CNS Drugs

, Volume 19, Issue 10, pp 821–832 | Cite as

Progress in the Identification of Stroke-Related Genes

Emerging New Possibilities to Develop Concepts in Stroke Therapy
  • Andrea Lippoldt
  • Andreas Reichet
  • Ursula Moenning
Leading Article

Abstract

Stroke is a very complex disease influenced by many risk factors: genetic, environmental and comorbidities, such as hypertension, diabetes mellitus, obesity and having had a previous stroke. Neuroprotective therapies that have been found to be successful in laboratory animals have failed to produce the same benefits in clinical trials. Currently, a re-analysis of the clinical trial failures is underway and new therapeutic approaches using the growing knowledge from neurogenesis and neuroinflammation studies, combined with the information from gene expression studies, are taking place. This review focusses on possible ways to identify therapeutic targets using the new discoveries in neuroinflammation and intrinsic regenerative mechanisms of the brain.

Molecular events associated with ischaemia trigger an environment for inflammation. Within the ischaemic region and its penumbra, a battery of chemokines and cytokines are released, which have both detrimental and beneficial effects, depending on the specific timepoint after injury and the current activation status of microglia/macrophages. Preventive therapies and treatments for stroke may be established by identifying the genes that are responsible for the induction of those phenotypic changes of microglia/macrophages that switch them to become players in tissue repair and regeneration processes.

To aid in the establishment of new target sources for novel therapeutic agents, animal stroke models should closely mimic stroke in humans. To do so, these models should take into account the various risk factors for stroke. For example, hypertensive animals have a more vulnerable blood-brain barrier that in turn may trigger a greater degree of damage after stroke. Furthermore, in aged animals an accelerated astrocytic and microglial reaction has been observed and the regenerative capacity of aged brains is not as high as young brains. Improvements in animal models may also help to ensure better success rates of potential therapies in clinical studies.

Inflammation in the brain is a double-edged sword — characterised by the deleterious effect of nerve cell damage and nerve cell death, as well as the beneficial influence on regeneration. The major challenge to develop successful stroke therapies is to broaden the knowledge regarding the underlying pathologic processes and the intrinsic mechanisms of the brain to drive regenerative and plasticity-related changes. On this basis, new concepts can be created leading to better stroke therapy.

Notes

Acknowledgements

The authors are grateful to numerous colleagues for helpful discussions over the years on this topic. No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    American Heart Assocation. Heart and stroke facts statistics: 1999 statistical supplement. Dallas (TX): American Heart Association, 1999Google Scholar
  2. 2.
    Adelman SM. The national survey of stroke: economic impact. Stroke 1981; 12: 169–87Google Scholar
  3. 3.
    Taylor TN, Davis PH, Torner JC, et al. Lifetime cost of stroke in the United States. Stroke 1996; 27: 1459–66PubMedCrossRefGoogle Scholar
  4. 4.
    Evers S, Struijs JN, Ament AJHA, et al. International comparison of stroke cost studies. Stroke 2004; 35: 1209–15PubMedCrossRefGoogle Scholar
  5. 5.
    Aslanyan S, Weir CJ, Lees KR, et al. Effect of area-based deprivation on the severity, subtype, and outcome of ischemic stroke. Stroke 2003; 34: 2623–8PubMedCrossRefGoogle Scholar
  6. 6.
    Carr FJ, McBride MW, Carswell HV, et al. Genetic aspects of stroke: human and experimental studies. J Cereb Blood Flow Metab 2002; 22: 767–73PubMedCrossRefGoogle Scholar
  7. 7.
    Alberts MJ. Stroke genetics update. Stroke 2003; 34: 342–4PubMedCrossRefGoogle Scholar
  8. 8.
    Hassan A, Markus HS. Genetics and ischemic stroke. Brain 2000; 123: 1784–812PubMedCrossRefGoogle Scholar
  9. 9.
    Legos JJ, Tuma RF, Barone FC. Pharmacological interventions for stroke: failures and future. Expert Opin Investig Drugs 2002; 11(5): 603–14PubMedCrossRefGoogle Scholar
  10. 10.
    Fisher M, Brott TG. Emerging therapies for acute ischemic stroke: new therapies on trial. Stroke 2003; 34: 359–61PubMedCrossRefGoogle Scholar
  11. 11.
    Legos JJ, Barone FC. Update on pharmacological strategies for stroke: prevention, acute intervention and regeneration. Curr Opin Investig Drugs 2003; 4: 847–58PubMedGoogle Scholar
  12. 12.
    Zheng Z, Lee JE, Yenari MA. Stroke: molecular mechanisms and potential targets for treatment. Curr Mol Med 2003; 3: 361–72PubMedCrossRefGoogle Scholar
  13. 13.
    Schwartz M. Macrophages and microglia in central nervous system injury: are they helpful or harmful? J Cereb Blood Flow Metab 2003; 23: 385–94PubMedCrossRefGoogle Scholar
  14. 14.
    Carmichael ST. Gene expression changes after focal stroke, traumatic brain and spinal cord injuries. Curr Opin Neurol 2003; 16: 699–704PubMedCrossRefGoogle Scholar
  15. 15.
    Hallbergson AF, Gnatenco C, Peterson DA. Neurogenesis and brain injury: managing a renewable resource for repair. J Clin Invest 2003; 112: 1128–33PubMedGoogle Scholar
  16. 16.
    Zhang W, Stanimirovic D. Current and future therapeutic strategies to target inflammation in stroke. Curr Drug Targets Inflamm Allergy 2002 Jun; 1(2): 151–66PubMedCrossRefGoogle Scholar
  17. 17.
    Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 2002; 33: 2123–36PubMedCrossRefGoogle Scholar
  18. 18.
    Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999 Sep; 22(9): 391–7PubMedCrossRefGoogle Scholar
  19. 19.
    Stoll G, Jander S, Schroeter M. Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. Adv Exp Med Biol 2002; 513: 87–113PubMedCrossRefGoogle Scholar
  20. 20.
    Arnett HA, Wang Y, Matsushima GK, et al. Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. J Neurosci 2003; 23: 9824–32PubMedGoogle Scholar
  21. 21.
    Batchelor PE, Porritt MJ, Martinello P, et al. Macrophages and microglia produce local trophic gradients that stimulate axonal sprouting toward but not beyond the wound edge. Mol Cell Neurosci 2002 Nov; 21(3): 436–53PubMedCrossRefGoogle Scholar
  22. 22.
    Shaked I, Porat Z, Gersner R, et al. Early activation of microglia as antigen-presenting cells correlate with T-cell mediated protection and repair of the injured CNS. J Neuroimmunol 2004; 146: 84–93PubMedCrossRefGoogle Scholar
  23. 23.
    Marchetti B, Abbracchio MP. To be or not to be (inflamed) —is that the question in anti-inflammatory drug therapy of neurodegenerative disorders? In pressGoogle Scholar
  24. 24.
    Han HS, Yenari MA. Cellular targets of brain inflammation in stroke. Curr Opin Investig Drugs 2003; 4: 522–9PubMedGoogle Scholar
  25. 25.
    Barlow C, Lockhardt DJ. DANN arrays and neurobiology-what’s new and what’s next? Curr Opin Neurobiol 2002; 12: 554–61PubMedCrossRefGoogle Scholar
  26. 26.
    Bates S, Read SJ, Harrison DC, et al. Characterisation of gene expression changes following permanent MCAO in the rat using subtractive hybridisation. Brain Res Mol Brain Res 2001; 93: 70–80PubMedCrossRefGoogle Scholar
  27. 27.
    Trendelenburg G, Prass K, Priller J, et al. Serial analysis of gene expression idetifies metallothionein-II as a major neuroprotective gene in mouse focal cerebral ischemia. J Neurosci 2002; 22: 5879–88PubMedGoogle Scholar
  28. 28.
    Kim YD, Sohn NW, Kang C, et al. DNA array reveals altered gene expression in response to focal cerebral ischemia. Brain Res Bull 2002; 58: 491–8PubMedCrossRefGoogle Scholar
  29. 29.
    Read SJ, Parsons AA, Harrison DC, et al. Stroke genomics: approaches to identify, validate, and understand ischemic stroke gene expression. J Cereb Blood Flow Metab 2001 Jul; 21(7): 755–78PubMedCrossRefGoogle Scholar
  30. 30.
    Bond BC, Virley DJ, Cairns NJ, et al. The quantification of gene expression in an animal model of brain ischemia using TaqMan real-time RT-PCR. Brain Res Mol Brain Res 2002; 106: 101–16PubMedCrossRefGoogle Scholar
  31. 31.
    Schmidt-Kastner R, Zhang B, Belayev L, et al. DNA Microarray analysis of cortical gene expression during early recirculation after focal brain ischemia in rat. Brain Res Mol Brain Res 2002; 108: 81–93PubMedCrossRefGoogle Scholar
  32. 32.
    Lu A, Tang Y, Ran R, et al. Genomics of the periinfarction cortex after focal cerebral ischemia. J Cereb Blood Flow Metab 2003 Jul; 23(7): 786–810PubMedCrossRefGoogle Scholar
  33. 33.
    Raghavendra Rao VL, Bowen KK, Dhodda VK, et al. Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischemia. J Neurochem 2002; 83: 1072–86PubMedCrossRefGoogle Scholar
  34. 34.
    Berti R, Williams AJ, Moffet JR, et al. Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia-reperfusion brain injury. J Cereb Blood Flow Metab 2002; 22: 1068–79PubMedCrossRefGoogle Scholar
  35. 35.
    Jin K, Mao XO, Eshoo MW, et al. Microarray analysis of hippocampal gene expression in global cerebral ischemia. Ann Neurol 2001; 50: 93–103PubMedCrossRefGoogle Scholar
  36. 36.
    Roth A, Gill R, Certa U. Temporal and spatial gene expression patterns after experimental stroke in a rat model and characterization of PC4, a potential regulator of transcription. Mol Cell Neurosci 2003; 22: 353–64PubMedCrossRefGoogle Scholar
  37. 37.
    Tang Y, Lu A, Aronow BJ, et al. Genomic responses of the brain to ischemic stroke, intracerebral hemorrhage, kainate seizures, hypoglycemia, and hypoxia. Eur J Neurosci 2002; 15: 1937–52PubMedCrossRefGoogle Scholar
  38. 38.
    Schwarz DA, Barry G, Mackay KB, et al. Identification of differentially expressed genes induced by transient ischemic stroke. Brain Res Mol Brain Res 2002; 101: 12–22PubMedCrossRefGoogle Scholar
  39. 39.
    Kitagawa K, Matsumoto M, Hori M. Protective and regenerative response endogenously induced in the ischemic brain. Can J Physiol Pharmacol 2001 Mar; 79(3): 262–5PubMedCrossRefGoogle Scholar
  40. 40.
    Liberto CM, Albrecht PJ, Herx LM, et al. Pro-regenerative properties of cytokine-activated astrocytes. J Neurochem 2004; 89: 1092–100PubMedCrossRefGoogle Scholar
  41. 41.
