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Role of astrocytes in pathogenesis of ischemic brain injury

Abstract

Astrocytes play an important role in the homeostasis of the CNS both in normal conditions and after ischemic injury. The swelling of astrocytes is observed during and several seconds after brain ischemia. Then ischemia stimulates sequential morphological and biochemical changes in glia and induces its proliferation. Reactive astrocytes demonstrate stellate morphology, increased glial fibrillary acidic protein (GFAP) immunoreactivity, increased number of mitochondria as well as elevated enzymatic and non-enzymatic antioxidant activities. Astrocytes can re-uptake and metabolize glutamate and in this way they control its extracellular concentration. The ability of astrocytes to protect neurons against the toxic action of free radicals depends on their specific energy metabolism, high glutathione level, increased antioxidant enzyme activity (catalase, superoxide dismutase, glutathione peroxidase) and overexpression of antiapoptoticbcl-2 gene. Astrocytes produce cytokines (TNF-±, IL-1, IL-6) involved in the initiation and maintaining of immunological response in the CNS. In astrocytes, like in neurones, ischemia induces the expression of immediate early genes:c-fos, c-jun, fos B, jun B, jun D, Krox-24, NGFI-B and others. The protein products of these genes modulate the expression of different proteins, both destructive ones and those involved in the neuroprotective processes.

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Reference

  • Abel, J. and de Ruiter, N. (1989) Inhibition of hydroxyl-radical-generated DNA degradation by metallothionein.Toxicol. Lett. 47, 191–196.

    PubMed  CAS  Article  Google Scholar 

  • Aggarwal, B.B. and Natarajan, K. (1996) Tumor necrosis factor: developments during the last decade.Eur. Cytokine Netw. 7, 93–124.

    PubMed  CAS  Google Scholar 

  • Angel, P., Hattori, K., Smeal, T. and Karin, M. (1988) Thejun protooncogene is positively autoregulated by its product JUN/AP-1.Cell 55, 875–885.

    PubMed  CAS  Article  Google Scholar 

  • Aoki, C, Milner, T.A., Berger, S.B., Shea, K.F., Blass, J.P. and Pickler, V.M. (1987) Glial glutamate dehydrogenase: ultrastructural localization and regional distribution in relation to the mitochondrial enzyme, cytochrome oxidase.J. Neurosci. 18, 305–318.

    CAS  Article  Google Scholar 

  • Aoki, C, Kaneko, T., Starr A. and Pickel, V.M. (1991a) Identification of mitochondrial and non-mitochondrial glutaminase within select neurons and glia of rat fore-brain by electron microscopic immunocytochemistry.J. Neurosci. Res. 28, 531–548.

    PubMed  CAS  Article  Google Scholar 

  • Aoki, C, Semba, R., Mikoshiba, K. and Kashiwamata, S. (1991b) Predominant localization in glial cells of free L-arginine. Immunocytochemical evidence.Brain Res. 547, 190–192.

    PubMed  CAS  Article  Google Scholar 

  • Arriza, J.L., Fairman, W.A., Wadiche, J.I., Murdoch, G.H., Kavanaugh, M.P. and Amara, S.G. (1994) Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex.J. Neurosci. 14, 5559–5569.

    PubMed  CAS  Google Scholar 

  • Arriza, J.L., Eliasof, S., Kavanaugh, M.P. and Amara S.G. (1997) Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance.Proc. Natl. Acad. Sci. USA 94, 4155–4160.

    PubMed  CAS  Article  Google Scholar 

  • Aschner, M. (1998) Astrocytic functions and physiological reactions to injury: the potential to induce and /or exacerbate neuronal dysfunction. A forum position paper.Neurotoxicology 19, 7–18.

    PubMed  CAS  Google Scholar 

  • Bakken, I.J., White, L.J., Unsgard, G., Aasly, J. and Sonnenwald, U. (1998) [U-13C] glutamate metabolism in astrocytes during hypoglycemia and hypoxia.J. Neurosci. Res. 51, 656–645.

    Article  Google Scholar 

  • Ballou, L.R., Laulederkind, S.J.K., Rosloniec, E.F., Raghow, R. (1996) Ceramide signaling and the immune response.Biochim. Biophys. Acta 1301, 273–287.

    PubMed  Google Scholar 

  • Barker, J.E., Heales, S.J.R., Cassidy, A., Bolaños, J.P., Land, J.M., Clark, J.B. (1996) Depletion of brain glutathione results in decrease of glutathione reductase activity: an enzyme susceptible to oxidative damage.Brain Res. 716, 118–122.

    PubMed  CAS  Article  Google Scholar 

  • Bartosz, G. (1988) The role of reactive oxygen species in apoptosis (in Polish).Post. Bioch. 44, 22–31.

    Google Scholar 

  • Beneviste, E.N. (1993) Astrocyte-microglia interactions. In: Murphy, S. (Ed),Astrocytes: Pharmacology and Function. (San Diego, Academic Press), pp. 355–383.

