & Lo, E. H. Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase. J. Neurotrauma 19, 615–625 (2002).

    Article  PubMed  Google Scholar 

  82. Gasche, Y., Copin, J. C., Sugawara, T., Fujimura, M. & Chan P. H. Matrix metalloproteinase inhibition prevents oxidative stress-associated blood–brain barrier disruption after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 21, 1393–1400 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Gu, Z. et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297, 1186–1190 (2002). Provides evidence that NOS nitrosylates MMPs and mediates anoikis-like cell death in neurons, thereby providing a link between nitrosative stress and extracellular proteolysis.

    Article  CAS  PubMed  Google Scholar 

  84. Anthony, D. C. et al. Matrix metalloproteinase expression in an experimentally induced DTH model of multiple sclerosis in rat CNS. J. Neuroimmunol. 87, 62–72 (1998).

    Article  CAS  PubMed  Google Scholar 

  85. Asahi, M. et al. Effects of matrix metalloproteinase 9 gene knockout on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J. Neurosci. 21, 7724–7732 (2001). This study showed that deletion of the MMP9 gene protected against blood–brain barrier leakage and infarction after focal ischaemia, directly implicating this protease as a mediator of injury to the neurovascular unit.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  87. Asahi, M., Sumii, T., Fini, M. E., Itohara, S. & Lo, E. H. Matrix metalloproteinase 2 gene knockout has no effect on acute brain injury after focal ischemia. Neuroreport 12, 3003–3007 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Pitman, R. N. & Beuttner, H. M. Degradation of extracellular matrix by neuronal proteases. Dev. Neurosci. 11, 361–375 (1989).

    Article  Google Scholar 

  89. Vivien, D. & Buisson, A. Serine protease inhibitors: novel therapeutic targets for stroke? J. Cereb. Blood Flow Metab. 20, 755–764 (2000).

    Article  CAS  PubMed  Google Scholar 

  90. Nagai, N. et al. Tissue type plasminogen activator is involved in the process of neuronal death by oxygen-glucose deprivation. J. Cereb. Blood Flow Metab. 21, 631–634 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Nicole, O. et al. The proteolytic activity of tissue-plasminogen activator enhances NMDA receptor-mediated signaling. Nature Med. 7, 59–64 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Yepes, M. et al. Neuroserpin reduces cerebral infarct volume and protects neurons from ischemia-induced apoptosis. Blood 96, 569–576 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Wang, Y. F. et al. Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nature Med. 4, 228–231 (1998). The first study to demonstrate that the thrombolytic agent tPA can directly exacerbate cerebral damage in stroke.

    Article  CAS  PubMed  Google Scholar 

  94. Tabrizi, P. et al. Tissue plasminogen activator deficiency exacerbates cerebrovascular fibrin deposition and brain injury. Arterioscler. Thromb. Vasc. Biol. 19, 2801–2806 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Ginsberg, M. D. On ischemic brain injury in genetically altered mice. Arterioscler. Thromb. Vasc. Biol. 19, 2581–2583 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Lo, E. H., Wang, X. & Cuzner, M. L. Extracellular proteolysis in brain injury and inflammation: role for plasminogen activators and matrix metalloproteinases. J. Neurosci. Res. 69, 1–9 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Montaner, J. et al. Matrix metalloproteinase expression is related to hemorrhagic transformation after cardioembolic stroke. Stroke 32, 2762–2767 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Aoki, T., Sumii, T., Mori, T., Wang, X. & Lo, E. H. Blood–brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats. Stroke 33, 2711–2717 (2002).

    Article  PubMed  Google Scholar 

  99. Sumii, T. & Lo, E. H. Involvement of matrix metalloproteinase in thrombolysis-associated hemorrhagic transformation after embolic focal ischemia in rats. Stroke 33, 831–836 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Lapchak, P. A., Chapman, D. F. & Zivin, J. A. Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 31, 3034–3040 (2000). References 99 and 100 provide evidence that tPA can amplify MMP levels in stroke, and showed that an MMP inhibitor given with tPA reduces tPA-related haemorrhagic transformation in brain.

    Article  CAS  PubMed  Google Scholar 

  101. Tagaya, M. et al. Rapid loss of microvascular integrin expression during focal brain ischemia reflects neuron injury. J. Cereb. Blood Flow Metab. 21, 835–846 (2001). This study showed that microvascular injury was related to neuronal cell death and therefore linked the response of these two cell components of the neurovascular unit.