    Rothwell N. Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential. Brain Behav Immun 2003; 17(3): 152–7PubMedCrossRefGoogle Scholar
  42. 42.
    Touzani O, Boutin H, LeFeuvre R, et al. Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor. J Neurosci 2002; 22(1): 38–43PubMedGoogle Scholar
  43. 43.
    Boutin H, LeFeuvre RA, Horaiu R, et al. Role of IL-lalpha and IL-1beta in ischemic brain damage. J Neurosci 2001; 21(15): 5528–34PubMedGoogle Scholar
  44. 44.
    Allan SM, Pinteauc E. The interleukin-1 system: an attractive and viable therapeutic target in neurodegenerative disease. Curr Drug Targets CNS Neurol Disord 2003; 2(5): 293–302PubMedCrossRefGoogle Scholar
  45. 45.
    Allan SM. Pragmatic target discovery from novel gene to functionally defined drug target: the interleukin-1 story. Methods Mol Med 2004; 104: 333–46Google Scholar
  46. 46.
    Vila N, Castillo J, Davalos A, et al. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 2000; 31: 2325–9PubMedCrossRefGoogle Scholar
  47. 47.
    Kito T, Kuroda E, Yokota A, et al. Cytotoxicity in glioma cells due to interleukin-12 and interleukin-18-stimulated macrophages mediated by interferon-gamma-regulated nitric oxide. J Neurosurg 2003 Feb; 98(2): 385–92PubMedCrossRefGoogle Scholar
  48. 48.
    Lee YB, Nagai A, Kim SU. Cytokines, chemokines, and cytokine receptors in human microglia. J Neurosci Res 2002 Jul 1; 69(1): 94–103PubMedCrossRefGoogle Scholar
  49. 49.
    Kouwenhoven M, Carlstrom C, Ozenci V, et al. Metalloproteinase and cytokine profiles in monocytes over the course of stroke. J Clin Immunol 2001 Sep; 21(5): 365–75PubMedCrossRefGoogle Scholar
  50. 50.
    Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nat Med 2002; 8(12): 1363–8PubMedCrossRefGoogle Scholar
  51. 51.
    Minami M, Satoh M. Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury. Life Sci 2003; 74: 312–27CrossRefGoogle Scholar
  52. 52.
    Wang L, Li Y, Chen X, et al. MCP-1, MIP-1, IL-8 and ischemic cerebral tissue enhance human bone marrow stromal cell migration in interface culture. Hematology 2002; 7(2): 113–7PubMedCrossRefGoogle Scholar
  53. 53.
    Küry P, Schroeter M, Jander S. Transcriptional response to circumscribed cortical brain ischemia: spatiotemporal patterns in ischemic vs remote non-ischemic cortex. Eur J Neurosci 2004; 19: 1708–20PubMedCrossRefGoogle Scholar
  54. 54.
    Wang X, Li X, Yaish-Ohad S, et al. Molecular cloning and expression of the rat monocyte chemotactic protein-3 gene: a possible role in stroke. Brain Res Mol Brain Res 1999; 71(2): 304–12PubMedCrossRefGoogle Scholar
  55. 55.
    Kremlev SG, Roberts RL, Palmer C. Differential expression of chemokines and chemokine receptors during microglial activation and inhibition. J Neuroimmunol 2004; 149(1-2): 1–9PubMedCrossRefGoogle Scholar
  56. 56.
    Hill WD, Hess DC, Martin-Studdard A, et al. SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol 2004; 63(1): 84–96PubMedGoogle Scholar
  57. 57.
    Tarazzo G, Campanella M, Ghiani M, et al. Expression of fractalkine and its receptor, CX3CR1, in response to ischemia-reperfusion brain injury in the rat. Eur J Neurosci 2002; 15: 1663–8CrossRefGoogle Scholar
  58. 58.
    Wang X, Li X, Schmidt DB, et al. Identification and molecular characterization of rat CXCR3: receptor expression and interferon-inducible protein-10 binding are increased in focal stroke. Mol Pharmacol 2000; 57: 1190–8PubMedGoogle Scholar
  59. 59.
    Bajetto A, Bonavia R, Barbero S, et al. Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J Neurochem 2002 Sep; 82(6): 1311–29PubMedCrossRefGoogle Scholar
  60. 60.
    Krathwohl MD, Kaiser JL. Chemokines promote quiescence and survival of human neural progenitor cells. Stem Cells 2004; 22(1): 109–18PubMedCrossRefGoogle Scholar
  61. 61.
    Lu M, Grove EA, Miller RJ. Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci U S A 2002 May 14; 99(10): 7090–5PubMedCrossRefGoogle Scholar
  62. 62.
    Ji JF, He BP, Dheen ST, et al. Expression of chemokine receptors CXCR4, CCR2, CCR5 and CX3CR1 in neural progenitor cells isolated from the subventricular zone of the adult rat brain. Neurosci Lett 2004 Jan 30; 355(3): 236–40PubMedCrossRefGoogle Scholar
  63. 63.
    Guan J, Miller OT, Waugh KM, et al. Insulin-like growth factor-1 improves somatosensory function and reduces the extent of cortical infarction and ongoing neuronal loss after hypoxia-ischemia in rats. Neuroscience 2001; 105(2): 299–306PubMedCrossRefGoogle Scholar
  64. 64.
    Smith PF. Neuroprotection against hypoxia-ischemia by insulin-like growth factor-I (IGF-I). IDrugs 2003; 6(12): 1173–7PubMedGoogle Scholar
  65. 65.
