Metabolic Brain Disease

, Volume 19, Issue 3–4, pp 151–167 | Cite as

Pathophysiology of Stroke: Lessons from Animal Models

  • Philipp Mergenthaler
  • Ulrich Dirnagl
  • Andreas Meisel


The current pathophysiological understanding of stroke is substantially based on experimental studies. Brain injury after cerebral ischemia develops from a complex signaling cascade that evolves in an at least partially unraveled spatiotemporal pattern. Early excitotoxicity can lead to fast necrotic cell death, which produces the core of the infarction. The ischemic penumbra that surrounds the infarct core suffers milder insults. In this area, both mild excitotoxic and inflammatory mechanisms lead to delayed cell death, which shows biochemical characteristics of apoptosis. While brain cells are challenged by these deleterious mechanisms, they activate innate protective programs of the brain, which can be studied by means of experimentally inducing ischemic tolerance (i.e., ischemic preconditioning). Importantly, cerebral ischemia not only affects the brain parenchyma, but also impacts extracranial systems. For example, stroke induces a dramatic immunosuppression via an overactivation of the sympathetic nervous system. As a result, severe bacterial infections such as pneumonia occur. Complex signaling cascades not only decide about cell survival, but also about the neurological deficit and the mortality after stroke. These mechanisms of damage and endogenous protection present distinct molecular targets that are the rational basis for the development of neuroprotective drugs.

Cerebral ischemia apoptosis inflammation endogenous neuroprotection immunodeficiency pneumonia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adams, H.P., Jr., Bendixen, B.H., Kappelle, L.J., Biller, J., Love, B.B., Gordon, D.L., and Marsh, E.E., III (1993). Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment. Stroke 24:35–41.PubMedGoogle Scholar
  2. Alvarez-Dolado, M., Pardal, R., Garcia-Verdugo, J.M., Fike, J.R., Lee, H.O., Pfeffer, K., Lois, C., Morrison, S.J., and Alvarez-Buylla, A. (2003). Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973.PubMedGoogle Scholar
  3. Asahi, M., Wang, X., Mori, T., Sumii, T., Jung, J.C., Moskowitz, M.A., Fini, M.E., and Lo, E.H. (2001). Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J. Neurosci. 21:7724–7732.PubMedGoogle Scholar
  4. Astrup, J., Siesjo, B.K., and Symon, L. (1981). Thresholds in cerebral ischemia—The ischemic penumbra. Stroke 12:723–725.PubMedGoogle Scholar
  5. Back, T., Ginsberg, M.D., Dietrich, W.D., and Watson, B.D. (1996). Induction of spreading depression in the ischemic hemisphere following experimental middle cerebral artery occlusion: Effect on infarct morphology.J. Cereb. Blood Flow Metab. 16:202–213.PubMedGoogle Scholar
  6. Back, T., Kohno, K., and Hossmann, K.A. (1994). Cortical negative DC deflections following middle cerebral artery occlusion and KCl-induced spreading depression: Effect on blood flow, tissue oxygenation, and electroencephalogram. J. Cereb. Blood Flow Metab. 14:12–19.PubMedGoogle Scholar
  7. Becker, K., Kindrick, D., McCarron, R., Hallenbeck, J., and Winn, R. (2003). Adoptive transfer of myelin basic protein-tolerized splenocytes to naive animals reduces infarct size: A role for lymphocytes in ischemic brain injury? Stroke 34:1809–1815.PubMedGoogle Scholar
  8. Becker, K., Kindrick, D., Relton, J., Harlan, J., and Winn, R. (2001). Antibody to the alpha4 integrin decreases infarct size in transient focal cerebral ischemia in rats. Stroke 32:206–211.PubMedGoogle Scholar
  9. Becker, K.J. (2001). Targeting the central nervous system inflammatory response in ischemic stroke. Curr. Opin Neurol.14:349–353.PubMedGoogle Scholar