    Article  CAS  PubMed  Google Scholar 

  102. Chen, Z. L. & Strickland, S. Neuronal death in the hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 91, 917–925 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Gary, D. & Mattson, M. P. Integrin signaling via the PI3-kinase–Akt pathway increases neuronal resistance to glutamate-induced apoptosis. J. Neurochem. 76, 1485–1496 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Corley, S. M., Ladiwala, U., Besson, A. & Yong, V. W. Astrocytes attenuate oligodendrocyte death in vitro through an α6 integrin–laminin-dependent mechanism. Glia 36, 281–294 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Lee, S. & Lo, E. H. Induction of caspase-mediated cell death by matrix metalloproteinase after hypoxia–reoxygenation in human brain microvascular endothelial cells. Stroke 34, 250 (2003).

    Google Scholar 

  106. McCawley, L. J. & Matrisian, L. M. Matrix metalloproteinases: they're not just for matrix anymore! Curr. Opin. Cell Biol. 13, 534–540 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Ridker, P. M., Hennekens, C. H., Buring, J. E. & Rifai, N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med. 342, 836–843 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Tanne, D. et al. 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 33, 2182–2186 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Stanimirovich, D. & Satoh, K. Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol. 10, 113–126 (2000).

    Article  Google Scholar 

  110. Frijns, C. J. M. & Kappelle, L. J. Inflammatory cell adhesion molecules in ischemic cerebrovascular disease. Stroke 33, 2115–2122 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Connolly, E. S. Jr et al. 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. 97, 209–216 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Connolly, E. S. Jr 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. 81, 304–310 (1997).

    Article  CAS  PubMed  Google Scholar 

  113. Del Zoppo, G. J. et al. Inflammation and stroke: putative role for cytokines, adhesion molecules, and iNOS in brain response to ischemia. Brain Pathol. 10, 95–112 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Huang, J. et al. Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein. Science 285, 595–598 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Enlimomab Acute Stroke Trial Investigators. Use of anti-ICAM-1 therapy in ischemic stroke: results of the Enlimomab Acute Stroke Trial. Neurology 57, 1428–1434 (2001).

  116. Furuya, K. et al. Examination of several potential mechanisms for the negative outcome in a clinical stroke trial of enlimomab, a murine anti-human intercellular adhesion molecule-1 antibody: a bedside-to-bench study. Stroke 32, 2665–2674 (2001). This study dissects the inflammatory complications from administering the anti-ICAM antibody, and offers a possible explanation for the failure of the Enlimomab Acute Stroke Trial.

    Article  CAS  PubMed  Google Scholar 

  117. Allan, S. M. & Rothwell, N. J. Cytokines and acute neurodegeneration. Nature Rev. Neurosci. 2, 734–744 (2001).

    Article  CAS  Google Scholar 

  118. Barone, F. C. & Feuerstein, G. Z. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J. Cereb. Blood Flow Metab. 19, 819–834 (1999). A comprehensive review of the multifaceted aspects of inflammation in cerebral ischaemia.

    Article  CAS  PubMed  Google Scholar 

  119. Hughes, P. M. et al. Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J. Cereb. Blood Flow Metab. 22, 308–317 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Iadecola, C. et al. Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc. Natl Acad. Sci. USA 98, 1294–1299 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Boutin, H. et al. Role of IL-1α and IL-1β in ischemic brain damage. J. Neurosci. 21, 5528–5534 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Schielke, G. P., Yang, G. Y., Shivers, B. D. & Betz, A. L. Reduced ischemic brain injury in interleukin-1β converting enzyme-deficient mice. J. Cereb. Blood Flow Metab. 18, 180–185 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. Nawahiro, H., Martin, D. & Hallenbeck, J. M. Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res. 778, 265–271 (1997).

    Article  Google Scholar 

  124. Bruce, A. J. et al. Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nature Med. 2, 788–794 (1996).

    Article  CAS  PubMed  Google Scholar 

  125. Fontaine, V. et al. Neurodegenerative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J. Neurosci. 22, RC216 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Zhang, Z. G. et al. VEGF enhances angiogenesis and promotes blood–brain barrier leakage in the ischemic brain. J. Clin. Invest. 106, 829–838 (2000). This study on VEGF provided evidence for an early detrimental role in blood–brain barrier leakage and a potentially beneficial angiogenic role in delayed recovery after stroke.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rosenberg, G. A. Matrix metalloproteinases in neuroinflammation. Glia 39, 279–291 (2002).

    Article  PubMed  Google Scholar 

  128. D'Ambrosio, A. L., Pinsky, D. J. & Connolly, E. S. The role of the complement cascade in ischemia-reperfusion injury: implications for neuroprotection. Mol. Med. 7, 367–382 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Qiong, Z. & McNamara, J. O. Fleeting activation of ionotropic glutamate receptors sensitizes cortical neurons to complement attack. Neuron 36, 363–374 (2002).