    Dempsey RJ, Sailor KA, Bowen KK, et al. Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF. J Neurochem 2003; 87(3): 586–97PubMedCrossRefGoogle Scholar
  66. 66.
    Ay I, Sugimori H, Finkelstein SP. Intravenous basic fibroblast growth factor (bFGF) decreases DANN fragmentation and prevents downregulation of Bcl-2 expression in the ischemic brain following middle cerebral artery occlusion in rats. Brain Res Mol Brain Res 2001; 87(1): 71–80PubMedCrossRefGoogle Scholar
  67. 67.
    Sugimori H, Speller H, Finklestein SP. Intravenous basic fibroblast growth factor produces a persistent reduction in infarct volume following permanent focal ischemia in rats. Neurosci Lett 2001; 300(1): 13–6PubMedCrossRefGoogle Scholar
  68. 68.
    Ma J, Qiu J, Hirt L, et al. Synergistic protective effect of caspase inhibitors and bFGF against brain injury induced by transient focal ischemia. Br J Pharmacol 2001; 133(3): 345–50PubMedCrossRefGoogle Scholar
  69. 69.
    Lippoldt A, Andbjer B, Rosen L, et al. Photochemically induced focal cerebral ischemia in rat: time dependent and global increase in expression of basic fibroblast growth factor mRNA. Brain Res 1993; 625(1): 45–56PubMedCrossRefGoogle Scholar
  70. 70.
    Wada K, Sugimori H, Bhide PG, et al. Effect of basic fibroblast growth factor treatment on brain progenitor cells after permanent focal ischemia in rats. Stroke 2003; 34(11): 2722–8PubMedCrossRefGoogle Scholar
  71. 71.
    Nakatomi H, Kuriu T, Okabe S, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002; 110(4): 429–41PubMedCrossRefGoogle Scholar
  72. 72.
    Song BW, Vinters HV, Wu D, et al. Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector. J Pharmacol Exp Ther 2002; 301(2): 605–10PubMedCrossRefGoogle Scholar
  73. 73.
    Hermann DM, Kilic E, Kugler S, et al. Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice. Neurobiol Dis 2001; 8(4): 655–66PubMedCrossRefGoogle Scholar
  74. 74.
    Bates B, Hirt L, Thomas SS, et al. Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: possible involvement of oxygen free radicals. Neurobiol Dis 2002; 9(1): 24–37PubMedCrossRefGoogle Scholar
  75. 75.
    Endres M, Fan G, Hirt L, et al. Stroke damage in mice after knocking the neurotrophin-4 gene into the brain-derived neurotrophic factor locus. J Cereb Blood Flow Metab 2003; 23(2): 150153Google Scholar
  76. 76.
    Ferrer I, Krupinsky J, Goutan E, et al. Brain-derived neurotrophic factor reduces cortical cell death by ischemia after middle cerebral artery occlusion in the rat. Acta Neuropathol (Berl) 2001; 101(3): 229–38Google Scholar
  77. 77.
    Kurozumi K, Nakamura K, Tamiya T, et al. BDNF genemodified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol Ther 2004; 9(2): 189–97PubMedCrossRefGoogle Scholar
  78. 78.
    Gustafsson E, Andsberg G, Darsalia V, et al. Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated viras increases neuronal death but promotes neurogenic response following stroke. Eur J Neurosci 2003; 17(12): 2667–78PubMedCrossRefGoogle Scholar
  79. 79.
    Yamagata K, Tagami M, Ikeda K, et al. Differential regulation of glial cell line-derived neurotrophic factor (GDNF) mRNA expression during hypoxia and reoxygenation in astrocytes isolated from stroke-prone spontaneously hypertensive rats. Glia 2002; 37(1): 1–7PubMedCrossRefGoogle Scholar
  80. 80.
    Arvidsson A, Kokaia Z, Airkasinen MS, et al. Stroke induces widespread changes of gene expression for glial cell line-derived neurotrophic factor family receptors in the adult rat brain. Neuroscience 2001; 106(1): 27–41PubMedCrossRefGoogle Scholar
  81. 81.
    Zhang WR, Hayashi T, Iwai M, et al. Time dependent amelioration against ischemic brain damage by glial cell line-derived neurotrophic factor after middle cerebral artery occlusion in rat. Brain Res 2001; 903(1-2): 253–6PubMedCrossRefGoogle Scholar
  82. 82.
    Justizia C, Perez-Asensio FJ, Burguete MC, et al. Administration of transforming growth factor-alpha reduces infarct volume after transient focal cerebral ischemia in the rat. J Cereb Blood Flow Metab 2001; 21(9): 1097–104CrossRefGoogle Scholar
  83. 83.
    Stoll G, Schroeter M, Jander S, et al. Lesion-associated expression of transforming growth factor-beta-2 in the rat nervous system: evidence for down-regulating the phagocytotic activity of microglia and macrophages. Brain Pathol 2004; 14(1): 51–8PubMedCrossRefGoogle Scholar
  84. 84.
    Buisson A, Lesne S, Docagne F, et al. Transforming growth factor-beta and ischemic brain injury. Cell Mol Neurobiol 2003; 23(4-5): 539–50PubMedCrossRefGoogle Scholar
  85. 85.
    Zhu Y, Yang GY, Ahlemeyer B, et al. Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. J Neurosci 2002; 22(10): 3898–909PubMedGoogle Scholar
  86. 86.
    Fagan SC, Hess DC, Machado LS, et al. Tactics for vascular protection after acute ischemic stroke. Pharmacoptherapy 2005; 25: 387–95CrossRefGoogle Scholar
  87. 87.