  10. Becker, K.J., McCarron, R.M., Ruetzler, C., Laban, O., Sternberg, E., Flanders, K.C., and Hallenbeck, J.M. (1997). Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia. Proc. Natl. Acad. Sci. U.S.A.94:10873–10878.PubMedGoogle Scholar
  11. Bogdan, C., Paik, J., Vodovotz, Y., and Nathan, C. (1992). Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J. Biol. Chem. 267:23301–23308.PubMedGoogle Scholar
  12. Boysen, G., and Christensen, H. (2001). Stroke severity determines body temperature in acute stroke. Stroke 32:413–417.PubMedGoogle Scholar
  13. Brines, M.L., Ghezzi, P., Keenan, S., Agnello, D., de Lanerolle, N.C., Cerami, C., Itri, L.M., and Cerami, A. (2000). Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc.Natl. Acad. Sci. U.S.A. 97:10526–10531.PubMedGoogle Scholar
  14. Bruce, A.J., Boling, W., Kindy, M.S., Peschon, J., Kraemer, P.J., Carpenter, M.K., Holtsberg, F.W., and Mattson, M.P. (1996). Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking TNF receptors. Nat. Med. 2:788–794.PubMedGoogle Scholar
  15. Busch, E., Gyngell, M.L., Eis, M., Hoehn-Berlage, M., and Hossmann, K.A. (1996). Potassium-induced cortical spreading depressions during focal cerebral ischemia in rats: Contribution to lesion growth assessed by diffusion-weighted NMR and biochemical imaging. J. Cereb. Blood Flow Metab. 16:1090–1099.PubMedGoogle Scholar
  16. Cao, G., Pei, W., Ge, H., Liang, Q., Luo, Y., Sharp, F.R., Lu, A., Ran, R., Graham, S.H., and Chen, J. (2002). 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.PubMedGoogle Scholar
  17. Caplan, L.R. (2000). Caplan's Stroke: A Clinical Approach, Butterworth-Heinemann, Boston.Google Scholar
  18. Castillo, J., Davalos, A., Marrugat, J., and Noya, M. (1998). Timing for fever-related brain damage in acute ischemic stroke. Stroke 29:2455–2460.PubMedGoogle Scholar
  19. Chen, H., Chopp, M., Zhang, R.L., Bodzin, G., Chen, Q., Rusche, J.R., and Todd, R.F., III (1994). Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann. Neurol. 35:458–463.PubMedGoogle Scholar
  20. Clark, W.M., Rinker, L.G., Lessov, N.S., Hazel, K., Hill, J.K., Stenzel-Poore, M., and Eckenstein, F. (2000). Lack of interleukin-6 expression is not protective against focal central nervous system ischemia. Stroke 31:1715–1720.PubMedGoogle Scholar
  21. Crow, J.P., and Beckman, J.S. (1995). The role of peroxynitrite in nitric oxide-mediated toxicity. Curr. Top.Microbiol. Immunol. 196:57–73.PubMedGoogle Scholar
  22. Datta, S.R., Brunet, A., and Greenberg, M.E. (1999). Cellular survival: A play in three Akts. Genes Dev. 13:2905–2927.PubMedGoogle Scholar
  23. Datta, S.R., Katsov, A., Hu, L., Petros, A., Fesik, S.W., Yaffe, M.B., and Greenberg, M.E. (2000). 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. Mol. Cell 6:41–51.Google Scholar
  24. Davenport, R.J. (2003). Starve a neuron, feed pneumonia. Sci. Aging Knowledge Environ. 36:nw 124.Google Scholar
  25. Davenport, R.J., Dennis, M.S., Wellwood, I., and Warlow, C.P. (1996). Complications after acute stroke. Stroke 27:415–420.PubMedGoogle Scholar
  26. Davies, C.A., Loddick, S.A., Toulmond, S., Stroemer, R.P., Hunt, J., and Rothwell, N.J. (1999). The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat. J. Cereb. Blood Flow Metab. 19:87–98.PubMedGoogle Scholar
  27. Del Zoppo, G., Ginis, I., Hallenbeck, J.M., Iadecola, C., Wang, X., and Feuerstein, G.Z. (2000). Inflammation and stroke: Putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol. 10:95–112.PubMedGoogle Scholar
  28. Del Zoppo, G.J. (1995). Why do all drugs work in animals but none in stroke patients? 1. Drugs promoting cerebral blood flow. J. Intern. Med. 237:79–88.PubMedGoogle Scholar
