Summary
1. Stroke is the neurological evidence of a critical reduction of cerebral blood flow in a circumscribed part of the brain, resulting from the sudden or gradually progressing obstruction of a large brain artery. Treatment of stroke requires the solid understanding of stroke pathophysiology and involves a broad range of hemodynamic and molecular interventions. This review summarizes research that has been carried out in many laboratories over a long period of time, but the main focus will be on own experimental research.
2. The first chapter deals with the hemodynamics of focal ischemia with particular emphasis on the collateral circulation of the brain, the regulation of blood flow and the microcirculation. In the second chapter the penumbra concept of ischemia is discussed, providing a detailed list of the physiological, biochemical and structural viability thresholds of ischemia and examples of how these thresholds can be applied for imaging the penumbra. The third chapter summarizes the pathophysiology of infarct progression, focusing on the role of peri-infarct depolarisation, the multitude of putative molecular injury pathways, brain edema and inflammation. Finally, the fourth chapter provides an overview of currently discussed therapeutic approaches, notably the effect of mechanical or thrombolytic reperfusion, arteriogenesis, pharmacological neuroprotection, ischemic preconditioning and regeneration.
3. The main emphasis of the review is placed on the balanced differentiation between hemodynamic and molecular factors contributing to the manifestation of ischemic injury in order to provide a rational basis for future therapeutic interventions.
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REFERENCES
Amin-Hanjani, S., Stagliano, N. E., Yamada, M., Huang, P. L., Liao, J. K., and Moskowitz, M. A. (2001). Mevastatin, an HMG-CoA reductase inhibitor, reduces stroke damage and upregulates endothelial nitric oxide synthase in mice. Stroke 32:980–985.
Aronowski, J., Strong, R., Kang, H. S., and Grotta, J. C. (2000). Selective up-regulation of I kappa B-alpha in ischemic penumbra following focal cerebral ischemia. Neuroreport 11:1529–1533.
Asahi, M., Asahi, K., Jung, J. C., del Zoppo, G. J., Fini, M. E., and Lo, E. H. (2000). Role for matrix metalloproteinase 9 after focal cerebral ischemia, effects of gene knockout and enzyme inhibition with BB-94. J. Cereb. Blood Flow Metab. 20:1681–1689.
Astrup, J., Symon, L., and Siesjö, B. K. (1981). Thresholds in cerebral ischemia—The ischemic penumbra. Stroke 12:723–725.
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.
Badaut, T., Lasbennes, T., Magistretti, P. J., and Regli, L. (2002). Aquaporins in brain: Distribution, physiology, and pathophysiology. J. Cereb. Blood Flow Metab. 22:367–378.
Beech, J. S., Reckless, J., Mosedale, D. E., Grainger, D. J., Williams, S. C. R., and Menon, D. K. (2001). Neuroprotection in ischemia-reperfusion injury: An antiinflammatory approach using a novel broad-spectrum chemokine inhibitor. J. Cereb. Blood Flow Metab. 21:683–689.
Betz, A. L., Keep, R. F., Beer, M. E., and Ren, X. D. (1994). Blood-brain barrier permeability and brain concentration of sodium, potassium, and chloride during focal ischemia. J. Cereb. Blood Flow Metab. 14:29–37.
Bidmon, H. J., Oermann, E., Schiene, K., Schmitt, M., Kato, K., Asayama, K., Witte, O. W., and Zilles, K. (2000). Unilateral upregulation of cyclooxygenase-2 following cerebral, cortical photothrombosis in the rat: Suppression by MK-801 and co-distribution with enzymes involved in the oxidative stress cascade [review]. J. Chem. Neuroanat. 20:163–176.
Borlongan, C. V., Koutouzis, T. K., Jorden, J. R., Martinez, R., Rodriguez, A. I., Poulos, S. G., Freeman, T. B., McKeown, P., Cahill, D. W., Nishino, H., and Sanberg, P. R. (1997). Neural transplantation as an experimental treatment modality for cerebral ischemia. Neurosci. Biobehav. Rev. 21:79–90.
Brinker, G., Franke, C., Hoehn, M., Uhlenkuken, U., and Hossmann, K. A. (1999). Thrombolysis of cerebral clot embolism in rat: Effect of treatment delay. Neuroreport 10:3269–3272.