    Google Scholar 

  • Benjamin, I.J., Kroger, B. and Williams, R.S. (1990) Activation of the heat shock transcription factor by hypoxia in mammalian cells.Proc. Natl. Acad. Sci. USA 87, 6263–6267.

    PubMed  CAS  Article  Google Scholar 

  • Bernardi, P. (1996) The permeability transition pore. Control points of a cyclosporin A. A sensitive mitochondrial channel involved in cell death.Biochim. Biophys. Acta 1275, 5–9.

    PubMed  Article  Google Scholar 

  • Blankelfeld, G.V., Enkvist, K. and Kettenmann H. (1995) Gamma-aminobutyric acid and glutamate receptors. In: Kettenmann, H. and Ranson, B.R. (Eds),Neuroglia, (New York, Oxford, University Press), pp. 335–345.

    Google Scholar 

  • Blaauwgeers, H.G.T., De Jong, J.M.B.V., Verspaget, H.W., Van den Berg, F.M. and Troost, D. (1996) Enhanced superoxide dismutase-2 immunoreactivity of astrocytes and occasional neurons in amyotrophic lateral sclerosis.J. Neurol. Sci. 140, 21–29.

    PubMed  CAS  Article  Google Scholar 

  • Borowsky, I.W. and Collins, R.C. (1989) Metabolic anatomy of brain: a comparison of regional capillary density, glucose metabolism and enzyme activities.J. Comp. Neurol. 288, 401–13.

    PubMed  CAS  Article  Google Scholar 

  • Bourke, R.S., Kimelberg, H.K., Daze, M. and Church G. (1983) Swelling and ion uptake in cat cerebrocortical slices: control by neurotransmitters and ion transport mechanisms.Neurochem. Res. 8, 5–24.

    PubMed  CAS  Article  Google Scholar 

  • Bossy-Wetzel, E., Bakiri, L. and Yaniv, M. (1997) Induction of apoptosis by the transcription factor c-Jun.EMBO J. 16, 1695–1709.

    PubMed  CAS  Article  Google Scholar 

  • Boyles, J.K., Pitas, R.E., Wilson, E., Mahley, R.W. and Taylor, J.M. (1985) Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system.J. Clin. Invest. 76, 1501–1513.

    PubMed  CAS  Article  Google Scholar 

  • Brainhard, J.R., Kyner, E. and Rosenberg, G.A. (1989)13C nuclear magnetic resonance evidence for y-aminobutyric acid formation via pyruvate carboxylase in rat brain: a metabolic basis for compartmentation.J. Neurochem. 53, 1285–1292.

    Article  Google Scholar 

  • Bruckner, G., Brauer, K., Hartig, W., Wolff, J.R., Rickman, M.J., Derouiche, A., Delpech, B., Girard, N., Oertel, W.H. and Reichenbach, A. (1993) Perineuronal nets provide a polyanionic glia-associated form of microenvironment around certain neurons in many parts of the rat brain.Glia 8, 183–200.

    PubMed  CAS  Article  Google Scholar 

  • Cesar, M. and Hamprecht, B. (1995) Immunocytochemical examination of neural rat and mouse primary cultures using monoclonal antibodies raised against pyruvate carboxylase.J. Neurochem. 64, 2312–2318.

    PubMed  CAS  Google Scholar 

  • Chan, P.H. (1996) Role of oxidants in ischaemia brain damage.Stroke 27, 1124–1129.

    PubMed  CAS  Google Scholar 

  • Choi, D.W. and Rothman, S.M. (1990) The role of glutamate neurotoxicity in hypoxic — ischemic neuronal death.Annu. Rev. Neurosci. 13, 171–182.

    PubMed  CAS  Article  Google Scholar 

  • Danbolt, N.C. (1994) The high affinity uptake system for excitatory amino acids in the brain.Prog. Neurobiol. 44, 377–396.

    PubMed  CAS  Article  Google Scholar 

  • Danysz, W., Frankiewicz, T. and Parsons, Ch. G. (1997) Glutamate receptors (in Polish). In: Nowak, J.Z., Zawilska, J.B. (Eds)Receptors. Their structure, characteristic, function. (Warszawa, Wydawnictwo Naukowe PWN) pp. 161–189.

    Google Scholar 

  • Dawson, T.M. (1992) A novel neuronal messenger molecule in brain: The free radical, nitric oxide.Ann. Neurol. 32, 297–311.

    PubMed  CAS  Article  Google Scholar 

  • Dell’Albani, P., Condorelli, D.F., Mudo, G., Amico, C, Bindoni, M. and Belluardo, N. (1993) Plateled-activating factor and its methoxy-analogue ET-18-OCH3 stimulate immediate early gene expression in rat astroglial cultures.Neurochem. Int. 22, 564–574.

    Google Scholar 

  • Dringen, R., Schmoll, D., Cesar, M. and Hamprecht B. (1993) Incorporation of radioactivity from C lactate into the glycogen of cultured mouse astroglial cells: Evidence for gluconeogenesis in brain cells.Biol.-Chem. Hoppe-Seyler 374, 343–347.