  29. Del Zoppo, G.J. (1998). Clinical trials in acute stroke: Why have they not been successful? Neurology 51:S59–S61.PubMedGoogle Scholar
  30. Del Zoppo, G.J., Schmid-Schonbein, G.W., Mori, E., Copeland, B.R., and Chang, C.M. (1991). Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22:1276–1283.PubMedGoogle Scholar
  31. Dirnagl, U., Iadecola, C., and Moskowitz, M.A. (1999). Pathobiology of ischaemic stroke: An integrated view.Trends Neurosci. 22:391–397.PubMedGoogle Scholar
  32. Dirnagl, U., Simon, R.P., and Hallenbeck, J.M. (2003). Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 26:248–254.PubMedGoogle Scholar
  33. Ehrenreich, H., Hasselblatt, M., Dembowski, C., Cepek, L., Lewczuk, P., Stiefel, M., Rustenbeck, H.H., Breiter, N., Jacob, S., Knerlich, F., Bohn, M., Poser, W., Ruther, E., Kochen, M., Gefeller, O., Gleiter, C., Wessel, T.C., De Ryck, M., Itri, L., Prange, H., Cerami, A., Brines, M., and Siren, A.L. (2002). Erythropoietin therapy for acute stroke is both safe and beneficial. Mol. Med. 8:495–505.PubMedGoogle Scholar
  34. Eliasson, M.J., Sampei, K., Mandir, A.S., Hurn, P.D., Traystman, R.J., Bao, J., Pieper, A., Wang, Z.Q., Dawson, T.M., Snyder, S.H., and Dawson, V.L. (1997). Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat. Med. 3:1089–1095.PubMedGoogle Scholar
  35. Emsley, H.C., and Tyrrell, P.J. (2002). Inflammation and infection in clinical stroke. J. Cereb. Blood Flow Metab. 22:1399–1419.PubMedGoogle Scholar
  36. Endres, M., and Dirnagl, U. (2002). Ischemia and stroke. Adv. Exp. Med. Biol. 513:455–473.PubMedGoogle Scholar
  37. Endres, M., Fink, K., Zhu, J., Stagliano, N.E., Bondada, V., Geddes, J.W., Azuma, T., Mattson, M.P., Kwiatkowski, D.J., and Moskowitz, M.A. (1999). Neuroprotective effects of gelsolin during murine stroke. J. Clin. Invest. 103:347–354.PubMedGoogle Scholar
  38. Endres, M., Wang, Z.Q., Namura, S., Waeber, C., and Moskowitz, M.A. (1997). Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J. Cereb. Blood Flow Metab. 17:1143–1151.PubMedGoogle Scholar
  39. Ferrer, I., and Planas, A.M. (2003). Signaling of cell death and cell survival following focal cerebral ischemia: Life and death struggle in the penumbra. J. Neuropathol. Exp. Neurol. 62:329–339.PubMedGoogle Scholar
  40. Finegold, S.M. (1991). Aspiration pneumonia. Rev. Infect. Dis. 13(Suppl. 9):S737–S742.PubMedGoogle Scholar
  41. Fiszer, U., Korczak-Kowalska, G., Palasik, W., Korlak, J., Gorski, A., and Czlonkowska, A. (1998). Increased expression of adhesion molecule CD18 (LFA-1beta) on the leukocytes of peripheral blood in patients with acute ischemic stroke. Acta Neurol. Scand. 97:221–224.PubMedGoogle Scholar
  42. Fontaine, V., Mohand-Said, S., Hanoteau, N., Fuchs, C., Pfizenmaier, K., and Eisel, U. (2002). 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.PubMedGoogle Scholar
  43. Friedlander, R.M. (2003). Apoptosis and caspases in neurodegenerative diseases. N.Engl.J.Med. 348:1365–1375.PubMedGoogle Scholar
  44. Gasche, Y., Fujimura, M., Morita-Fujimura, Y., Copin, J.C., Kawase, M., Massengale, J., and Chan, P.H. (1999). Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: A possible role in blood–brain barrier dysfunction. J. Cereb. Blood Flow Metab. 19:1020–1028.PubMedGoogle Scholar
  45. Georgilis, K., Plomaritoglou, A., Dafni, U., Bassiakos, Y., and Vemmos, K. (1999). Aetiology of fever in patients with acute stroke. J. Intern. Med. 246:203–209.PubMedGoogle Scholar
  46. Ginsberg, M.D. (2003). Adventures in the pathophysiology of brain ischemia: Penumbra, gene expression, neuroprotection: The 2002 Thomas Willis Lecture. Stroke 34:214–223.PubMedGoogle Scholar