Buchan, A. M., Xue, D., and Slivka, A. (1992). A new model of temporary focal neocortical ischemia in the rat. Stroke 23:273–279.
Burda, J., Hrehorovska, M., Bonilla, L. G., Danielisova, V., Cizkova, D., Burda, R., Nemethova, M., Fando, J. L., and Salinas, M. (2003). Role of protein synthesis in the ischemic tolerance acquisition induced by transient forebrain ischemia in the rat. Neurochem. Res. 28:1213–1219.
Busch, H. J., Buschmann, I. R., Mies, G., Bode, C., and Hossmann, K. -A. (2003). Arteriogenesis in hypoperfused rat brain. J. Cereb. Blood Flow Metab. 23:621–628.
Buschmann, I. R., Busch, H. J., Mies, G., and Hossmann, K. -A. (2003). Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte-macrophage colony-stimulating factor. Circulation 108:610–615.
Chan, P. H. (1996). Role of oxidants in ischemic brain damage. Stroke 27:1124–1129.
Chen, J. L., Li, Y., Katakowski, M., Chen, X. G., Wang, L., Lu, D. Y., Lu, M., Gautam, S. C., and Chopp, M. (2003). Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J. Neurosci. Res. 73:778–786.
Choi, D. W. (1996). Ischemia-induced neuronal apoptosis. Curr. Opin. Neurobiol. 6:667–672.
Choi, D. W., and Koh, J. Y. (1998). Zinc and brain injury [review]. Ann. Rev. Neurosci. 21:347–375.
Chu, K., Kim, M., Park, K. I., Jeong, S. W., Park, H. K., Jung, K. H., Lee, S. T., Kang, L., Lee, K., Park, D. K., Kim, S. U., and Roh, J. K. (2004). Human neural stem cells improve sensorimotor deficits in the adult rat brain with experimental focal ischemia. Brain Res. 1016:145–153.
Clark, W. M., Rinker, L. G., Lessov, N. S., Lowery, S. L., and Cipolla, M. J. (2001). Efficacy of antioxidant therapies in transient focal ischemia in mice. Stroke 32:1000–1004.
Dalkara, T., and Moskowitz, M. A. (1994). The complex role of nitric oxide in the pathophysiology of focal cerebral ischemia. Brain Pathol. 4:49–57.
Degraba, T. J., Ostrow, P. T., and Grotta, J. C. (1993). Threshold of calcium disturbances after focal cerebral ischemia in rats—Implications of the window of therapeutic opportunity. Stroke 24:1212–1217.
DeGracia, D. J., Adamczyk, S., Folbe, A. J., Konkoly, L. L., Pittman, J. E., Neumar, R. W., Sullivan, J. M., Scheuner, D., Kaufman, R. J., White, B. C., and Krause, G. S. (1999). Eukaryotic initiation factor 2 alpha kinase and phosphatase activity during postischemic brain reperfusion. Exp. Neurol. 155:221–227.
Del Zoppo, G. J., and Hallenbeck, J. M. (2000). Advances in the vascular pathophysiology of ischemic stroke. Thromb. Res. 98:V73–V81.
Dempsey, R. J., Sailor, K. A., Bowen, K. K., Tureyen, K., and Vemuganti, R. (2003). Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF. J. Neurochem. 87:586–597.
Dirnagl, U., and Pulsinelli, W. (1990). Autoregulation of cerebral blood flow in experimental focal brain ischemia. J. Cereb. Blood Flow Metab. 10:327–336.
Dirnagl, U., Simon, R. P., and Hallenbeck, J. M. (2003). Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 26:248–254.
Du, C., Hu, R., Csernansky, C. A., Hsu, C. Y., and Choi, D. W. (1996). Very delayed infarction after mild focal cerebral ischemia: A role for apoptosis?. J. Cereb. Blood Flow Metab. 16:195–201.
Eliasson, M. J. L., Huang, Z. H., Ferrante, R. J., Sasamata, M., Molliver, M. E., Snyder, S. H., and Moskowitz, M. A. (1999). Neuronal nitric oxide synthase activation and peroxynitrite formation in ischemic stroke linked to neural damage. J. Neurosci.e 19:5910–5918.
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.