    Harvey BK, Hoffer BJ, Wang Y. Stroke and TGF-beta proteins: glial cell line-derived neurotrophic factor and bone morphogenetic protein. Pharmacol Ther 2005; 105: 113–25PubMedCrossRefGoogle Scholar
  88. 88.
    Sun Y, Jin K, Xie L, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 2003; 111(12): 1843–51PubMedGoogle Scholar
  89. 89.
    Alzheimer C, Werner S. Fibroblast growth factor and neuroprotection. Adv Exp Med Biol 2002; 513: 335–51PubMedCrossRefGoogle Scholar
  90. 90.
    Vemuganti R, Dempsey RJ, Bowen KK. Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke 2004 Jan; 35(1): 179–84PubMedCrossRefGoogle Scholar
  91. 91.
    Ishikawa M, Cooper D, Russell J, et al. Molecular determinants of the prothrombogenic and inflammatory phenotype assumed by the postischemic cerebral microcirculation. Stroke 2003 Jul; 34(7): 1777–82PubMedCrossRefGoogle Scholar
  92. 92.
    Justicia C, Panes J, Sole S, et al. Neutrophil infiltration increases matrix metalloproteinase-9 in the ischemic brain after occlu-sion/reperfusion of the middle cerebral artery in rats. J Cereb Blood Flow Metab 2003 Dec; 23(12): 1430–40PubMedCrossRefGoogle Scholar
  93. 93.
    Danton GH, Dietrich WD. Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 2003 Feb; 62(2): 127–36PubMedGoogle Scholar
  94. 94.
    Stoll G, Jander S, Schroeter M. Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. Adv Exp Med Biol 2002; 513: 87–113PubMedCrossRefGoogle Scholar
  95. 95.
    Aldskogius H. Regulation of microglia-potential new drug targets in the CNS. Expert Opin Ther Targets 2001; 5: 655–68PubMedCrossRefGoogle Scholar
  96. 96.
    Cajal SR. Degeneration and regeneration of the nervous system. Vols 1 & 2. Translated by May RM. London: Oxford University Press, 1928Google Scholar
  97. 97.
    Choi YS, Lee MY, Sung KW, et al. Regional differences in enhanced neurogenesis in the dentate gyrus of adult rats after transient forebrain ischemia. Mol Cells 2003 Oct; 16(2): 232–8PubMedGoogle Scholar
  98. 98.
    Kokaia Z, Lindvall O. Neurogenesis after ischemic brain insults. Curr Opin Neurobiol 2003 Feb; 13(1): 127–32PubMedCrossRefGoogle Scholar
  99. 99.
    Yagita Y, Kitagawa K, Sasaki T, et al. Differential expression of Musashil and nestin in the adult rat hippocampus after ischemia. J Neurosci Res 2002 Sep; 69(6): 750–6PubMedCrossRefGoogle Scholar
  100. 100.
    Sharp FR, Liu J, Barnabeu R. Neurogenesis following brain ischemia. Brain Res Dev Brain Res 2002 Mar; 134(1-2): 23–30PubMedCrossRefGoogle Scholar
  101. 101.
    Takasawa K, Kitagawa K, Yagita Y, et al. Increased proliferation of neural progenitor cells but reduced survival of newborn cells in the contralateral hippocampus after focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2002 Mar; 22(3): 299–307PubMedCrossRefGoogle Scholar
  102. 102.
    Yagita Y, Kitagawa K, Ohtsuki T, et al. Neurogenesis by progenitor cells in the ischemic adult rat hippocampus. Stroke 2001 Aug; 32(8): 1890–6PubMedCrossRefGoogle Scholar
  103. 103.
    Jin K, Miami M, Lan JQ, et al. Neurogenesis in dentate sub-granular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci U S A 2001 Apr; 98(8): 4710–5PubMedCrossRefGoogle Scholar
  104. 104.
    Parent JM. Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist 2003 Aug; 9(4): 261–72PubMedCrossRefGoogle Scholar
  105. 105.
    Parent JM, Vexler ZS,Gong C, et al. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 2002 Dec; 52(6): 802–13PubMedCrossRefGoogle Scholar
  106. 106.
    Jin K, Sun Y, Xie L, et al. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci 2003; 24: 171–89PubMedCrossRefGoogle Scholar
  107. 107.
    Jiang W, Gu W, Brannstrom T, et al. Cortical neurogenesis in adult rats after transient middle cerebral artery occlusion. Stroke 2001 May; 32(5): 1201–7PubMedCrossRefGoogle Scholar
  108. 108.
    Gu W, Brannstrom T, Wester P. Cortical neurogenesis in adult rats after reversible photothrombotic stroke. J Cereb Blood Flow Metab 2000 Aug; 20(8): 1166–73PubMedCrossRefGoogle Scholar
  109. 109.
    Arlotta P, Magavi SS, Macklis JD. Induction of adult neurogenesis: molecular manipulation of neural precursors in situ. Ann N Y Acad Sci 2003 Jun; 991: 229–36PubMedCrossRefGoogle Scholar
  110. 110.
    Felling RJ, Levison SW. Enhanced neurogenesis following stroke. J Neurosci Res 2003; 73: 277–83PubMedCrossRefGoogle Scholar
  111. 111.
    Nakatomi H, Kuriu T, Okabe S, et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002 Aug; 110(4): 429–41PubMedCrossRefGoogle Scholar
  112. 112.
    Teramoto T, Qiu J, Plumier JC, et al. EGF amplifies the replacement of parvalbumin-expressing striatal interneurons after ischemia. J Clin Invest 2003; 111: 1125–32PubMedGoogle Scholar
  113. 113.