    PubMed  CAS  Google Scholar 

  • Eberhard, D.A., Brown, M.D. and Van den Berg, SR. (1994) Alternations of annexin in pathological neuronal and glial reactions: Immunohistochemical localization of annexin I, II (p36 and p11 subunits), IV, and VI in the human hippocampus.Am. J. Pathol. 145, 640.

    PubMed  CAS  Google Scholar 

  • Eddleston, M. and Mucke L. (1993) Molecular profile of reactive astrocytes-implications for their role in neurologic disease.Neuroscience 54, 15–36.

    PubMed  CAS  Article  Google Scholar 

  • Eliasson, M.J.L., Sampei, K., Mandrin, A.S., Hum, P.D., Traytsman, R.J., Bao, J., Pieper, A., Wang, Z., Dawson, T.M., Snyder, S.H. and Dawson, V.L. (1997) Poly (ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia.Nature Med. 3, 1089–1095.

    PubMed  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  • Erb, P., Kennedy, M., Hagmann, I., Wassmer, P., Huegli, G., Fierz, W. and Fontana, A. (1996) Accessory cells and activation and expression of different T cell functions, (Clifton, Humana Press).

    Google Scholar 

  • Fairman, W.A., Vandenberg, R.J., Arriza, J.L., Kavanaugh, M.P. and Amara, S.G. (1995) An excitatory amino acid transporter with properties of a ligand-gated chloride channel.Nature 375, 599–603.

    PubMed  CAS  Article  Google Scholar 

  • Faris, M., Kokot, N., Latinis, K., Kasibhatla, S., Green, D.R., Koretzky, G.A. and Nel A. (1998) The c-Jun N-terminal kinase cascade plays a role in stress-induced apoptosis in Jurkat cells by up-regulating Fas ligand expression.J. Immunol. 160, 134–144.

    PubMed  CAS  Google Scholar 

  • Feinstein, D.L., Galea, E., Aquino, D.A., Li, G.C., Xu, H. and Reis D.J. (1996) Heat shock protein 70 suppress astroglial iNOS expression by decreasing NFkB activation.J. Biol. Chem. 271, 17724–17732.

    PubMed  CAS  Article  Google Scholar 

  • Feuerstein, G.Z., Wang, X. and Barone, F.C. (1997) Inflammatory gene expression in cerebral ischemia and trauma.Ann. N.Y. Acad. Sci. 825, 179–193.

    PubMed  CAS  Article  Google Scholar 

  • Fontana, A., Frei, K., Bodmer, S. and Hofer, E. (1987) Immune-mediated encephalitis: On the role of antigen presenting cells in brain tissue.Immunol. Rev. 100, 185–201.

    PubMed  CAS  Article  Google Scholar 

  • Forstermann, U., Boissel, J.P. and Kleinert, H. (1998) Expressional control of the “constitutive” isoforms of nitric oxide synthase (NOS I and NOS III).FASEB J. 12, 773–790.

    PubMed  CAS  Google Scholar 

  • Forstermann, U. and Kleinert, H. (1995) Nitric oxide synthase: expression and expressional control of the three isoforms.Naunyn-Schmiedebergs Arch. Pharmacol. 352, 351–364.

    PubMed  CAS  Google Scholar 

  • Forstermann, U., Kleinert, H., Gath, I., Schwarz, P., Closs, E.I. and Dun, N.J. (1995) Expression and expressional control of nitric oxide synthases in various cell types.Adv. Pharmacol. 34, 171–186.

    PubMed  CAS  Article  Google Scholar 

  • Frohman, E.M., Frohman, T.C., Dustin, M.L., Vayuvegula, B., Choi, B., Gupta, A., Van den Noort, S. and Gupta, S. (1989) The induction of intracellular adhesion molecule 1 (ICAM-1) expression on human fetal astrocytes by interferon-y, tumor necrosis factor-a, lyphotoxin, and interleukin-1: Relevance to intracerebral antigen presentation.J. Neuroimmunol. 23, 117–124.

    PubMed  CAS  Article  Google Scholar 

  • Gegelashvili, G., Civenni, G., Racagni, G., Danbolt, N.C, Schousboe, I. and Schousboe, A. (1996) Glutamate receptor agonist up-regulate glutamate transporter GLAST in astrocytes.NeuroReport 8, 261–265.

    PubMed  CAS  Article  Google Scholar 

  • Greenlund, L.J., Korsmeyer, S.J. and Johnson, E.M. (1995) Role of BCL-2 in the survival and function of developing and mature sympathetic neurones.Neuron 15, 649–661.

    PubMed  CAS  Article  Google Scholar 

  • Grutter, M.G., van Oostrum, J. and Priestle, J.P. (1994) A mutational analysis of receptor binding sites of inter-leukin-ip: differences in binding of human inter-leukin-ip muteins to human and mouse receptors.Protein Eng. 7, 663–671.

    PubMed  CAS  Article  Google Scholar 

  • Hall, E.D. (1993) Cerebral ischaemic, free radicals and antioxidant protection.Biochem. Soc. Trans. 21, 334–339.