Erdo, F., Buhrle, C., Blunk, J., Hoehn, M., Xia, T., Fleischmann, B., Focking, M., Kustermann, E., Kolossov, E., Hescheler, T., Hossmann, K. A., and Trapp, T. (2003). Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J. Cereb. Blood Flow Metab. 23:780–785.
Fisher, M. (2004). The ischemic penumbra: Identification, evolution and treatment concepts. Cerebrovasc. Dis. 17:1–6.
Gill, R., Andine, P., Hillered, L., Persson, L., and Hagberg, H. (1992). The effect of MK-801 on cortical spreading depression in the penumbral zone following focal ischemia in the rat. J. Cereb. Blood Flow Metab. 12:371–379.
Ginsberg, M. D. (1997). Injury mechanisms in the ischaemic penumbra—approaches to neuroprotection in acute ischaemic stroke. Cerebrovasc. Dis. 7(2):7–12.
Ginsberg, M. D. (2003). Adventures in the pathophysiology of brain ischemia: Penumbra, gene expression, neuroprotection. The 2002 Thomas Willis Lecture. Stroke 34:214–223.
Göbel, U., Theilen, H., and Kuschinsky, W. (1990). Congruence of total and perfused capillary network in rat brains. Circ. Res. 66:271–281.
Grabowski, M., Sorensen, J. C., Mattsson, B., Zimmer, J., and Johansson, B. B. (1995). Influence of an enriched environment and cortical grafting on functional outcome in brain infarcts of adult rats. Exp. Neurol. 133:96–102.
Green, D. R., and Kroemer, G. (2004). The pathophysiology of mitochondrial cell death. Science 305:626–629.
Griesdale, D. E. G., and Honey, C. R. (2004). Aquaporins and brain edema. Surg. Neurol. 61:418–421.
Gu, W. G., Brannstrom, T., and Wester, P. (2000). Cortical neurogenesis in adult rats after reversible photothrombotic stroke. J. Cereb. Blood Flow Metab. 20:1166–1173.
Guadagno, J. V., Donnan, G. A., Markus, R., Gillard, J. H., and Baron, J. C. (2004). Imaging the ischaemic penumbra. Curr. Opin. Neurol. 17:61–67.
Gyngell, M. L., Back, T., Hoehn-Berlage, M., Kohno, K., and Hossmann, K. -A. (1994). Transient cell depolarization after permanent middle cerebral artery occlusion: An observation by diffusion-weighted MRI and localized 1H-MRS. Magn. Reson. Med. 31:337–341.
Hakim, A. M. (1987). The cerebral ischemic penumbra. Can. J. Neurol. Sci. 14:557–559.
Hall, E. D. (1997). Acute therapeutic interventions—free radical scavengers and antioxidants. Neurosurg. Clin. North Am. 8:195.
Hara, H., Friedlander, R. M., Gagliardini, V., Ayata, C., Fink, K., Huang, Z. H., Shimizusasamata, M., Yuan, J. Y., and Moskowitz, M. A. (1997). Inhibition of interleukin 1-beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc. Natl. Acad. Sci. U. S. A. 94:2007–2012.
Hata, R., Maeda, K., Hermann, D., Mies, G., and Hossmann, K. -A. (2000a). Dynamics of regional brain metabolism and gene expression after middle cerebral artery occlusion in mice. J. Cereb. Blood Flow Metab. 20:306–315.
Hata, R., Maeda, K., Hermann, D., Mies, G., and Hossmann, K. -A. (2000b). Evolution of brain infarction after transient focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 20:937–946.
Hata, R., Mies, G., Wiessner, C., and Hossmann, K. -A. (1998). Differential expression of c-fos and hsp72 mRNA in focal cerebral ischemia of mice. Neuroreport 9:27–32.
Heiss, W. D. (1992). Experimental evidence of ischemic thresholds and functional recovery. Stroke 23:1668–1672.
Heiss, W. D. (2000). Ischemic penumbra: Evidence from functional imaging in man [review]. J. Cereb. Blood Flow Metab. 20:1276–1293.
Hilger, T., Niessen, F., Diedenhofen, M., Hossmann, K. –A., and Hoehn, M. (2002). Magnetic resonance angiography of thromboembolic stroke in rats: Indicator of recanalization probability and tissue survival after recombinant tissue plasminogen activator treatment. J. Cereb. Blood Flow Metab. 22:652–662.