  47. Gladstone, D.J., Black, S.E., and Hakim, A.M. (2002). Toward wisdom from failure: Lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33:2123–2136.PubMedGoogle Scholar
  48. Grau, A.J., Buggle, F., Schnitzler, P., Spiel, M., Lichy, C., and Hacke, W. (1999). Fever and infection early after ischemic stroke. J. Neurol. Sci. 171:115–120.PubMedGoogle Scholar
  49. Gregersen, R., Lambertsen, K., and Finsen, B. (2000). Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J. Cereb. Blood Flow Metab. 20:53–65.PubMedGoogle Scholar
  50. Hajat, C., Hajat, S., and Sharma, P. (2000). Effects of poststroke pyrexia on stroke outcome: A meta-analysis of studies in patients. Stroke 31:410–414.PubMedGoogle Scholar
  51. Hara, H., Friedlander, R.M., Gagliardini, V., Ayata, C., Fink, K., Huang, Z., Shimizu-Sasamata, M., Yuan, J., and Moskowitz, M.A. (1997). Inhibition of interleukin 1beta converting enzyme family.proteases reduces ischemic and excitotoxic neuronal damage. Proc. Natl. Acad. Sci. U.S.A. 94:2007-2012.PubMedGoogle Scholar
  52. Heiss, W.D., Kracht, L.W., Thiel, A., Grond, M., and Pawlik, G. (2001). Penumbral probability thresholds of cortical flumazenil binding and blood flow predicting tissue outcome in patients with cerebral ischaemia. Brain 124:20–29.PubMedGoogle Scholar
  53. Hengartner, M.O. (2000). The biochemistry of apoptosis. Nature 407:770–776.Google Scholar
  54. Heo, J.H., Lucero, J., Abumiya, T., Koziol, J.A., Copeland, B.R., and del Zoppo, G.J. (1999). Matrix metallo-proteinases increase very early during experimental focal cerebral ischemia. J. Cereb. Blood Flow Metab. 19:624–633.PubMedGoogle Scholar
  55. Hilker, R., Poetter, C., Findeisen, N., Sobesky, J., Jacobs, A., Neveling, M., and Heiss, W.D. (2003). Nosocomial pneumonia after acute stroke: Implications for neurological intensive care medicine. Stroke 34:975–981.PubMedGoogle Scholar
  56. Hindfelt, B. (1976). The prognostic significance of subfebrility and fever in ischaemic cerebral infarction. Acta Neurol. Scand. 53:72–79.PubMedGoogle Scholar
  57. Hoehn-Berlage, M. (1995). Diffusion-weighted NMR imaging: Application to experimental focal cerebral is-chemia. NMR Biomed. 8:345–358.PubMedGoogle Scholar
  58. Iadecola, C., Niwa, K., Nogawa, S., Zhao, X., Nagayama, M., Araki, E., Morham, S., and Ross, M.E. (2001). Reduced susceptibility to ischemic brain injury and N-methyl-d-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc. Natl. Acad. Sci. U.S.A. 98:1294–1299.PubMedGoogle Scholar
  59. Iadecola, C., Zhang, F., Casey, R., Nagayama, M., and Ross, M.E. (1997). Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J. Neurosci. 17:9157–9164.PubMedGoogle Scholar
  60. Iijima, T., Mies, G., and Hossmann, K.A. (1992). Repeated negative DC deflections in rat cortex following middle cerebral artery occlusion are abolished by MK-801: Effect on volume of ischemic injury. J. Cereb. Blood Flow Metab. 12:727–733.PubMedGoogle Scholar
  61. Johnston, K.C., Li, J.Y., Lyden, P.D., Hanson, S.K., Feasby, T.E., Adams, R.J., Faught, R.E., Jr., and Haley, E.C., Jr. (1998). Medical and neurological complications of ischemic stroke: Experience from the RANTTAS trial.RANTTAS Investigators. Stroke 29:447–453.PubMedGoogle Scholar
  62. Kammersgaard, L.P., Jorgensen, H.S., Rungby, J.A., Reith, J., Nakayama, H., Weber, U.J., Houth, J., and Olsen, T.S. (2002). Admission body temperature predicts long-term mortality after acute stroke: The Copenhagen Stroke Study. Stroke 33:1759–1762.PubMedGoogle Scholar
  63. Katzan, I.L., Cebul, R.D., Husak, S.H., Dawson, N.V., and Baker, D.W. (2003). The effect of pneumonia on mortality among patients hospitalized for acute stroke. Neurology 60:620–625.PubMedGoogle Scholar