    Article  Google Scholar 

  130. Hacke, W. et al. Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology 53, S3–S15 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Garcia, J. H., Liu, K. F. & Ho, K. L. Neuronal necrosis after middle cerebral artery occlusion in Wistar rats progresses at different time intervals in the caudoputamen and the cortex. Stroke 26, 636–642 (1995).

    Article  CAS  PubMed  Google Scholar 

  132. Furlan, A. et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 282, 2003–2011 (1999).

    Article  CAS  PubMed  Google Scholar 

  133. Baron, J. -C. Mapping the ischaemic penumbra with PET: a new approach. Brain 124, 2–4 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. Heiss, W. -D. et al. Penumbral probability thresholds of cortical flumazenil binding and blood flow predicting tissue outcome in patients with cerebral ischaemia. Brain 124, 20–29 (2001). A quantitative imaging study that defines ratios of penumbra and core in stroke patients.

    Article  CAS  PubMed  Google Scholar 

  135. Baird, A. E. & Warach, S. Magnetic resonance imaging of acute stroke. J. Cereb. Blood Flow Metab. 18, 583–609 (1998).

    Article  CAS  PubMed  Google Scholar 

  136. Asahi, M., Asahi, K., Wang, X. & Lo, E. H. 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. 20, 452–457 (2000).

    Article  CAS  PubMed  Google Scholar 

  137. 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. 119, 209–216 (1993).

    Article  CAS  PubMed  Google Scholar 

  138. Zivin, J. A. & Mazzarella, V. Tissue plasminogen activator plus glutamate antagonist improves outcome after embolic stroke. Arch. Neurol. 48, 1235–1238 (1991).

    Article  CAS  PubMed  Google Scholar 

  139. Andersen, M., Overgaard, K., Meden, P., Boysen, G. & Choi, S. C. Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model. Stroke 30, 1464–1471 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. 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 39, 881–888 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. Bowes, M. P., Rothlein, R., Fagan, S. C. & Zivin, J. A. Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. Neurology 45, 815–819 (1995).

    Article  CAS  PubMed  Google Scholar 

  142. Shuaib, A., Yang, Y., Nakada, M. T., 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. 22, 215–222 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Lyden, P. et al. for the CLASS IHT Investigators. The Clomethiazole Acute Stroke Study in Tissue-Type Plasminogen Activator-Treated Stroke (CLASS-T): final results. Neurology 57, 1199–1205 (2001).

    Article  CAS  PubMed  Google Scholar 

  144. Grotta, J. Combination Therapy Stroke Trial: recombinant tissue-type plasminogen activator with/without lubeluzole. Cerebrovasc. Dis. 12, 258–263 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Schmid-Elsaesser, R., Hungerhuber, E., Zausinger, S., Baethmann, A. & Reulen, H. J. Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia. Stroke 30, 1891–1899 (1999).

    Article  CAS  PubMed  Google Scholar 

  146. Singhal, A. B., Dijkhuizen, R. M., Rosen, B. R. & Lo, E. H. Normobaric hyperoxia reduces MRI diffusion abnormalities and infarct size in experimental stroke. Neurology 58, 945–952 (2002).

    Article  PubMed  Google Scholar 

  147. Nogawa, S. et al. Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia. Proc. Natl Acad. Sci. USA 95, 10966–10971 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Lyden, P. D., Jackson-Friedman, C., Shin, C. & Hassid, S. Synergistic combinatorial stroke therapy: a quantal bioassay of a GABA agonist and a glutamate antagonist. Exp. Neurol. 163, 477–489 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Barth, A., Barth, L. & Newell, D. W. Combination therapy with MK-801 and α-phenyl-tert-butyl-nitrone enhances protection against ischemic neuronal damage in organotypic hippocampal slice cultures. Exp. Neurol. 141, 330–336 (1996).

    Article  CAS  PubMed  Google Scholar 

  150. Onal, M. Z. et al. Synergistic effects of citicoline and MK-801 in temporary experimental focal ischemia in rats. Stroke 28, 1060–1065 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  152. Ma, J., Endres, M. & Moskowitz, M. A. Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice. Br. J. Pharmacol. 124, 756–762 (1998). The first demonstration that anti-apoptosis agents can be combined with anti-excitotoxic therapies enhance benefit in experimental stroke.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Barth, A., Barth, L., Morrison, R. S. & Newell, D. W. bFGF enhances the protective effects of MK-801 against ischemic neuronal injury in vitro. Neuroreport 7, 1461–1464 (1996).

    Article  CAS  PubMed  Google Scholar 

  154. Schmid-Elsaesser, R., Hungerhuber, E., Zausinger, S., Baethmann, A. & Reulen, H. J. Neuroprotective efficacy of combination therapy with two different antioxidants in rats subjected to transient focal ischemia. Brain Res. 816, 471–479 (1999).