Hillered, L., and Chan, P. H. (1988). Role of arachidonic acid and other free fatty acids in mitochondrial dysfunction in brain ischemia. J. Neurosci. Res. 20:451–456.
Hoehn, M., Kustermann, E., Blunk, J., Wiedermann, D., Trapp, T., Wecker, S., Focking, M., Arnold, H., Hescheler, J., Fleischmann, B. K., Schwindt, W., and Buhrle, C. (2002). Monitoring of implanted stem cell migration in vivo: A highly resolved in vivo magnetic resonance imaging investigation of experimental stroke in rat. Proc. Natl. Acad. Sci. U. S. A. 99:16267–16272.
Hoehn-Berlage, M., Norris, D. G., Kohno, K., Mies, G., Leibfritz, D., and Hossmann, K. -A. (1995). Evolution of regional changes in apparent diffusion coefficient during focal ischemia of rat brain: The relationship of quantitative diffusion NMR imaging to reduction in cerebral blood flow and metabolic disturbances. J. Cereb. Blood Flow Metab. 15:1002–1011.
Hossmann, K. -A. (1989). The pathophysiology of experimental brain edema. Neurosurg. Rev. 12:263–280.
Hossmann, K. -A. (1993). Disturbances of cerebral protein synthesis and ischemic cell death. Prog. Brain Res. 96:161–177.
Hossmann, K. -A. (1994a). Glutamate-mediated injury in focal cerebral ischemia: The excitotoxin hypothesis revised. Brain Pathol. 4:23–36.
Hossmann, K. -A. (1994b). Viability thresholds and the penumbra of focal ischemia. Ann. Neurol. 36:557–565.
Hossmann, K. -A. (1996). Periinfarct depolarizations. Cerebrovasc. Brain Metab. Rev. 8:195–208.
Hossmann, K. -A. (1997). Reperfusion of the brain after global ischemia—hemodynamic disturbances. Shock 8:95–101.
Hossmann, K. -A., and Hoehn-Berlage, M. (1995). Diffusion and perfusion MR imaging of cerebral ischemia. Cerebrovasc. Brain Metab. Rev. 7:187–217.
Hudetz, A. G. (1997). Blood flow in the cerebral capillary network—a review emphasizing observations with intravital microscopy [review]. Microcirculation-London 4:233–252.
Iadecola, C., Forster, C., Nogawa, S., Clark, H. B., and Ross, M. E. (1999). Cyclooxygenase-2 immunoreactivity in the human brain following cerebral ischemia. Acta Neuropathol. 98:9–14.
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.
Imitola, J., Park, K. I., Teng, Y. D., Nisim, S., Lachyankar, M., Ourednik, J., Mueller, F. J., Yiou, R., Atala, A., Sidman, R. L., Tuszynski, M., Khoury, S. J., and Snyder, E. Y. (2004). Stem cells: Cross-talk and developmental programs. Philos. Trans.R. Soc. Lond.B Biol. Sci. 359:823–837.
Kiessling, M., and Gass, P. (1994). Stimulus-transcription coupling in focal cerebral ischemia. Brain Pathol. 4:77–83.
Kilic, E., Hermann, D. M., and Hossmann, K .-A. (2000). Recombinant tissue-plasminogen activator-induced thrombolysis after cerebral thromboembolism in mice. Acta Neuropathol. 99:219–222.
Kim, Y. H., Kim, E. Y., Gwag, B. J., Sohn, S., and Koh, J. Y. (1999). Zinc-induced cortical neuronal death with features of apoptosis and necrosis, mediation by free radicals. Neuroscience 89:175–182.
Kirino, T. (2002). Ischemic tolerance. J. Cereb. Blood Flow Metab. 22:1283–1296.
Krajewski, S., Krajewska, M., Ellerby, L. M., Welsh, K., Xie, Z. H., Deveraux, Q. L., Salvesen, G. S., Bredesen, D. E., Rosenthal, R. E., Fiskum, G., and Reed, J. C. (1999). Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc. Natl. Acad. Sci. U. S. A. 96:5752–5757.
Kristian, T., Gido, G., Kuroda, S., Schutz, A., and Siesjö, B. K. (1998). Calcium metabolism of focal and penumbral tissues in rats subjected to transient middle cerebral artery occlusion. Exp. Brain Res. 120:503–509.