    PubMed  CAS  Google Scholar 

  • Halliwell, B. (1992) Reactive oxygen species and the central nervous system.J. Neurochem. 59, 1609–1623.

    PubMed  CAS  Article  Google Scholar 

  • Harold, D. and Waltz, W. (1992) Metabolic inhibition and electrical properties of type-1-like astrocytes.Neuroscience 47, 203–211.

    PubMed  CAS  Article  Google Scholar 

  • He, L. and Fox, M.H. (1996) Comparison of flow cytometry and western blotting to measure Hsp 70.Cytometry 25, 280–286.

    PubMed  CAS  Article  Google Scholar 

  • Herdegen, T., Claret, F.X., Kallunki, T., Martin-Villaba, A., Winter, C, Hunter, T. and Karin, M. (1998) Lasting N-terminal phosphorylation of c-Jun and activation of JNK/SAPK kinases following neuronal injury.J. Neurosci. 18, 5124–5135.

    PubMed  CAS  Google Scholar 

  • Hertz, L. and Schousboe, A. (1988) Metabolism of glutamate and glutamine in neurons and astrocytes in primary cultures. In: Kuamme, E. (Ed)Glutamine and glutamate in mammals (Boca Raton, CRC Press), pp. 39–55.

    Google Scholar 

  • Hertz, L. (1990) Regulation of potassium homeostasis by glial cells. In: Levi, G. (Ed)Development and function of glial cells (New York, Wiley-Liss), pp. 225–234.

    Google Scholar 

  • Hertz, L. and Peng, L. (1992) Energy metabolism at the cellular level of the CNS.Can. J. Phys. Pharmacol. 70, 145–157.

    Google Scholar 

  • Hibi, M., Lin, A., Smeal, T., Minden, A. and Karin, M. (1993) Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentates the c-Jun activation domain.Genes Dev. 7, 2135–2148.

    PubMed  CAS  Article  Google Scholar 

  • Hossain, M.Z., Peeling, J., Sutherland, G.R., Hertzberg, E.L. and Nagy J.I. (1994) Ischemia-induced cellular redistribution of the astrocytic gap junctional protein connexin43 in rat brain.Brain Res. 652, 311–322.

    PubMed  CAS  Article  Google Scholar 

  • Hossmann, K.A. (1994) Glutamate-mediated injury in focal cerebral ischemia: the excitotoxin hypothesis revised.Brain Pathol. 4, 23–36.

    PubMed  CAS  Google Scholar 

  • Huang, R., Peng, L., Chen, Y., Hayek, I., Zhao, Z. and Hertz, L. (1994) Signalling effect of monoamines and of elevated potassium concentrations on brain energy metabolism at the cellular level.Dev. Neurosci. 16, 337–351.

    PubMed  CAS  Article  Google Scholar 

  • Huang, R. and Hertz, L. (1994) Effect of anoxia on glutamate formation from glutamine in cultured neurons: dependence on neuronal subtype.Brain Res. 660, 129–137.

    PubMed  CAS  Article  Google Scholar 

  • Iadecola, C, Zhang, F. and Xu, S. (1995) Inducible nitric oxide synthase gene expression in brain following cerebral ischaemia.J. Cereb. Blood Flow Metab. 15, 378–384.

    PubMed  CAS  Google Scholar 

  • Iadecola, C. (1997) Bright and dark sides of nitric oxide in ischemic brain injury.Trends Neurosci. 20, 132–139.

    PubMed  CAS  Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Jackson, G.R., Apffel, L., Werrbach-Perez, K. and Perez-Polo, J.R. (1990) Role of nerve growth factor in oxidant-antioxidant balance and neuronal injury. I. Stimulation of hydrogen peroxide resistance.J. Neurosci. Res. 25, 360–368.

    PubMed  CAS  Article  Google Scholar 

  • Jaworska-Adamu, J., Cybulska, R. and Wawrzyniak-Gacek, A. (1993) The contribution of astrocytes to neuronal microenvironment regulation (in Polish).Post. Biol. Kom. 20, 355–362.

    Google Scholar 

  • Jedrzejczak, W.W. and Kruszewski A. (1997) Cytokine receptors (in Polish). In: Nowak, J.Z., Zawilska, J.B. (Eds) Receptors.Their structure, characteristic, function. (Warszawa, Wydawnictwo Naukowe PWN) pp. 255–273.

    Google Scholar 

  • Kader, A., Frazzini, V.I. and Solomon, R.A. (1993) Nitric oxide production during focal cerebral ischemia in rats.Stroke 24, 1709–1716.

    PubMed  CAS  Google Scholar 

  • Kallunki, T., Deng, T.L., Hibi, M. and Karin, M. (1996) c-Jun can recruit JNK to phosphorylate dimerization partners via specific docking interactions.Cell 87, 929–939.

    PubMed  CAS  Article  Google Scholar 

  • Kanai, Y. and Hediger, M.A. (1992) Primary structure and functional characterisation of a high-affinity glutamate transporter.Nature 360, 467–471.

