Abstract
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.
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REFERENCES
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.
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.
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.
Astrup, J., Siesjo, B.K., and Symon, L. (1981). Thresholds in cerebral ischemia—The ischemic penumbra. Stroke 12:723–725.
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.
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.
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.
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.
Becker, K.J. (2001). Targeting the central nervous system inflammatory response in ischemic stroke. Curr. Opin Neurol.14:349–353.
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.
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.
Boysen, G., and Christensen, H. (2001). Stroke severity determines body temperature in acute stroke. Stroke 32:413–417.
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.
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.
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.
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.
Caplan, L.R. (2000). Caplan's Stroke: A Clinical Approach, Butterworth-Heinemann, Boston.
Castillo, J., Davalos, A., Marrugat, J., and Noya, M. (1998). Timing for fever-related brain damage in acute ischemic stroke. Stroke 29:2455–2460.
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.
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.
Crow, J.P., and Beckman, J.S. (1995). The role of peroxynitrite in nitric oxide-mediated toxicity. Curr. Top.Microbiol. Immunol. 196:57–73.
Datta, S.R., Brunet, A., and Greenberg, M.E. (1999). Cellular survival: A play in three Akts. Genes Dev. 13:2905–2927.
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.
Davenport, R.J. (2003). Starve a neuron, feed pneumonia. Sci. Aging Knowledge Environ. 36:nw 124.
Davenport, R.J., Dennis, M.S., Wellwood, I., and Warlow, C.P. (1996). Complications after acute stroke. Stroke 27:415–420.
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.
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.
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.
Del Zoppo, G.J. (1998). Clinical trials in acute stroke: Why have they not been successful? Neurology 51:S59–S61.
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.
Dirnagl, U., Iadecola, C., and Moskowitz, M.A. (1999). Pathobiology of ischaemic stroke: An integrated view.Trends Neurosci. 22:391–397.
Dirnagl, U., Simon, R.P., and Hallenbeck, J.M. (2003). Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 26:248–254.
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.
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.
Emsley, H.C., and Tyrrell, P.J. (2002). Inflammation and infection in clinical stroke. J. Cereb. Blood Flow Metab. 22:1399–1419.
Endres, M., and Dirnagl, U. (2002). Ischemia and stroke. Adv. Exp. Med. Biol. 513:455–473.
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.
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.
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.
Finegold, S.M. (1991). Aspiration pneumonia. Rev. Infect. Dis. 13(Suppl. 9):S737–S742.
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.
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.
Friedlander, R.M. (2003). Apoptosis and caspases in neurodegenerative diseases. N.Engl.J.Med. 348:1365–1375.
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.
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.
Ginsberg, M.D. (2003). Adventures in the pathophysiology of brain ischemia: Penumbra, gene expression, neuroprotection: The 2002 Thomas Willis Lecture. Stroke 34:214–223.
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.
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.
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.
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.
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.
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.
Hengartner, M.O. (2000). The biochemistry of apoptosis. Nature 407:770–776.
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.
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.
Hindfelt, B. (1976). The prognostic significance of subfebrility and fever in ischaemic cerebral infarction. Acta Neurol. Scand. 53:72–79.
Hoehn-Berlage, M. (1995). Diffusion-weighted NMR imaging: Application to experimental focal cerebral is-chemia. NMR Biomed. 8:345–358.
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.
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.
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.
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.
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.
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.
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.
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.
Kirino, T. (2002). Ischemic tolerance. J. Cereb. Blood Flow Metab. 22:1283–1296.
Kokaia, Z., and Lindvall, O. (2003). Neurogenesis after ischaemic brain insults. Curr. Opin. Neurobiol. 13:127–132.
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.
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.
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.
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.
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.
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.
Lo, E.H., Dalkara, T., and Moskowitz, M.A. (2003). Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4:399–415.
Love, S. (2003). Apoptosis and brain ischaemia. Prog. Neuropsychopharmacol. Biol. Psychiatry 27:267–282.
Marik, P.E. (2001). Aspiration pneumonitis and aspiration pneumonia. N. Engl. J. Med. 344:665–671.
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.
Mattson, M.P., Culmsee, C., and Yu, Z.F. (2000). Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res. 301:173–187.
Mattson, M.P., Duan, W., Pedersen, W.A., and Culmsee, C. (2001). Neurodegenerative disorders and ischemic brain diseases. Apoptosis 6:69–81.
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.
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.
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.
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.
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.
Nadareishvili, Z., and Hallenbeck, J. (2003). Neuronal regeneration after stroke. N.Engl.J.Med. 348:2355–2356.
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.
Nawahiro, H., Martin, D., and Hallenbeck, J. M. (1997). Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res. 778:265–271.
Nedergaard, M., and Hansen, A.J. (1993). Characterization of cortical depolarizations evoked in focal cerebral ischemia. J. Cereb. Blood Flow Metab. 13:568–574.
Perry, L., and Love, C.P. (2001). Screening for dysphagia and aspiration in acute stroke: A systematic review. Dysphagia 16:7–18.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Schurr, A. (2001). Glucose and the ischemic brain: A sour grape or a sweet treat? Curr. Opin. Clin. Nutr. Metab Care 4:287–292.
Siesjo, B.K. (1988). Acidosis and ischemic brain damage. Neurochem. Pathol. 9:31–88.
Sims, N.R., and Anderson, M.F. (2002). Mitochondrial contributions to tissue damage in stroke. Neurochem. Int. 40:511–526.
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.
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.
Stoll, G., Jander, S., and Schroeter, M. (1998). Inflammation and glial responses in ischemic brain lesions. Prog.Neurobiol. 56:149–171.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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Mergenthaler, P., Dirnagl, U. & Meisel, A. Pathophysiology of Stroke: Lessons from Animal Models. Metab Brain Dis 19, 151–167 (2004). https://doi.org/10.1023/B:MEBR.0000043966.46964.e6
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DOI: https://doi.org/10.1023/B:MEBR.0000043966.46964.e6