Kuroda, S., and Siesjö, B. K. (1997). Reperfusion damage following focal ischemia—pathophysiology and therapeutic windows [review]. Clin. Neurosci. 4:199–212.
Lansberg, M. G., Thijs, V. N., O’Brien, M. W., Ali, J. O., de Crespigny, A. J., Tong, D. C., Moseley, M. E., and Albers, G. W. (2001). Evolution of apparent diffusion coefficient, diffusion-weighted, and T2-weighted signal intensity of acute stroke. Am. J. Neuroradiol. 22:637–644.
Leniger-Follert, E., and Lübbers, D. W. (1977). Regulation of microflow and behaviour of local tissue PO2 during activation and anoxia of the brain cortex. Bibl. Anat. 15:345–349.
Liebeskind, D. S. (2003). Collateral circulation. Stroke 34:2279–2284.
Lipton, P. (1999). Ischemic cell death in brain neurons [review]. Physiol. Rev. 79:1431–1568.
Lipton, S. A., and Nicotera, P. (1998). Calcium, free radicals and excitotoxins in neuronal apoptosis [review]. Cell Calcium 23:165–171.
Lust, W. D., Taylor, C., Pundik, S., Selman, W. R., and Ratcheson, R. A. (2002). Ischemic cell death: Dynamics of delayed secondary energy failure during reperfusion following focal ischemia. Metab. Brain Dis. 17:113–121.
Markus, H., and Cullinane, M. (2001). Severely impaired cerebrovascular reactivity predicts stroke and TIA risk in patients with carotid artery stenosis and occlusion. Brain 124:457–467.
Marshall, R. S., Rundek, T., Sproule, D. M., Fitzsimmons, B. F. M., Schwartz, S., and Lazar, R. M. (2003). Monitoring of cerebral vasodilatory capacity with transcranial Doppler carbon dioxide inhalation in patients with severe carotid artery disease. Stroke 34:945–949.
Mattson, M. P., Culmsee, C., and Yu, Z. F. (2000). Apoptotic and antiapoptotic mechanisms in stroke [review]. Cell Tissue Res. 301:173–187.
Memezawa, H., Smith, M. -L., and Siesjö, B. K. (1992). Penumbral tissues salvaged by reperfusion following middle cerebral artery occlusion in rats. Stroke 23:552–559.
Mies, G., Auer, L. M., Ebhardt, G., Traupe, H., and Heiss, W. -D. (1983). Flow and neuronal density in tissue surrounding chronic infarction. Stroke 14:22–27.
Mies, G., Iijima, T., and Hossmann, K. -A. (1993). Correlation between periinfarct DC shifts and ischemic neuronal damage in rat. NeuroReport 4:709–711.
Mies, G., Ishimaru, S., Xie, Y., Seo, K., and Hossmann, K. -A. (1991). Ischemic thresholds of cerebral protein synthesis and energy state following middle cerebral artery occlusion in rat. J. Cereb. Blood Flow Metab. 11:753–761.
Mies, G., Trapp, T., Kilic, E., Oláh, L., Hata, R., Hermann, D. M., and Hossmann, K. -A. (2001). Relationship between DNA fragmentation, energy state, and protein synthesis after transient focal cerebral ischemia in mice. In: Maturation Phenomenon in Cerebral Ischemia IV, Springer-Verlag, Berlin, Heidelberg, pp. 85–92.
Modo, M., Rezaie, P., Heuschling, P., Patel, S., Male, D. K., and Hodges, H. (2002). Transplantation of neural stem cells in a rat model of stroke: Assessment of short-term graft survival and acute host immunological response. Brain Res. 958:70–82.
Nagayama, M., Niwa, K., Nagayama, T., Ross, M. E., and Iadecola, C. (1999). The cyclooxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury in wild-type mice but not in mice with deletion of the inducible nitric oxide synthase gene. J. Cereb. Blood Flow Metab. 19:1213–1219.
Nedergaard, M., and Astrup, J. (1986). Infarct rim: effect of hyperglycemia on direct current potential and (14C)- deoxyglucose phosphorylation. J. Cereb. Blood Flow Metab. 6:607–615.
Nicotera, P. (2003). Molecular switches deciding the death of injured neurons. Toxicol. Sci. 74:4–9.