    PubMed  CAS  Article  Google Scholar 

  • Kanai, Y., Trotti, D., Nussberger, S. and Hediger M.A. (1997) The high- affinity glutamate transporter family. In: Reith, M.E.A. (Ed)Neurotransmitter Transporters: Structure, Function and Regulation (Totowa, NJ: Humana Press), pp. 171–213.

    Google Scholar 

  • Kim, J.S. (1996) Cytokines and adhesion molecules in stroke and related diseases.J. Neurol. Sci. 137, 69–78.

    PubMed  CAS  Article  Google Scholar 

  • Knight, R. and Buxton, D.B. (1996) Stimulation of c-JUN kinase and mitogen activated protein kinase by ischemia and reperfusion in the perfused rat heart.Biochem. Biophys. Res. Commun. 218, 83–88.

    PubMed  CAS  Article  Google Scholar 

  • Kostyk, S.K., Kowall, N.W. and Hause, S.L. (1989) Substance P immunoreactive astrocytes are present in multiple sclerosis plaques.Brain Res. 504: 289–232.

    Article  Google Scholar 

  • Kraemer, B., Wiegmann, K. and Kronke, M. (1995) Regulation of the human TNF promoter by the transcription factor Ets.J. Biol. Chem. 270, 6577–6583.

    CAS  Article  Google Scholar 

  • Kraig, R.P. and Chesler, M. (1990) Astrocytic acidosis in hyperglycemic and complete ischemia.J. Cereb. Blood Flow Metab. 10, 104–114.

    PubMed  CAS  Google Scholar 

  • Kyriakis, J.M., Banerjee, P., Nikolakaki, E., Dai, T., Rubie, E.A., Ahmad, M., Avruch, J. and Woodgett, R.J. (1994) The stress-activated protein kinase subfamily of c-Jun kinases.Nature 369, 156–160.

    PubMed  CAS  Article  Google Scholar 

  • Labriola-Tomkins, E., Chandran, C. and Varnell, T.A. Structure-function analysis of human IL-la: identification of residues required for binding to the human type I IL-1 receptor.Protein Eng. 6, 535–539.

  • Lason, W. (1997) Gene expression as a result of ligand-receptor interaction (in Polish). In: Nowak, J.Z., Zawilska, J.B. (Eds)Receptors. Their structure, characteristic, function. (Warszawa, Wydawnictwo Naukowe PWN) pp. 358–369.

    Google Scholar 

  • Lazo, J.S., Kondo, Y., Dellapiazza, D., Michalska, A.E., Choo, K.H.A. and Pitt, B.R. (1995) Enhanced sensitivity to oxidative stress in cultured embryonic cells from transgenic mice deficient in metallothionein I and II genes.J. Biol. Chem. 270, 5506–5510.

    PubMed  CAS  Article  Google Scholar 

  • Lee, K.S., Tetzlaff, W. and Kreutzberg, G.W. (1986) Rapid down regulation of hippocampal adenosine receptors following brief anoxia.Brain Res. 380, 155–158.

    PubMed  CAS  Article  Google Scholar 

  • Lin, H.L. and Murphy, S. (1997) Regulation of astrocyte nitric oxide synthase type II. Expression by ATP and glutamate involves loss of transcription factor binding to DNA.J. Neurochem. 69, 612–616.

    PubMed  CAS  Google Scholar 

  • Lin, L-L., Wartmann, M., Lin, A.Y., Knopf, J.L., Seth, A. and Davis, R.J. (1993) cPLA2 is phosphorylated and activated by MAP kinase.Cell 72, 269–278.

    PubMed  CAS  Article  Google Scholar 

  • Lipton, S.A., Choi, Y.B., Pan, Z.H., Lei, S.Z., Chen, H.S.V., Sueher, N.J., Loscalzo, J., Singel, D.I. and Stamler, J.S. (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds.Nature 364, 626–632.

    PubMed  CAS  Article  Google Scholar 

  • Liu, X-H., Kato, H., Nakata, N., Kogure, K., Kato, K. (1993) An immunohistochemical study of copper/zinc superoxide dismutase in rat hippocampus after transient cerebral ischemia.Brain Res. 625, 29–37.

    PubMed  CAS  Article  Google Scholar 

  • Liu, X., Kim, C.N., Yang, J., Jemmerson, R., and Wang, X. (1996) Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c.Cell 86, 147–157.

    PubMed  CAS  Article  Google Scholar 

  • Lazarewicz, J.W. (1992) Excitotoxic action of the excitory aminoacid neurotransmitters in brain: their role in ischemic neuron injury (in Polish). In: Pile, A. (Ed)Excitatory amino acids. IX Winter School organized by Institute of Pharmacology Polish Academy of Science (Liszki, Platan), pp. 65–74.

    Google Scholar 

  • Martin, D.L. (1992) Synthesis and release of neuroactive substances by glial cells.Glia 5, 81–94.