    Article  CAS  PubMed  Google Scholar 

  155. Schabitz, W. R. et al. Synergistic effects of a combination of low-dose bFGF and citicoline after temporary experimental focal ischemia. Stroke 30, 427–432 (1999).

    Article  CAS  PubMed  Google Scholar 

  156. Ma, J., Qiu, J., Hirt, L., Dalkara, T. & Moskowitz, M. A. Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischaemia. Br. J. Pharmacol. 133, 345–350 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. De Keyser, J., Sulter, G. & Luiten, P. G. Clinical trials with neuroprotective drugs in acute ischaemic stroke: are we doing the right thing? Trends Neurosci. 22, 535–540 (2000).

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  159. Kitagawa, K. et al. 'Ischemic tolerance' phenomenon found in the brain. Brain Res. 528, 21–24 (1990).

    Article  CAS  PubMed  Google Scholar 

  160. Baxter, G. F. Ischaemic preconditioning of myocardium. Ann. Med. 29, 345–352 (1997).

    Article  CAS  PubMed  Google Scholar 

  161. Nandagopal, K., Dawson, T. M. & Dawson, V. L. Critical role for nitric oxide signaling in cardiac and neuronal ischemic preconditioning and tolerance. J. Pharmacol. Exp. Ther. 297, 474–478 (2001).

    CAS  PubMed  Google Scholar 

  162. Carroll, R. & Yellon, D. M. Myocardial adaptation to ischaemia: the preconditioning phenomenon. Int. J. Cardiol. 68, S93–S101 (1999).

    Article  PubMed  Google Scholar 

  163. Moncayo, J., de Freitas, G. R., Bogousslavsky, J., Altieri, M. & van Melle, G. Do transient ischemic attacks have a neuroprotective effect? Neurology 54, 2089–2094 (2000).

    Article  CAS  PubMed  Google Scholar 

  164. Gonzalez-Zulueta, M. et al. Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. Proc. Natl Acad. Sci. USA 97, 436–441 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Impey, S., Obrietan, K. & Storm, D. R. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity. Neuron 23, 11–14 (1999).

    Article  CAS  PubMed  Google Scholar 

  166. Inamasu, J. & Ichikizaki, K. Mild hypothermia in neurologic emergency: an update. Ann. Emerg. Med. 40, 220–230 (2002). A comprehensive review on the use of hypothermia in several neurological diseases.

    Article  PubMed  Google Scholar 

  167. Busto, R. et al. Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J. Cereb. Blood Flow Metab. 7, 729–738 (1987). The first demonstration that very small reductions in brain temperature profoundly protect against ischaemic injury, indicating that tissue survival was independent of lowered metabolic rate.

    Article  CAS  PubMed  Google Scholar 

  168. Minard, F. N. & Grant, D. S. Hypothermia as a mechanism for drug-induced resistance to hypoxia. Biochem. Pharmacol. 31, 1197–1203 (1982).

    Article  CAS  PubMed  Google Scholar 

  169. Markarian, G. Z., Lee, J. H., Stein, D. J. & Hong, S. -C. Mild hypothermia: therapeutic window after experimental cerebral ischemia. Neurosurgery 38, 542–551 (1996).

    CAS  PubMed  Google Scholar 

  170. Welsh, F. A. & Harris, V. A. Postischemic hypothermia fails to reduce ischemic injury in gerbil hippocampus. J. Cereb. Blood Flow Metab. 11, 617–620 (1991).

    Article  CAS  PubMed  Google Scholar 

  171. Ginsberg, M. D. in Primer on Cerebrovascular Diseases (eds Welch, K. M. A., Caplan, L. R., Reis, D. J. B., Siesjo, K. & Weir, B.) 272–275 (Academic, San Diego, 1997).

    Book  Google Scholar 

  172. Corbett, D., Hamilton, M. & Colbourne, F. Persistent neuroprotection with prolonged postischemic hypothermia in adult rats subjected to transient middle cerebral artery occlusion. Exper. Neurol. 163, 200–206 (2000).

    Article  CAS  Google Scholar 

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

  174. Bernard, S. A. et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N. Engl. J. Med. 346, 557–563 (2002). References 173 and 174 show that hypothermia can significantly improve neurological outcomes in patients suffering from transient global cerebral ischaemia.

    Article  PubMed  Google Scholar 

  175. Shiozaki, T. et al. A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. Mild Hypothermia Study Group in Japan. J. Neurosurg. 94, 50–54 (2001).