    Sailor KA, Dhodda VK, Rao VL, et al. Osteopontin infusion into normal adult rat brain fails to increase cell proliferation in dentate gyrus and subventricular zone. Acta Neurochir Suppl 2003; 86: 181–5PubMedCrossRefGoogle Scholar
  114. 114.
    Wang X, Louden C, Yue TL, et al. Delayed expression of osteopontin after focal stroke in the rat. J Neurosci 1998 Mar; 18(6): 2075–83PubMedGoogle Scholar
  115. 115.
    Ellison JA, Barone FC, Feuerstein GZ. Matrix remodeling after stroke: de novo expression of matrix proteins and integrin receptors. Ann N Y Acad Sci 1999; 890: 204–22PubMedCrossRefGoogle Scholar
  116. 116.
    Gustafsson E, Lindvall O, Kokaia Z. Intraventricular infusion of TrkB-Fc fusion protein promotes ischemia-induced neurogenesis in adult rat dentate gyrus. Stroke 2003; 34: 2710–5PubMedCrossRefGoogle Scholar
  117. 117.
    Sun Y, Jin K, Xie L, et al. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 2003; 111: 1843–51PubMedGoogle Scholar
  118. 118.
    Zhu DY, Liu SH, Sun HS, et al. Expression of inducible nitric oxide synthetase after focal cerebral ischemia stimulates neurogenesis in the adult rodent dentate gyrus. J Neurosci 2003; 23: 223–9PubMedGoogle Scholar
  119. 119.
    Uchida K, Kumihashi K, Kurosawa S, et al. Stimulatory effects of prostaglandin E2 on neurogenesis in the dentate gyrus of the adult rat. Zoolog Sci 2002; 19: 1211–6PubMedCrossRefGoogle Scholar
  120. 120.
    Sasaki T, Kitagawa K, Sugiura S, et al. Implication of cyclooxygenase-2 on enhanced proliferation of neural progenitor cells in the adult mouse hippocampus after ischemia. J Neurosci Res 2003; 72: 461–71PubMedCrossRefGoogle Scholar
  121. 121.
    Kumihashi K, Uchida K, Miyazaki H, et al. Acetylsalicylic acid reduces ischemia-induced proliferation of dentate cells in gerbils. Neuroreport 2001; 12: 915–7PubMedCrossRefGoogle Scholar
  122. 122.
    Arvidsson A, Kokaia Z, Lindvall O. N-methy-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke. Eur J Neurosci 2001 Jul; 14(1): 10–8PubMedCrossRefGoogle Scholar
  123. 123.
    Villoslada P, Genain CP. Role of nerve growth factor and other trophic factors in brain inflammation. Prog Brain Res 2004; 146: 403–14PubMedCrossRefGoogle Scholar
  124. 124.
    Morganti-Kossmann MC, Rancan M, Stahel PF, et al. Inflammatory response in acute traumatic brain injury: a double-edged sword. Curr Opin Crit Care 2002 Apr; 8(2): 101–5PubMedCrossRefGoogle Scholar
  125. 125.
    Piehl F, Lidman O. Neuroinflammation in the rat-CNS cells and their role in the regulation of immune reactions. Immunol Rev 2001 Dec; 184: 212–25PubMedCrossRefGoogle Scholar
  126. 126.
    Liao SL, Chen WY, Raung SL, et al. Association of immune responses and ischemic brain infarction in rat. Neuroreport 2001 Jul; 12(9): 1943–7PubMedCrossRefGoogle Scholar
  127. 127.
    Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19: 312–8PubMedCrossRefGoogle Scholar
  128. 128.
    Bezzi P, Domercq M, Brambilla L, et al. CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 2001 Jul; 4(7): 702–10PubMedCrossRefGoogle Scholar
  129. 129.
    Ekdahl CT, Claasen JH, Bonde S, et al. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A 2003; 100: 13632–7PubMedCrossRefGoogle Scholar
  130. 130.
    Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science 2003; 302: 1760–5PubMedCrossRefGoogle Scholar
  131. 131.
    Batchelor PE, Porritt MJ, Nilsson SK, et al. Periwound dopaminergic sprouting is dependent on numbers of wound macrophages. Eur J Neurosci 2002 Mar; 15(5): 826–32PubMedCrossRefGoogle Scholar
  132. 132.
    Otten U, Marz P, Heese K, et al. Cytokines and neurotrophins interact in normal and diseased states. Ann N Y Acad Sci 2000; 917: 322–30PubMedCrossRefGoogle Scholar
  133. 133.
    Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nat Med 2002 Dec; 8(12): 1363–8PubMedCrossRefGoogle Scholar
  134. 134.
    Iliev AI, Stringaris AK, Nau R, et al. Neuronal injury mediated via stimulation of microglial toll-like receptor 9 (TLR9). FASEB J 2004 Feb; 18(2): 412–4PubMedGoogle Scholar
  135. 135.
    Han HS, Karabiyikoglu M, Kelly S, et al. Mild hyperthermia inhibits nuclear factor-kappaB translocation in experimental stroke. J Cereb Blood Flow Metab 2003 May; 23(5): 589–98PubMedCrossRefGoogle Scholar
  136. 136.
    Cai Z, Pang Y, Lin S, et al. Differential roles of tumor necrosis factor-alpha and interleukin-1 beta in lipopolysaccharide-induced brain injury in the neonatal rat. Brain Res 2003 Jun; 975(1-2): 37–47PubMedCrossRefGoogle Scholar
  137. 137.