  64. Kilic, E., Dietz, G.P., Hermann, D.M., and Bahr, M. (2002). Intravenous TAT-Bcl-Xl is protective after middle cerebral artery occlusion in mice. Ann. Neurol. 52:617–622.PubMedGoogle Scholar
  65. Kim, Y., Busto, R., Dietrich, W.D., Kraydieh, S., and Ginsberg, M.D. (1996). Delayed postischemic hyperthermia in awake rats worsens the histopathological outcome of transient focal cerebral ischemia. Stroke 27:2274–2280.PubMedGoogle Scholar
  66. Kirino, T. (2002). Ischemic tolerance. J. Cereb. Blood Flow Metab. 22:1283–1296.PubMedGoogle Scholar
  67. Kokaia, Z., and Lindvall, O. (2003). Neurogenesis after ischaemic brain insults. Curr. Opin. Neurobiol. 13:127–132.PubMedGoogle Scholar
  68. Lapchak, P.A., Chapman, D.F., and Zivin, J.A. (2000). Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke. Stroke 31:3034–3040.PubMedGoogle Scholar
  69. Le, D.A., Wu, Y., Huang, Z., Matsushita, K., Plesnila, N., Augustinack, J.C., Hyman, B.T., Yuan, J., Kuida, K., Flavell, R.A., and Moskowitz, M.A. (2002). Caspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc. Natl. Acad. Sci. U.S.A. 99:15188–15193.PubMedGoogle Scholar
  70. Letterio, J.J. (2000). Murine models define the role of TGF-beta as a master regulator of immune cell function. Cytokine Growth Factor Rev. 11:81–87.PubMedGoogle Scholar
  71. Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S.M., Ahmad, M., Alnemri, E.S., and Wang, X. (1997). Cy-tochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489.CrossRefPubMedGoogle Scholar
  72. Lindsberg, P.J., Carpen, O., Paetau, A., Karjalainen-Lindsberg, M.L., and Kaste, M. (1996). Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 94:939–945.PubMedGoogle Scholar
  73. Linnik, M.D., Zahos, P., Geschwind, M.D., and Federoff, H.J. (1995). Expression of bcl-2 from a defective herpes simplex virus-1 vector limits neuronal death in focal cerebral ischemia. Stroke 26:1670–1674, discussion 1675.PubMedGoogle Scholar
  74. Lo, E.H., Dalkara, T., and Moskowitz, M.A. (2003). Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4:399–415.PubMedGoogle Scholar
  75. Love, S. (2003). Apoptosis and brain ischaemia. Prog. Neuropsychopharmacol. Biol. Psychiatry 27:267–282.PubMedGoogle Scholar
  76. Marik, P.E. (2001). Aspiration pneumonitis and aspiration pneumonia. N. Engl. J. Med. 344:665–671.PubMedGoogle Scholar
  77. Martinou, J.C., Dubois-Dauphin, M., Staple, J.K., Rodriguez, I., Frankowski, H., Missotten, M., Albertini, P., Talabot, D., Catsicas, S., Pietra, C., et al. (1994). Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017–1030.PubMedGoogle Scholar
  78. Mattson, M.P., Culmsee, C., and Yu, Z.F. (2000). Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res. 301:173–187.PubMedGoogle Scholar
  79. Mattson, M.P., Duan, W., Pedersen, W.A., and Culmsee, C. (2001). Neurodegenerative disorders and ischemic brain diseases. Apoptosis 6:69–81.PubMedGoogle Scholar
  80. Meisel, C., Prass, K., Braun, J., Victorov, I., Wolf, T., Megow, D., Halle, E., Volk, H.D., Dirnagl, U., and Meisel, A. Preventive antibacterial treatment improves the general medical and neurological outcome in a mouse model of stroke. Stroke 35:2–6.Google Scholar
  81. Meyer, S., Fiischer, C., Treib, J., Georg, T., and Schrittmatter, M. (2001). Autonomic and cardiovascular dysfunk-tion in acute cerebral ischemia. Akt. Neurol. 28:170–175.Google Scholar
  82. Mies, G., Iijima, T., and Hossmann, K.A. (1993). Correlation between peri-infarct DC shifts and ischaemic neuronal damage in rat. Neuroreport 4:709–711.PubMedGoogle Scholar