    Article  CAS  PubMed  Google Scholar 

  176. Schwab, S. et al. Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke 29, 2461–2466 (1998).

    Article  CAS  PubMed  Google Scholar 

  177. Kammersgaard, L. P. et al. 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 31, 2251–2256 (2000).

    Article  CAS  PubMed  Google Scholar 

  178. Krieger, D. W. et al. Cooling for acute ischemic brain damage (COOL AID): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke 32, 1847–1854 (2001).

    Article  CAS  PubMed  Google Scholar 

  179. Colbourne, F., Sutherland, G. & Corbett, D. Postischemic hypothermia: a critical appraisal with implications for clinical treatment. Molec. Neurobiol. 14, 171–201 (1997).

    Article  CAS  Google Scholar 

  180. Prosser, C. L. in Comparative Animal Physiology (ed. Prosser, C. L.) 362–428 (Saunders, Philadelphia, 1973).

    Google Scholar 

  181. Ginsberg, M. D. & Busto, R. Combating hyperthermia in acute stroke: a significant clinical concern. Stroke 29, 529–534 (1998).

    Article  CAS  PubMed  Google Scholar 

  182. Azzimondi, G. et al. Fever in acute stroke worsens prognosis: a prospective study. Stroke 26, 2040–2043 (1995).

    Article  CAS  PubMed  Google Scholar 

  183. Reith, J. et al. Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome. Lancet 347, 422–425 (1996).

    Article  CAS  PubMed  Google Scholar 

  184. Yamada, M. et al. Endothelial nitric oxide synthase-dependent cerebral blood flow augmentation by L-arginine after chronic statin treatment. J. Cereb. Blood Flow Metab. 20, 709–717 (2000).

    Article  CAS  PubMed  Google Scholar 

  185. Zhang, F., White, J. G. & Iadecola, C. Nitric oxide donors increase blood flow and reduce brain damage in focal ischemia: evidence that nitric oxide is beneficial in the early stages of cerebral ischemia. J. Cereb. Blood Flow Metab. 14, 217–226 (1994).

    Article  CAS  PubMed  Google Scholar 

  186. Morikawa, E. et al. L-Arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow and reduces infarction volume in the rat. Stroke 25, 429–435 (1994).

    Article  CAS  PubMed  Google Scholar 

  187. Laufs, U., LaFata, V., Plutzky, J. & Liao, K. Upregulation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Circulation 97, 1129–1135 (1998).

    Article  CAS  PubMed  Google Scholar 

  188. Endres, M. et al. Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase. Proc. Natl Acad. Sci. USA 95, 8880–8885 (1998). This study showed that statins protect brain from ischaemic injury by directly upregulating endogenous eNOS levels and improving blood flow.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Laufs, U. et al. Neuroprotection mediated by changes in the endothelial actin cytoskeleton. J. Clin. Invest. 106, 15–24 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 7–22 (2002).

  191. Limbourg, F. P. et al. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J. Clin. Invest. 110, 1729–1738 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Hafezi-Moghadam, A. et al. Cardiovascular protective effects of corticosteroids mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nature Med. 8, 473–479 (2002).

    Article  CAS  PubMed  Google Scholar 

  193. Hafezi-Moghadam, A. et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nature Med. 8, 473–479 (2002).

    Article  CAS  PubMed  Google Scholar 

  194. Chen, Z. et al. Estrogen receptor a mediates the nongenomic ativation of endothelial nitric oxide synthase by estrogen. J. Clin. Invest. 103, 401–406 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. McCullough, L. D., Alkayed, N. J., Traystman, R. J., Williams, M. J., & Hurn, P. D. Postischemic estrogen reduces hypoperfusion and secondary ischemia after experimental stroke. Stroke 32, 796–802 (2001).

    Article  CAS  PubMed  Google Scholar 

  196. Belayev, L. et al. Albumin therapy of transient focal cerebral ischemia. In vivo analysis of dynamic microvascular responses. Stroke 33, 1077–1084 (2002).

    Article  PubMed  Google Scholar 

  197. Belayev, L., Liu, Y., Zhao, W., Busto, R. & Ginsberg, M. D. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke 32, 553–560 (2001).

    Article  CAS  PubMed  Google Scholar 

  198. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br. Med. J. 324, 71–86 (2002).

  199. Stapf, C. & Mohr, J. P. Ischemic stroke therapy. Ann. Rev. Med. 53, 453–475 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Becker, K. J. et al. Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia. Proc. Natl Acad. Sci. USA 94, 10873–10878 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Takeda, H. et al. Induction of mucosal tolerance of E-selectin prevents ischemic and hemorrhagic stroke in spontaenously hypertensive genetically stroke-prone rats. Stroke 33, 2156–2164 (2002).

    Article  CAS  PubMed  Google Scholar 

  202. Stys, P. K. Anoxic and ischemic injury of myelinated axons in CNS white matter. J. Cereb. Blood Flow Metab. 18, 2–25 (1998).