Norris, D. G., Hoehn-Berlage, M., Dreher, W., Kohno, K., Busch, E., and Schmitz, B. (1998). Characterization of middle cerebral artery occlusion infarct development in the rat using fast nuclear magnetic resonance proton spectroscopic imaging and diffusion-weighted imaging. J. Cereb. Blood Flow Metab. 18:749–757.
Opitz, E., and Schneider, M. (1950). Über die Sauerstoffversorgung des Gehirns und den Mechanismus der Mangelwirkungen. Ergebn. Physiol. 46:126–260.
Paschen, W. (1996). Disturbances of calcium homeostasis within the endoplasmic reticulum may contribute to the development of ischemic- cell damage. Med. Hypotheses 47:283–288.
Paschen, W. (2001). Dependence of vital cell function on endoplasmic reticulum calcium levels: implications for the mechanisms underlying neuronal cell injury in different pathological states [review]. Cell Calcium 29:1–11.
Paschen, W. (2003). Shutdown of translation: Lethal or protective? Unfolded protein response versus apoptosis. J. Cereb. Blood Flow Metab. 23:773–779.
Paschen, W., Mies, G., and Hossmann, K. -A. (1992). Threshold relationship between cerebral blood flow, glucose utilization, and energy metabolites during development of stroke in gerbils. Exp. Neurol. 117:325–333.
Prass, K., and Dirnagl, U. (1998). Glutamate antagonists in therapy of stroke [review]. Restorative Neurol. Neurosci. 13:3–10.
Prass, K., Scharff, A., Ruscher, K., Lowl, D., Muselmann, C., Victorov, I., Kapinya, K., Dirnagl, U., and Meisel, A. (2003). Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke 34:1981–1986.
Rabuffetti, M., Sciorati, C., Tarozzo, G., Clementi, E., Manfredi, A. A., and Beltramo, M. (2000). Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. J. Neurosci. 20:4398–4404.
Roitberg, B. (2004). Transplantation for stroke. Neurol. Res. 26:256–264.
Rosand, J., and Schwamm, L. H. (2001). Management of brain edema complicating stroke [review]. J. Intensive Care Med. 16:128–141.
Rosenberg, G. A. (1999). Ischemic brain edema [review]. Prog. Cardiovasc. Dis. 42:209–216.
Rothwell, N. J., and Luheshi, G. N. (2000). Interleukin I in the brain: biology, pathology and therapeutic target [review]. Trends Neurosci. 23:618–625.
Samdani, A. F., Dawson, T. M., and Dawson, V. L. (1997). Nitric oxide synthase in models of focal ischemia [review]. Stroke 28:1283–1288.
Schlaug, G., Benfield, A., Baird, A. E., Siewert, B., Lovblad, K. O., Parker, R. A., Edelman, R. R., and Warach, S. (1999). The ischemic penumbra—operationally defined by diffusion and perfusion MRI. Neurology 53:1528–1537.
Schneeloch, E., Mies, G., Busch, H. J., Buschmann, L. R., and Hossmann, K. A. (2004). Granulocyte-macrophage colony-stimulating factor-induced arteriogenesis reduces energy failure in hemodynamic stroke. Proc. Natl. Acad. Sci. U. S. A. 101:12730–12735.
Schuier, F. J., and Hossmann, K. -A. (1980). Experimental brain infarcts in cats. II. Ischemic brain edema. Stroke 11:593–601.
Seegers, H., Grillon, E., Trioullier, Y., Vath, A., Verna, J. M., and Blum, D. (2000). Nuclear factor-kappa B activation in permanent intraluminal focal cerebral ischemia in the rat. Neurosci. Lett. 288:241–245.
Selman, W. R., VanderVeer, C., Whittingham, T. S., LaManna, J. C., and Lust, W. D. (1987). Visually defined zones of focal ischemia in the rat brain. Neurosurgery 21:825–830.
Shimada, N., Graf, R., Rosner, G., and Heiss, W.-D. (1993). Ischemia-induced accumulation of extracellular amino acids in cerebral cortex, white matter, and cerebrospinal fluid. J. Neurochem. 60:66–71.