  83. Moncayo, J., de Freitas, G.R., Bogousslavsky, J., Altieri, M., and van Melle, G. (2000). Do transient ischemic attacks have a neuroprotective effect? Neurology 54:2089–2094.PubMedGoogle Scholar
  84. Mori, E., del Zoppo, G.J., Chambers, J.D., Copeland, B.R., and Arfors, K.E. (1992). Inhibition of polymorphonu-clear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 23:712–718.PubMedGoogle Scholar
  85. Nadareishvili, Z., and Hallenbeck, J. (2003). Neuronal regeneration after stroke. N.Engl.J.Med. 348:2355–2356.PubMedGoogle Scholar
  86. Namura, S., Zhu, J., Fink, K., Endres, M., Srinivasan, A., Tomaselli, K.J., Yuan, J., and Moskowitz, M.A. (1998). Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J. Neurosci. 18:3659–3668.PubMedGoogle Scholar
  87. Nawahiro, H., Martin, D., and Hallenbeck, J. M. (1997). Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res. 778:265–271.PubMedGoogle Scholar
  88. Nedergaard, M., and Hansen, A.J. (1993). Characterization of cortical depolarizations evoked in focal cerebral ischemia. J. Cereb. Blood Flow Metab. 13:568–574.PubMedGoogle Scholar
  89. Perry, L., and Love, C.P. (2001). Screening for dysphagia and aspiration in acute stroke: A systematic review. Dysphagia 16:7–18.PubMedGoogle Scholar
  90. Prass, K., Meisel, C., Hoflich, C., Braun, J., Halle, E., Wolf, T., Ruscher, K., Victorov, I.V., Priller, J., Dirnagl, U., Volk, H.D., and Meisel, A. (2003a). Stroke-induced immunodeficiency promotes spontaneous bacte-rial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J. Exp. Med. 198:725–736.PubMedGoogle Scholar
  91. Prass, K., Meisel, C., Wolf, T., Volk, H.D., Dirnagl, U., and Meisel, A. (2003b). Striking the immune system— Stroke induced immune depression. In (J. Krieglstein, ed.), Pharmacology of Cerebral Ischemia, Medpharm, Stuttgart, Germany, pp. 217–221.Google Scholar
  92. Prass, K., Ruscher, K., Karsch, M., Isaev, N., Megow, D., Priller, J., Scharff, A., Dirnagl, U., and Meisel, A. (2002). Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro. J. Cereb. Blood Flow Metab. 22:520–525.PubMedGoogle Scholar
  93. Prass, K., Scharff, A., Ruscher, K., Lowl, D., Muselmann, C., Victorov, I., Kapinya, K., Dirnagl, U., and Meisel, A. (2003c). Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke 34:1981-1986.PubMedGoogle Scholar
  94. Prehn, J.H., Backhauss, C., and Krieglstein, J. (1993). Transforming growth factor-beta 1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J. Cereb. Blood Flow Metab. 13:521–525.PubMedGoogle Scholar
  95. Priller, J., Flugel, A., Wehner, T., Boentert, M., Haas, C.A., Prinz, M., Fernandez-Klett, F., Prass, K., Bechmann, I., de Boer, B.A., Frotscher, M., Kreutzberg, G.W., Persons, D.A., and Dirnagl, U. (2001a). Targeting gene-modified hematopoietic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 7:1356–1361.PubMedGoogle Scholar
  96. Priller, J., Persons, D.A., Klett, F.F., Kempermann, G., Kreutzberg, G.W., and Dirnagl, U. (2001b). Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J. Cell Biol. 155:733–738.PubMedGoogle Scholar
  97. Reith, J., Jorgensen, H.S., Pedersen, P.M., Nakayama, H., Raaschou, H.O., Jeppesen, L.L., and Olsen, T.S. (1996). Body temperature in acute stroke: Relation to stroke severity, infarct size, mortality, and outcome. Lancet 347:422–425.PubMedGoogle Scholar
  98. Rosenberg, G.A., Estrada, E.Y., and Dencoff, J.E. (1998). Matrix metalloproteinases and TIMPs are associated with blood–brain barrier opening after reperfusion in rat brain. Stroke 29:2189–2195.PubMedGoogle Scholar
  99. Ruscher, K., Freyer, D., Karsch, M., Isaev, N., Megow, D., Sawitzki, B., Priller, J., Dirnagl, U., and Meisel, A. (2002). Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: Evidence from an in vitro model. J. Neurosci. 22:10291–10301.PubMedGoogle Scholar