    Schroeter M, Kury P, Jander S. Inflammatory gene expression in focal cortical brain ischemia-differences between rats and mice. Brain Res Mol Brain Res 2003 Sep; 117(1): 1–7PubMedCrossRefGoogle Scholar
  138. 138.
    Tomimoto H, Ihara M, Wakita H, et al. Chronic cerebral hypoperfusion induces white matter lesions and loss of oligoden-droglia with DNA fragmentation in the rat. Acta Neuropathol (Berlin) 2003 Dec; 106(6): 527–34CrossRefGoogle Scholar
  139. 139.
    Arnett HA, Mason J, Marino M, et al. TNF alpha promotes prolieration of oligodendrocyte progenitors and remyelination. Nat Neurosci 2001; 4: 1116–22PubMedCrossRefGoogle Scholar
  140. 140.
    Ferrer I, Planas AM. Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol 2003 Apr; 62(4): 329–39PubMedGoogle Scholar
  141. 141.
    Belayev L, Busto R, Zhao W, et al. Middle cerebral artery occlusion in the mouse by intraluminal suture coated with poly-L-lysine: neurological and histological validation. Brain Res 1999 Jul; 833(2): 181–90PubMedCrossRefGoogle Scholar
  142. 142.
    Aspey BS, Cohen S, Patel Y, et al. Middle cerebral artery occlusion in the rat: consietent protocol for a model of stroke. Neuropathol Appl Neurobiol 1998 Dec; 24(6): 487–97PubMedCrossRefGoogle Scholar
  143. 143.
    Takano K, Tatlisumak T, Bergmann AG, et al. Reproducibility and reliability of middle cerebral artery occlusion using a silicone-coated suture (Koizumi) in rats. J Neurol Sci 1997 Dec; 153(1): 8–11PubMedCrossRefGoogle Scholar
  144. 144.
    Pevsner PH, Eichenbaum JW, Miller DC, et al. A photothrombotic model of small early ischemic infarcts in the rat brain with histologie and MRI correlation. J Pharmacol Toxicol Methods 2001 May–Jun; 45(3): 227–33PubMedCrossRefGoogle Scholar
  145. 145.
    Callaway JK, Knight MJ, Watkins DJ, et al. A novel, rapid, computerized method for quantification of neuronal damage in a rat model of stroke. J Neurosci Methods 2000 Oct; 102(1): 53–60PubMedCrossRefGoogle Scholar
  146. 146.
    Yamory Y. Implication of hypertensive rat models for primordial nutrition prevention of cardiovascular diseases. Clin Exp Pharmacol Physiol 1999 Jul; 26(7): 568–72CrossRefGoogle Scholar
  147. 147.
    Yamori Y. Predictive and preventive pathology of cardiovascular diseases. Acta Pathol Jpn 1989 Nov; 39(11): 683–705PubMedGoogle Scholar
  148. 148.
    Kiprov D. Experimental models of hypertension. Cor Vasa 1970; 22(1-2): 116–28Google Scholar
  149. 149.
    Meng X, Fisher M, Shen Q, et al. Characterizing the diffusion/ perfusion mismatch in experimental focal cerebral ischemia. Ann Neurol 2004 Feb; 55(2): 207–12PubMedCrossRefGoogle Scholar
  150. 150.
    Tsuchiya D, Hong S, Kayama T, et al. Effect of suture size and carotid clip application upon blood flow and infarct volume after permanent and temporary middle cerebral artery occlusion in mice. Brain Res 2003 Apr; 970(1-2): 131–9PubMedCrossRefGoogle Scholar
  151. 151.
    Badan I, Platt D, Kessler C, et al. Temporal dynamics of degenerative and regenerative events associated with cerebral ischemia in aged rats. Gerontology 2003; 49: 356–65PubMedCrossRefGoogle Scholar
  152. 152.
    Abraham CS, Harada N, Deli MA, et al. Transient forebrain ischemia increases the blood-brain barrier permeability for albumin in stroke.prone spontaneously hypertensive rats. Cell Mol Neurobiol 2002 Aug; 22(4): 455–62PubMedCrossRefGoogle Scholar
  153. 153.
    Takemori K, Ito H, Suzuki T. Effects of the ATI receptor antagonist on adhesion molecule expression in leukocytes and brain microvessels of stroke-prone spontaneously hypertensive rats. Am J Hypertens 2000 Nov; 13(11): 1233–41PubMedCrossRefGoogle Scholar
  154. 154.
    Hazama F, Chue CH, Kataoka H, et al. Pathogenesis of lacuna-like cyst formation and diffuse degeneration of the white matter in the brain of stroke.prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol Suppl 1995 Dec; 22(1): S260–1PubMedCrossRefGoogle Scholar
  155. 155.
    Fredriksson K, Nordborg C, Kalimo H, et al. Cerebral microangiopathy in stroke-prone spontaneously hypertensive rats: an immunohistochemical and ultrastructural study. Acta Neuropathol (Berl) 1988; 75(3): 241–52CrossRefGoogle Scholar
  156. 156.
    Clark JB, Palmer J, Shaw WN. The diabetic Zucker fatty rat (41611). Proc Soc Exp Biol Med 1983; 173: 68–75PubMedGoogle Scholar
  157. 157.
    Kurtz TW, Morris RC, Pershadsingh HA. The Zucker fatty rat as a genetic model of obesity and hypertension. Hypertension 1989; 13: 897–901Google Scholar
  158. 158.