Siesjö, B. K., Elmer, E., Janelidze, S., Keep, M., Kristian, T., Ouyang, Y. B., and Uchino, H. (1999). Role and mechanisms of secondary mitochondrial failure. Curr. Prog. Understanding Sec. Brain Damage Trauma Ischemia 73:7–13.
Siesjö, B. K., and Siesjö, P. (1996). Mechanisms of secondary brain injury [review]. Eur. J. Anaesthesiol. 13:247–268.
Siren, A. L., and Ehrenreich, H. (2001). Erythropoietin—a novel concept for neuroprotection. Eur. Arch. Psych. Clin. Neurosci. 251:179–184.
Soriano, S. G., Lipton, S. A., Wang, Y. M. F., Xiao, M., Springer, T. A., Gutierrezramos, 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.
Stagliano, N. E., Perez-Pinzon, M. A., Moskowitz, M. A., and Huang, P. L. (1999). Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J. Cereb. Blood Flow Metab. 19:757–761.
Stroemer, R. P., and Rothwell, N. J. (1997). Cortical protection by localized striatal injection of IL-1ra following cerebral ischemia in the rat. J. Cereb. Blood Flow Metab. 17:597–604.
Suzuki, T., Ooto, S., Akagi, T., Amemiya, K., Igarashi, R., Mizushima, Y., and Takahashi, M. (2003). Effects of prolonged delivery of brain-derived neurotrophic factor on the fate of neural stem cells transplanted into the developing rat retina. Biochem. Biophys. Res. Commun. 309:843–847.
Symon, L., Branston, N. M., Strong, A. J., and Hope, T. D. (1977). The concepts of thresholds of ischaemia in relation to brain structure and function. J. Clin. Pathol. 30(Suppl. 11):149–154.
Takahashi, K., Pieper, A. A., Croul, S. E., Zhang, J., Snyder, S. H., and Greenberg, J. H. (1999). Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuates cerebral damage in focal ischemia. Brain Res. 829:46–54.
Tomita, M. (2005). Pathophysiology of brain edema. In: Kalimo, H. (Ed.), Cerebrovascular Diseases, ISN Neuropath, Basel, Switzerland, pp. 33–46.
Touzani, O., Boutin, H., Chuquet, J., and Rothwell, N. (1999). Potential mechanisms of interleukin-1 involvement in cerebral ischaemia. J. Neuroimmunol. 100:203–215.
Vogel, J., Hermes, A., and Kuschinsky, W. (1999). Evolution of microcirculatory disturbances after permanent middle cerebral artery occlusion in rats. J. Cereb. Blood Flow Metab. 19:1322–1328.
Wahlgren, N. G., and Ahmed, N. (2004). Neuroprotection in cerebral ischaemia: Facts and fancies. The need for new approaches. Cerebrovasc. Dis. 17:153–166.
Walz, B., Zimmermann, C., Bottger, S., and Haberl, R. L. (2002). Prognosis of patients after hemicraniectomy in malignant middle cerebral artery infarction. J. Neurol. 249:1183–1190.
Wang, X. K., and Feuerstein, G. Z. (1995). Induced expression of adhesion molecules following focal brain ischemia. J. Neurotrauma 12:825–832.
Warach, S., Gaa, J., Siewert, B., Wielopolski, P., and Edelman, R. R. (1995). Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann. Neurol. 37:231–241.
Willing, A. E., Lixian, J., Milliken, M., Poulos, S., Zigova, T., Song, S., Hart, C., Sanchez-Ramos, J., and Sanberg, P. R. (2003). Intravenous versus intrastriatal cord blood administration in a rodent model of stroke. J. Neurosci. Res. 73:296–307.
Yang, G. Y., Schielke, G. P., Gong, C., Mao, Y., Ge, H. L., Liu, X. H., and Betz, A. L. (1999). Expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 after focal cerebral ischemia in interleukin-1 beta converting enzyme deficient mice. J. Cereb. Blood Flow Metab. 19:1109–1117.
Zülch, K. -J. (1985). The Cerebral Infarct. Pathology, Pathogenesis, and Computed Tomography, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo.
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Hossmann, KA. Pathophysiology and Therapy of Experimental Stroke. Cell Mol Neurobiol 26, 1055–1081 (2006). https://doi.org/10.1007/s10571-006-9008-1
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DOI: https://doi.org/10.1007/s10571-006-9008-1