    PubMed  CAS  Article  Google Scholar 

  • Martin-Villaba, A., Herr, I., Jeremias, I., Hahne, M, Brandt, R., Vogel, J., Schenkel, J., Herdegen, T. and Debatin, K.M. (1999) CD95 ligand (Fas-L/Apo-IL) and Tumor Necrosis Factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons.J. Neurosci. 19, 3809–3817.

    Google Scholar 

  • Mattson, M.P., Goodman, Y., Luo, H., Wieming, F. and Furu-kawa, K. (1997) Activation of NF-kB protects hippocampal neurons against oxidative stress-induced apoptosis: Evidence for induction of superoxide dismutase and suppresion of peroxynitrite production and protein tyrosine nitration.J. Neurosci. Res. 49, 681–697.

    PubMed  CAS  Article  Google Scholar 

  • Mizuno, M. and Yoshida, J. (1996) Tumor necrosis factor-alfa gene transfer augmets anti-Fas antibody-mediated apoptosis in human glioma cells.Jpn. J. Cancer Res. 87, 543–547.

    PubMed  CAS  Google Scholar 

  • Morley, P., Hogan, M.J. and Hakim, A.M. (1994) Calcium-mediated mechanisms of ischemic injury and protection.Brain Pathol. 4, 37–47.

    PubMed  CAS  Article  Google Scholar 

  • Mucke, L. and Eddleston, M. (1993) Astrocytes in infections and immune-mediated diseases of the central nervous system.FASEB J. 7, 1226–1232.

    PubMed  CAS  Google Scholar 

  • Nakai, A., Tanabe, M., Kawazoe, Y., Inazawa, J., Morimoto, R.I. and Nagata, K. (1997) HSF4, a new member of the human heat shock factor family which lacks properties of a transcriptional activator.Mol. Cell Biol. 17, 469–481.

    PubMed  CAS  Google Scholar 

  • Norenberg, M.D. (1996) Reactive astrocytosis. In: Aschner, M., Kimelberg, H.K.K. (Eds.)The role of glia in neurotoxicity (Boca Raton, CRC Press), pp. 93–107.

    Google Scholar 

  • Obeid, L.M., Linardic, CM., Karolak, L.A. and Hannun, Y. (1993) Programmed cell death induced by ceramide.Science 259, 1769–1771.

    PubMed  CAS  Article  Google Scholar 

  • Onodera, H. and Kogure, K. (1990) Calcium antagonist, adenosine Al, and muscarinic bindings in rat hippocampus after transient ischemia.Stroke 21, 771–776.

    PubMed  CAS  Google Scholar 

  • Orita, T., Akimura, T., Nishizaki, T., Kamiryo, T., Ikeyama, Y., Aoki, H. and Ito, H. (1990) Transferrin receptors in injured brain.Acta Neuropath. 79, 686–688.

    PubMed  CAS  Article  Google Scholar 

  • Ou-Yang, Y.B., Kristian, T., Mellergard, P. and Sjesjo, B.K. (1994) The influence of pH on glutamate- and depolarisation-induced increases of intracellular calcium concentration in cortical neurones in primary culture.Brain Res. 646, 65–72.

    PubMed  CAS  Article  Google Scholar 

  • Park, S.K., Lin, H.L. and Murphy, S. (1997) Nitric oxide regulates nitric oxide synthase-2 gene expression by inhibiting NF-kB binding to DNA.Biochem. J. 322, 609–613.

    PubMed  CAS  Google Scholar 

  • Pascual, J.M., Carceller, F., Roda, J.M. and Cerdan, S. (1998) Glutamate, glutamine and GABA as substrates for the neuronal and glial compartments after focal cerebral ischemia in rats.Stroke 29, 1048–1057.

    PubMed  CAS  Google Scholar 

  • Peng, L., Schousboe, A. and Hertz, L. (1991) Utilization of a-ketoglutarate as a precursor for transmitter glutamate in cultured cerebellar granule cells.Neurochem Res. 16, 29–34.

    PubMed  CAS  Article  Google Scholar 

  • Peng, H. Libby, P. and Liao, J.K. (1995) Induction and stabilization of IkBα by nitric oxide mediates inhibition of NF-kB.J. Biol. Chem. 270, 14214–14219.

    PubMed  CAS  Article  Google Scholar 

  • Petito, C.K. (1986) Transformation of perineuronal glial cells. 1. Electron microscopic studies.J. Cell Blood Flow Metabol. 6, 616–624.

    CAS  Google Scholar 

  • Pines, G., Danbolt, N.C., Bjoras, M., Zhang, Y., Bendahan, A., Eide, L., Koepsell, H., Storm-Matisen, J., Seeberg, E. and Kanner, B.I. (1992) Cloning and expression of rat brain L-glutamate transporter.Nature 360, 464–467.

    PubMed  CAS  Article  Google Scholar 

  • Posada, J. and Cooper, J.A. (1992) Molecular signal integration: interplay between serine, threonine and tyrosine phosphorylation.Mol. Cell Biol. 3, 583–592.