    Article  CAS  PubMed  Google Scholar 

  203. Li, S., Mealing, G. A., Morley, P. & Stys, P. K. Novel injury mechanism in anoxia and trauma of spinal cord white matter: glutamate release via reverse Na-dependent glutamate transport. J. Neurosci. 19, RC16 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Imai, H., Masayasu, H., Dewar, D., Graham, D. I. & Macrae, I. M. Ebselen protects both gray and white matter in a rodent model of focal cerebral ischemia. Stroke 32, 2149–2154 (2001).

    Article  CAS  PubMed  Google Scholar 

  205. Petty, M. A. & Wettstein, J. G. White matter ischemia. Brain Res. Rev. 31, 58–64 (1999).

    Article  CAS  PubMed  Google Scholar 

  206. Stys, P. K. & Jiang, Q. Calpain-dependent neurofilament breakdown in anoxic and ischemic rat central axons. Neurosci. Lett. 328, 150–154 (2002).

    Article  CAS  PubMed  Google Scholar 

  207. Irving, E. A., Bentley, D. L. & Parsons, A. A. Assessment of white matter injury following prolonged focal cerebral ischemia in rat. Acta Neuropathologica 102, 627–635 (2001).

    Article  CAS  PubMed  Google Scholar 

  208. McDonald, J. W., Althomsons, S. P., Hyra, K. L., Choi, D. W. & Goldberg, M. P. Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor mediated excitotoxicity. Nature Med. 4, 291–297 (1998). This study demonstrated that glutamate and AMPA receptor agonists are toxic to oligodendroglia, thereby implicating excitotoxicity in white matter strokes.

    Article  CAS  PubMed  Google Scholar 

  209. Matute, C., Alberdi, E., Ibarretxe, G. & Sanchez-Gomez, M. V. Excitotoxicity in glial cells. Eur. J. Pharmacol. 447, 239–246 (2002).

    Article  CAS  PubMed  Google Scholar 

  210. Gu, C., Casaccia, P., Srinivasan, A. & Chao, M. V. Oligodendrocyte apoptosis mediated by caspase activation. J. Neurosci. 19, 3043–3049 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Yin, X. et al. Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons. J. Neurosci. 18, 1953–1962 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Garbern, J. Y. et al. Patients lacking the major CNS myelin protein proteolipid 1 develop length dependent axonal degeneration in the absence of demyelination and inflammation. Brain 125, 551–561 (2002).

    Article  PubMed  Google Scholar 

  213. Chandler, S. et al. Matrix metalloproteinases degrade myelin basic protein. Neurosci. Lett. 201, 223–226 (1995).

    Article  CAS  PubMed  Google Scholar 

  214. Rosenberg, G. A., Sullivan, N. & Esiri, M. M. White matter damage is associated with matrix metalloproteinases in vascular dementia. Stroke 32, 1162–1168 (2001).

    Article  CAS  PubMed  Google Scholar 

  215. Sharp, F. R., Massa, S. M. & Swanson, R. A. Heat-shock protein protection. Trends Neurosci. 22, 97–99 (1999).

    Article  CAS  PubMed  Google Scholar 

  216. Shimazaki, K., Ishida, A., & Kawai, N. Increase in bcl-2 oncoprotein and the tolerance to ischemia-induced neuronal death in the gerbil hippocampus. Neurosci. Res. 20, 95–99 (1994).

    Article  CAS  PubMed  Google Scholar 

  217. Majda, B. T., Meloni, B. P., Rixon, N. & Knuckey, N. W. Suppression subtraction hybridization and northern analysis reveal upregulation of heat shock, trkB, and sodium calcium exchanger genes following global cerebral ischemia in the rat. Brain Res. Mol. Brain Res. 93, 173–179 (2001).

    Article  CAS  PubMed  Google Scholar 

  218. Sugawara, T., Noshita, N., Lewen, A., Kim, G. W. & Chan, P. H. Neuronal expression of the DNA repair protein Ku 70 after ischemic preconditioning corresponds to tolerance to global cerebral ischemia. Stroke 32, 2388–2393 (2001).

    Article  CAS  PubMed  Google Scholar 

  219. Ginis, I. et al. TNF-α-induced tolerance to ischemic injury involves differential control of NF-κB transactivation: the role of NF-κB association with p300 adaptor. J. Cereb. Blood Flow Metab. 22, 142–152 (2002).

    Article  CAS  PubMed  Google Scholar 

  220. Bernaudin, M. et al. Normobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J. Cereb. Blood Flow Metab. 22, 393–403 (2002).