  100. Ruscher, K., Isaev, N., Trendelenburg, G., Weih, M., Iurato, L., Meisel, A., and Dirnagl, U. (1998). Induction of hypoxia inducible factor 1 by oxygen glucose deprivation is attenuated by hypoxic preconditioning in rat cultured neurons. Neurosci. Lett. 254:117–120.PubMedGoogle Scholar
  101. Sairanen, T., Ristimaki, A., Karjalainen-Lindsberg, M.L., Paetau, A., Kaste, M., and Lindsberg, P.J. (1998).Cyclooxygenase-2 is induced globally in infarcted human brain. Ann. Neurol. 43:738–747.PubMedGoogle Scholar
  102. Saito, A., Hayashi, T., Okuno, S., Ferrand-Drake, M., and Chan, P.H. (2003). Interaction between XIAP and Smac/DIABLO in the mouse brain after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 23:1010–1019.PubMedGoogle Scholar
  103. Sakanaka, M., Wen, T.C., Matsuda, S., Masuda, S., Morishita, E., Nagao, M., and Sasaki, R. (1998). In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl. Acad. Sci. U.S.A. 95:4635–4640.PubMedGoogle Scholar
  104. Savitz, S.I., Rosenbaum, D.M., Dinsmore, J.H., Wechsler, L.R., and Caplan, L.R. (2002). Cell transplantation for stroke. Ann. Neurol. 52:266–275.PubMedGoogle Scholar
  105. Schurr, A. (2001). Glucose and the ischemic brain: A sour grape or a sweet treat? Curr. Opin. Clin. Nutr. Metab Care 4:287–292.PubMedGoogle Scholar
  106. Siesjo, B.K. (1988). Acidosis and ischemic brain damage. Neurochem. Pathol. 9:31–88.PubMedGoogle Scholar
  107. Sims, N.R., and Anderson, M.F. (2002). Mitochondrial contributions to tissue damage in stroke. Neurochem. Int. 40:511–526.PubMedGoogle Scholar
  108. Soriano, S.G., Lipton, S.A., Wang, Y.F., Xiao, M., Springer, T.A., Gutierrez-Ramos, J.C., and Hickey, P.R. (1996). Intercellular adhesion molecule-1-deficient mice are less susceptible to cerebral ischemia-reperfusion injury.Ann. Neurol. 39:618–624.PubMedGoogle Scholar
  109. Spera, P.A., Ellison, J.A., Feuerstein, G.Z., and Barone, F.C. (1998). IL-10 reduces rat brain injury following focal stroke. Neurosci. Lett. 251:189–192.PubMedGoogle Scholar
  110. Stoll, G., Jander, S., and Schroeter, M. (1998). Inflammation and glial responses in ischemic brain lesions. Prog.Neurobiol. 56:149–171.PubMedGoogle Scholar
  111. Strle, K., Zhou, J.H., Shen, W.H., Broussard, S.R., Johnson, R.W., Freund, G.G., Dantzer, R., and Kelley, K.W. (2001). Interleukin-10 in the brain. Crit. Rev. Immunol. 21:427–449.PubMedGoogle Scholar
  112. Sugimoto, K., and Iadecola, C. (2003). Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res. 960:273–276.PubMedGoogle Scholar
  113. Takagi, K., Ginsberg, M.D., Globus, M.Y., Martinez, E., and Busto, R. (1994). Effect of hyperthermia on glutamate release in ischemic penumbra after middle cerebral artery occlusion in rats. Am. J. Physiol. 267:H1770–H1776.PubMedGoogle Scholar
  114. Takeda, H., Spatz, M., Ruetzler, C., McCarron, R., Becker, K., and Hallenbeck, J. (2002). Induction of mucosal tolerance to E-selectin prevents ischemic and hemorrhagic stroke in spontaneously hypertensive genetically stroke-prone rats. Stroke 33:2156–2163.PubMedGoogle Scholar
  115. Tarozzo, G., Campanella, M., Ghiani, M., Bulfone, A., and Beltramo, M. (2002). Expression of fractalkine and its receptor, CX3CR1, in response to ischaemia-reperfusion brain injury in the rat. Eur. J. Neurosci. 15:1663–1668.PubMedGoogle Scholar
  116. Trapp, T., Korhonen, L., Besselmann, M., Martinez, R., Mercer, E.A., and Lindholm, D. (2003). Transgenic mice overexpressing XIAP in neurons show better outcome after transient cerebral ischemia. Mol. Cell. Neurosci. 23:302–313.PubMedGoogle Scholar