    CAS  Google Scholar 

  • Queiroz, G., Meyer, D.K., Meyer, A., Starke, K. and Von Kügelgen, I. (1999) A study of the mechanism of release of ATP from rat cortical astroglial cells evoked by activation of glutamate receptors.Neuroscience 91, 1171–1181.

    PubMed  CAS  Article  Google Scholar 

  • Radi, R., Beckman, J.S., Bush, K.M. and Freeman, B.A. (1991) Peroxynitrite oxidation of sulphydryls. The cytotoxic potential of superoxide and nitric oxide.J. Biol. Chem. 266, 4244–4250.

    PubMed  CAS  Google Scholar 

  • Raichle, M.E. (1983) The pathophysiology of brain ischemia.Ann. Neurol. 13, 2–10.

    PubMed  CAS  Article  Google Scholar 

  • Relton, J.K. and Rothwell, N.J. (1992) Interleukin-1 receptor antagonists inhibits ischaemic and excitotoxic neuronal damage in the rat.Brain Res. Bull. 29, 243–246.

    PubMed  CAS  Article  Google Scholar 

  • Reyes, J.G., Robayna, I.G., Delgado, P.S., Gonzales, I.H., Aguiar, J.Q., Rosas, F.E., Fanjul, L.F. and De Galarreta, C.M.R. (1996) c-Jun is a downstream target for ceramide-acivated protein phosphatase in A431 cells.J. Biol. Chem. 271, 21375–21380.

    PubMed  CAS  Article  Google Scholar 

  • Robinson, M.B. and Dowd, L.A. (1997) Heterogeneity and functional properties of subtypes of sodium-dependent glutamate transporters in the mammalian central nervous system.Adv. Pharmacol. 37, 69–115.

    PubMed  CAS  Article  Google Scholar 

  • Rothstein, J.D., Martin, L., Levey, A.I., Dykes-Hoberg, M., Jin, L., Wu, D., Nash, N. and Kuncl, R.W. (1994) Localisation of neuronal and glial glutamate transporters.Neuron 13, 713–725.

    PubMed  CAS  Article  Google Scholar 

  • Rothwell, N.J. and Relton, J.K. (1993) Involvement of cytokines in acute neurodegeneration of the CNS.Neurosci. Behav. Rev. 17, 217–227.

    CAS  Google Scholar 

  • Rutter, G.A., Theler, J.M., Murgia, M., Wollheim, C.B., Pozzan, T. and Rizzuto, R. (1993) Stimulated Ca+2 influx raises mitochondrial free Ca to supramicromolar levels in a pancreatic β-cell line. Possible role in glucose and agonist-induced insulin secretion.J. Biol. Chem. 268, 22385–22390.

    PubMed  CAS  Google Scholar 

  • Sabala, P. (1997) Purynergic receptors (in Polish). In: Nowak, J.Z., Zawilska, J.B. (Eds)Receptors. Their structure, characteristic, function. (Warszawa, Wydawnictwo Naukowe PWN) pp. 211–223.

    Google Scholar 

  • Sagara, J., Miura, K. and Bannai, S. (1993) Maintenance of neuronal glutathione by glial cells.J. Neurochem. 61, 1672–1676.

    PubMed  CAS  Article  Google Scholar 

  • Saluja, I., Song, D., O’Regan, M.H. and Phillis, J.W. (1997) Role of phospholipase A2 in the release of free fatty acids during ischemia-reperfusion in the rat cerebral cortex.Neurosci. Lett. 233, 97–100.

    PubMed  CAS  Article  Google Scholar 

  • Sato, M. and Bremner, I. (1993) Oxygen free radicals and metallothionein.Free Radical Biol. Med. 14, 325–337.

    CAS  Article  Google Scholar 

  • Schinder, A.F., Olson, E.C., Spitzer, N.C. and Montal, M. (1996) Mitochondrial dysfunction is a primary event in glutamate neurotoxicity.J. Neurosci. 16, 6125–6133.

    PubMed  CAS  Google Scholar 

  • Schmoll, D., Fuhrmann, E., Gebhard, R. and Hamprech, B. (1995) Significant amounts of glycogen are synthesized from 3-carbon compounds in astroglial primary cultures from mice with participation of the mitochondrial phos-phoenolopyruvate carboxykinase i isoenzyme.Eur. J. Biochem. 227, 308–315.

    PubMed  CAS  Article  Google Scholar 

  • Schwartz, M.A., Lazo, J.S., Yalowich, J.C., Allen, W.P., Whitmore, M, Bergonia, H.A., Tzeng, E., Billar, T.R., Robbits, P.D. and Lancaster, J.R. (1995) Metallothionein protects against the cytotoxic and DNA-damaging effects of nitric oxide.Proc. Natl. Acad. Sci. 92, 4452–4456.

    Article  Google Scholar 

  • Schwiebert, E.M., Egan, M.E., Hwang, T., Fulmer, S.B., Allen, S.S., Cutting, G.R. and Guggino, W.B. (1995) CFRT regulates outwardly rectifying chloride channels through an autocrine mechanism involving ATP.Cell 81, 1063–1073.