    Article  CAS  PubMed  Google Scholar 

  221. Dawson, T. M. Preconditioning-mediated neuroprotection through erythropoietin? Lancet 359, 96–97 (2002).

    Article  PubMed  Google Scholar 

  222. Shamloo, M. & Wieloch, T. Changes in protein tyrosine phosphorylation in the rat brain after cerebral ischemia in a model of ischemic tolerance. J. Cereb. Blood Flow Metab. 19, 173–183 (1999).

    Article  CAS  PubMed  Google Scholar 

  223. Gu, Z., Jiang, Q. & Zhang, G. Extracellular signal-regulated kinase and c-Jun N-terminal protein kinase in ischemic tolerance. Neuroreport 12, 3487–3491 (2001).

    Article  CAS  PubMed  Google Scholar 

  224. Astrup, J., Sorensen, P. M. & Sorensen, H. R. Inhibition of cerebral oxygen and glucose consumption in the dog by hypothermia, pentobarbital and lidocaine. Anesthesiology 55, 263–268 (1981).

    Article  CAS  PubMed  Google Scholar 

  225. Chopp, M. et al. The metabolic effects of mild hypothermia on global cerebral ischemia and recirculation in the cat: Comparison to normothermia and hyperthermia. J. Cereb. Blood Flow Metab. 9, 141–148 (1989).

    Article  CAS  PubMed  Google Scholar 

  226. 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. 57, 1814–1817 (1991).

    Article  CAS  PubMed  Google Scholar 

  227. Maeda, T. et al. Mechanisms of excitatory amino acid release in contused brain tissue: effects of hypothermia and in situ administration of Co2+ on extracellular levels of glutamate. J. Neurotrauma 15, 655–664 (1998).

    Article  CAS  PubMed  Google Scholar 

  228. Globus, M. Y. -T., Busto, R., Lin, B., Schnippering, H. & Ginsberg, M. D. Detection of free radical activity during transient global ischemia and recirculation: effects of intraischemic brain temperature modulation. J. Neurochem. 65, 1250–1256 (1995).

    Article  CAS  PubMed  Google Scholar 

  229. Mori, K. et al. Effects of mild (33 degrees C) and moderate (29 degrees C) hypothermia on cerebral blood flow and metabolism, lactate, and extracellular glutamate in experimental head injury. Neurol. Res. 20, 719–726 (1998).

    Article  CAS  PubMed  Google Scholar 

  230. Yenari, M. A. et al. Mild hypothermia attenuates cytochrome c release but does not alter Bcl-2 expression or caspase activation after experimental stroke. J. Cereb. Blood Flow Metab. 22, 29–38 (2002).

    Article  CAS  PubMed  Google Scholar 

  231. Xu, R. X. et al. Specific inhibition of apoptosis after cold-induced brain injury by moderate postinjury hypothermia. Neurosurgery 43, 107–114 (1998).

    Article  CAS  PubMed  Google Scholar 

  232. Dempsey, R. J. et al. Moderate hypothermia decreases postischemic edema development and leukotriene production. Neurosurgery 21, 177–181 (1987).

    Article  CAS  PubMed  Google Scholar 

  233. Kumar, K. & Evans, A. T. Effect of hypothermia on microglial reaction in ischemic brain. Neuroreport 8, 947–950 (1997).

    Article  CAS  PubMed  Google Scholar 

  234. Han, H. S., Qiao, Y., Karabiyikoglu, M., Giffard, R. G. & Yenari, M. A. Hypothermia might alter the inflammatory cell-associated inducible nitric oxide synthase (iNOS) and subsequent nitric oxide (NO) and peroxynitrite generation in experimental stroke and inflammation. J. Neurosci. 22, 3921–3928 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Chatzipanteli, K. et al. Importance of posttraumatic hypothermia and hyperthermia on the inflammatory response after fluid percussion brain injury: biochemical and immunocytochemical studies. J. Cereb. Blood Flow Metab. 20, 531–542 (2000).

    Article  CAS  PubMed  Google Scholar 

  236. Dietrich, D. W. et al. The importance of brain temperature in alterations of the blood–brain barrier following cerebral ischemia. J. Neuropathol. Exp. Neurol. 49, 486–497 (1990).

    Article  CAS  PubMed  Google Scholar 

  237. 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. 13, 389–394 (1993).

    Article  CAS  PubMed  Google Scholar 

  238. Takemoto, M. & Liao, J. K. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler. Thromb. Vasc. Biol. 21, 1712–1719 (2001).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the members of the NINDS Stroke PRG for stimulating our interest in aspects of this review, and especially J. Grotta, T. Jacobs, J. Marler, M. E. Michel, B. Radziszewska, P. Scott and K. Woodbury-Harris for organizing this effort. We apologize to our colleagues whose work could not be cited because of space limitations.