    Lippoldt A, Kniesel U, Liebner S, et al. Structural alterations of tight junctions are associated with loss of polarity in stroke-prone spontaneously hypertensive rat blood-brain barrier endothelial cells. Brain Res 2000 Dec; 885(2): 251–61PubMedCrossRefGoogle Scholar
  159. 159.
    Absher PM, Hendley E, Jaworski DM, et al. Impairment of the blood-brain barrier: a potential surrogate delineating the determinants of cerebral bleeding caused by fibrinolytic drugs. Coron Artery Dis 1999 Sep; 10(6): 413–20PubMedCrossRefGoogle Scholar
  160. 160.
    Wennberg R, Zimmermann C. The PROGRESS trial three years later: time for a balanced report of effectiveness. BMJ 2004; 329: 968–9PubMedCrossRefGoogle Scholar
  161. 161.
    MacMahon S, Neal B, Rodgers A, et al. Commentary: The PROGRESS trial three years later: time for more action, less distraction. BMJ 2004; 329: 970–1PubMedCrossRefGoogle Scholar
  162. 162.
    Schrader J, Lüders S, Kulschewski A, et al. Morbidiy and mortality after stroke: eprosartan compared with nitrendipine for secondary prevention. Stroke 2005; 36: 1218–26PubMedCrossRefGoogle Scholar
  163. 163.
    Bennai F, Morsing P, Paliege A, et al. Normalizing the expression of nitric oxide synthase by low-dose AT1 receptor antagonism parallels improved vascular morphology in hypertensive rats. J Am Soc Nephrol 1999 Jan; 10Suppl. 11: S104–15PubMedGoogle Scholar
  164. 164.
    Takahashi M, Fritz-Zieroth B, Ohta Y, et al. Therapeutic effects of imidapril on cerebral lesions observed with magnetic resonance imaging in malignant stroke-prone spontaneously hypertensive rats. J Hypertens 1994 Jul; 12(7): 761–8PubMedCrossRefGoogle Scholar
  165. 165.
    Hankey GJ. Angiotensin-converting enzyme inhibitors for stroke prevention: is there HOPE for PROGRESS after LIFE? Stroke 2003; 34: 354–6PubMedCrossRefGoogle Scholar
  166. 166.
    Dahlof B, Burke TA, Kronot K, et al. Population impact of losartan use on stroke in the European Union (EU): projections from the Losartan intervention for endpoint reduction in hypertension (LIFE) study. J Hum Hypertens 2004; 18/6: 367–73CrossRefGoogle Scholar
  167. 167.
    Devereux RB, Lyle PA. Losartan for the treatment of hypertension and left ventricular hypertrophy: the losartan intervention for endpoint reduction in hypertension (LIFE) study. Expert Opin Pharmacother 2004; 5/11: 2311–20CrossRefGoogle Scholar
  168. 168.
    SCRIP. Leader in world pharmaceutical news [newsletter]. 2003; 2837: 20Google Scholar
  169. 169.
    Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastin Survival Study (4S). Scandanavian Simvastatin Survival Study Group. Lancet 1994; 344: 1383–9Google Scholar
  170. 170.
    Pederson TR, Kjekshus J, Pyörälä K, et al. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastin Survival Study (4S). Am J Cardiol 1998; 81: 333–5CrossRefGoogle Scholar
  171. 171.
    Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after MI in patients with average cholesterol levels. New Engl J Med 1996; 335: 1001–9PubMedCrossRefGoogle Scholar
  172. 172.
    Plehn JF, Davis PR, Sacks FM, et al. Reduction of stroke incidence after myocardial infarction with pravastatin: the cholesterol and recurrent events (CARE) study. Circ 1999; 99: 216–23CrossRefGoogle Scholar
  173. 173.
    White HD, Simes RJ, Anderson NE, et al. Pravastatin therapy and the risk of stroke. New Eng J Med 2000; 343: 317–26PubMedCrossRefGoogle Scholar
  174. 174.
    Long-term effectiveness and safety of prvastatin in 9014 patients with coronary heart disease and average choldesterol concentrations: the LIPID trial follow-up. The LIPID Study Group. Lancet 2000; 359: 1379-87Google Scholar
  175. 175.
    Deanfield JE. Clinical trials: evidence and unanswered ques-tions-hyperlipidaemia. Cerebrovasc Dis 2003; 16 Suppl. 3: 25–32CrossRefGoogle Scholar
  176. 176.
    Marti-Fabregas J, Gomis M, Abroix A, et al. Favorable outcome of ischemic stroke in patients pretreated with statins. Stroke 2004; 35: 1117–23PubMedCrossRefGoogle Scholar
  177. 177.
    The SPARCL investigators. Design and baseline characteristics of the stroke prevention by aggressive reduction of cholesterol levels (SPARCL) study. Cerebrovasc Dis 2003; 16: 389–95CrossRefGoogle Scholar
  178. 178.
    Gorelick PB. Stroke prevention therapy beyond antithrombotics: unifying mechanisms in ischemic stroke pathogenesis and implications for therapy. Stroke 2002; 33: 862–75PubMedCrossRefGoogle Scholar
  179. 179.
    Emsley HCA, Tyrrell PJ. Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab 2002; 22: 1399–419PubMedCrossRefGoogle Scholar
  180. 180.
    Mancia G. Prevention and treatment of stroke in patients with hypertension. Clin Ther 2004; 26/5: 631-48CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Andrea Lippoldt
    • 1
  • Andreas Reichet
    • 1
  • Ursula Moenning
    • 2
  1. 1.Department of Radiopharmaceuticals ResearchSchering AG BerlinBerlinGermany
  2. 2.Department of Research PharmacokineticsSchering AG BerlinBerlinGermany

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