  117. Trendelenburg, G., Prass, K., Priller, J., Kapinya, K., Polley, A., Muselmann, C., Ruscher, K., Kannbley, U., Schmitt, A.O., Castell, S., Wiegand, F., Meisel, A., Rosenthal, A., and Dirnagl, U. (2002). Serial analysis of gene expression identifies metallothionein-II as major neuroprotective gene in mouse focal cerebral ischemia. J. Neurosci. 22:5879–5888.PubMedGoogle Scholar
  118. van Gurp, M., Festjens, N., van Loo, G., Saelens, X., and Vandenabeele, P. (2003). Mitochondrial intermembrane proteins in cell death. Biochem. Biophys. Res. Commun. 304:487–497.PubMedGoogle Scholar
  119. Vernino, S., Brown, R.D., Jr., Sejvar, J.J., Sicks, J.D., Petty, G.W., and O'Fallon, W.M. (2003). Cause-specific mortality after first cerebral infarction: A population-based study. Stroke 34:1828–1832.PubMedGoogle Scholar
  120. Wass, C.T., Lanier, W.L., Hofer, R.E., Scheithauer, B.W., and Andrews, A.G. (1995). Temperature changes of >or =1 degree C alter functional neurologic outcome and histopathology in a canine model of complete cerebral ischemia. Anesthesiology 83:325–335.PubMedGoogle Scholar
  121. Weih, M., Kallenberg, K., Bergk, A., Dirnagl, U., Harms, L., Wernecke, K.D., and Einhaupl, K.M. (1999). Attenuated stroke severity after prodromal TIA: A role for ischemic tolerance in the brain? Stroke 30:1851–1854.PubMedGoogle Scholar
  122. Weih, M., Prass, K., Ruscher, K., Trendelenburg, G., Dirnagl, U., Riepe, M.W., and Meisel, A. (2001). [Ischemia tolerance; model for research, hope for clinical practice?]. Nervenarzt 72:255–260.PubMedGoogle Scholar
  123. Wiessner, C., Allegrini, P.R., Rupalla, K., Sauer, D., Oltersdorf, T., McGregor, A.L., Bischoff, S., Bottiger, B.W., and van der Putten, H. (1999). Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice. Neurosci. Lett. 268:119–122.PubMedGoogle Scholar
  124. Wolf, T., Lindauer, U., Reuter, U., Back, T., Villringer, A., Einhaupl, K., and Dirnagl, U. (1997). Noninvasive near infrared spectroscopy monitoring of regional cerebral blood oxygenation changes during peri-infarct depolarizations in focal cerebral ischemia in the rat. J. Cereb. Blood Flow Metab. 17:950–954.PubMedGoogle Scholar
  125. Ying, W., Garnier, P., and Swanson, R.A. (2003). NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes. Biochem. Biophys. Res. Commun. 308:809–813.PubMedGoogle Scholar
  126. Yrjanheikki, J., Tikka, T., Keinanen, R., Goldsteins, G., Chan, P.H., and Koistinaho, J. (1999). A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc. Natl. Acad. Sci. U.S.A. 96:13496–13500.PubMedGoogle Scholar
  127. Yu, S.W., Wang, H., Poitras, M.F., Coombs, C., Bowers, W.J., Federoff, H.J., Poirier, G.G., Dawson, T.M., and Dawson, V.L. (2002). Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259–263.PubMedGoogle Scholar
  128. Zhang, F., Casey, R.M., Ross, M.E., and Iadecola, C. (1996). Aminoguanidine ameliorates and l-arginine worsens brain damage from intraluminal middle cerebral artery occlusion. Stroke 27:317–323.PubMedGoogle Scholar
  129. Zhang, R.L., Chopp, M., Jiang, N., Tang, W.X., Prostak, J., Manning, A.M., and Anderson, D.C. (1995a). Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 26:1438–1442, discussion 1443.PubMedGoogle Scholar
  130. Zhang, R.L., Chopp, M., Zaloga, C., Zhang, Z.G., Jiang, N., Gautam, S.C., Tang, W.X., Tsang, W., Anderson, D.C., and Manning, A.M. (1995b). The temporal profiles of ICAM-1 protein and mRNA expression after transient MCA occlusion in the rat. Brain Res. 682:182–188.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 2004

Authors and Affiliations

  • Philipp Mergenthaler
    • 1
  • Ulrich Dirnagl
    • 1
  • Andreas Meisel
    • 1
  1. 1.Department of Experimental Neurology CharitéHumboldt UniversityBerlinGermany

Personalised recommendations