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Authors and Affiliations

  1. Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Eng H. Lo

  2. Department of Neurology, Faculty of Medicine, Hacettepe University, Ankara, 06100, Turkey

    Turgay Dalkara

  3. Departments of Radiology and Neurology, Stroke and Neurovascular Regulation Laboratory, Neuroscience Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Michael A. Moskowitz

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  1. Eng H. Lo
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  2. Turgay Dalkara
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  3. Michael A. Moskowitz
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Correspondence to Michael A. Moskowitz.

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DATABASES

LocusLink

ACE

APOE

Bad

Bax

bFGF

Bid

COX2

CREB

DFF45

eNOS

FADD

FGB

Icam1

MMPs

P53

PARP1

Smac/Diablo

TNFR1

TNFR2

ZO-1

Glossary

VASCULAR DEMENTIA

A state of diminished cognition that results from repeated cerebral strokes, with a step-like deterioration in intellectual functions.

MULTIPLE SCLEROSIS

A neurodegenerative disorder characterized by demyelination of central nervous system tracts. Symptoms depend on the site of demyelination and include sensory loss, weakness in leg muscles, speech difficulties, loss of coordination and dizziness.

ATHEROSCLEROSIS

A condition in which lipids accumulate on the inner walls of arteries and eventually obstruct blood flow.

POLYMORPHISM

The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.

REPERFUSION

The restoration of blood flow to an ischaemic region. Reperfusion might cause additional tissue damage after a stroke.

OEDEMA

The presence of abnormally large amounts of fluid in the intercellular tissue spaces.

MICRODIALYSATE

A product of microdialysis — a technique to monitor the composition of the extracellular space in living tissue. A physiological solution is slowly pumped through a microdialysis probe. With time, this solution equilibrates with the extracellular fluid, making it possible to measure the concentration of the molecules of interest in the microdialysate.

SPREADING DEPRESSION

A slowly moving depression of electrical activity in the cerebral cortex. It consists of a wave of depolarization that can last for up to 2 minutes and travels at a speed between 3 and 12 mm min−1. Wave passage is accompanied by increased blood flow and is followed by a prolonged period of vasodilation. Spreading depression seems to be related to migraine, and has been observed to accompany cerebral ischaemia.

MITOCHONDRIAL TRANSITION PORE

Regulated mitochondrial megachannel, the formation of which presumably requires the apposition of proteins of the inner and outer mitochondrial membranes. Opening of this pore can lead to the collapse of the mitochondrial transmembrane potential, uncoupling of the respiratory chain, production of superoxide ions, outflow of calcium and release of soluble intermembrane proteins.

APOPTOSOME

A multiprotein complex that consists of several (probably seven) molecules of APAF1 bound to cytochrome c and caspase 9. The apoptosome represents a holoenzyme complex, which maintains caspase 9 in an active conformation.

TUNEL METHOD

This method enables the visualization of cells undergoing apoptosis by labelling the broken ends of the double-stranded DNA with biotin-conjugated dUTP, using the enzyme terminal deoxynucleotidyl transferase.

ANNEXIN STAINING

Annexin V is a calcium- and phospholipid-binding family of proteins with vascular anticoagulant activity. As apoptotic cells express phosphatidylserine in their membranes, the affinity of annexin for this phospholipid makes this protein useful for labelling cells undergoing programmed cell death.

ZYMOGEN

Any inactive enzyme precursor that, following secretion, is chemically altered to the active form of the enzyme.

ANOIKIS

Induction of programmed cell death by detachment of cells from the extracellular matrix.

THROMBOGENESIS

The formation of a thrombus. A thrombus is an aggregation of blood factors — primarily platelets and fibrin — with entrapment of cellular elements, which frequently causes vascular obstruction at its site of formation.

COMPLEMENT

A set of plasma proteins that attack extracellular pathogens. The pathogen becomes coated with complement proteins that facilitate pathogen removal by phagocytes. Complement components are also involved in inflammation and tissue destruction.

THROMBOEMBOLISM

The obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel.

ANGIOPLASTY

The surgical repair of a blood vessel. A balloon angioplasty is a non-invasive procedure during which a balloon-tipped catheter is introduced into a diseased blood vessel. As the balloon is inflated, the vessel opens further allowing improved blood flow.

ARRHYTHMIA

Any variation from the normal rhythm of the heartbeat.

COAGULOPATHY

A defect in the mechanism of blood clotting.

ATHEROMATOUS PLAQUE

A well-demarcated yellow area or swelling on the inner surface of an artery, produced by the deposition of lipids.

HAEMATOCRIT

The relative volume of blood occupied by red blood cells.

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Lo, E., Dalkara, T. & Moskowitz, M. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4, 399–414 (2003). https://doi.org/10.1038/nrn1106

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