    PubMed  CAS  Article  Google Scholar 

  • Selmaj, K.W., Farooq, M., Norton, W.T., Raine, C.S. and Brosnan, C.F. (1990) Proliferation of astrocytes in vitro in response to cytokines. A primary role for tumor necrosis factor.J. Immunol. 144, 129–135.

    PubMed  CAS  Google Scholar 

  • Shank, R.P., Bennet, G.S., Freytag, S.D. and Campbell, G.L. (1985) Pyruvate carboxylase: an astrocyte-specific enzyme implicated in the replenishment of amino acid neurotransmitter pools.Brain Res. 29, 364–367.

    Article  Google Scholar 

  • Siesjo, B.K. and Bengtsson, F. (1989) Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia and spreading depression: a unifying hypothesis.J. Cereb. Blood Flow Metab. 9, 127–140.

    PubMed  CAS  Google Scholar 

  • Sochocka, E., Juurlink, B.H.J., Code, W.E., Hertz, V., Peng, L. and Hertz, L. (1994) Cell death in primary cultures of mouse neurons and astrocytes during exposure and recovery from hypoxia, substrate deprivation and simulated ischemia.Brain Res. 638, 21–28.

    PubMed  CAS  Article  Google Scholar 

  • Storck, T., Schulte, S., Hofmann, K. and Stoffel, W. (1992) Structure, expression and functional analysis of Na+-dependent glutamate/aspartate transporter from rat brain.Proc. Natl. Acad. Sci. USA 89, 10955–10959.

    PubMed  CAS  Article  Google Scholar 

  • Susin, S.A., Zamzani, N., Castedo, M., Daugas, E., Wang, H.G., Geley, S., Fassy, F., Reed, J.C. and Kroemer, G. (1997) The central executioner of apoptosis: multiple connections between protease activation and mitochondria in Fas/APO-l/CD95 and ceramide-induced apoptosis.J. Exp. Med. 186, 25–37.

    PubMed  CAS  Article  Google Scholar 

  • Suzuki, K., Nakajima, K., Kawaharada, U., Uehara, U., Hara, F., Otaki, N., Kimura, M. and Tamura, Y. (1992) Metallothionein in the human brain.Acta Histochem. Cytochem. 25, 617–622.

    CAS  Google Scholar 

  • Sweeney, M.I., Yager, J.Y., Walz, W. and Juurlink, B.H.J. (1995) Cellular mechanisms involved in brain ischemia.Can. J. Physiol. Pharmacol. 73, 1525–1535.

    PubMed  CAS  Google Scholar 

  • Sweeney, M.I. (1995) Both adenosine release and uptake in neurones occur via a nucleoside transporter modulated by G-proteins. Proceedings of the 38 Meeting of the Canadian Federation of Biological Societes. June 14–17, Saskatoon,Sask Abstr. 087.

  • Sweeney, M.I. and Logan, M. (1995) Endogenous adenosine protects neurons, but not astrocytes, from hypoxic death. Proceedings of the 38th Meeting of the Canadian Federation of Biological Societes. June 14–17, Saskatoon,Sask. Abstr. 088.

  • Szczudlik, A. (1999) Phathophysiology of ischemic stroke (in Polish). In: Prusi’nski, A., Domzaf, T.M., Kozubski, W., Szczudlik A. (Eds)Ischemic brain strokes (Bielsko-Biafa, a-medica press), pp. 58–85.

    Google Scholar 

  • Takizawa, S., Matsushima, K., Shinohara, Y., Komatsu, N., Utsunomiya, H. and Watanabe, K. (1994) Immunohisto-chemical localization of glutathione peroxidase in infracted human brain.J. Neurol. Sci. 122, 66–73.

    PubMed  CAS  Article  Google Scholar 

  • Tansey, F.A., Farooq, M. and Cammer, W. (1991) Glutamine synthetase in oligodendrocytes and astrocytes: New biochemical and immunocytochemical evidence.J. Neurochem. 56, 266–272.

    PubMed  CAS  Article  Google Scholar 

  • Tombaugh, G.C. and Sapolsky, R.M. (1993) Evolving concepts about the role of acidosis in ischemic neuropathology.J. Neurochem. 61, 793–803.

    PubMed  CAS  Article  Google Scholar 

  • Torp, R., Lekieffre, D., Levy, L.M., Haug, F.M., Danbolt, N.C., Meldrum, B.S. and Ottersen, O.P. (1995) Reduced postischemic expression of a glial glutamate transporter, GLT-1, in the rat hippocampus.Brain Res. 103, 51–58.

    CAS  Google Scholar 

  • Traystman, R.J, Kirch, J.R. and Koehler, R.C. (1991) Oxygen radical mechanism of brain injury following ischemia and reperfusion.J. Appl. Physiol. 71, 1185–1195.

    PubMed  CAS  Google Scholar 

  • Tymianski, M. (1996) Cytosolic calcium concentrations and cell death in vitro.Adv. Neurol. 71, 85–105.

    PubMed  CAS  Google Scholar 

  • Umemura, A., Mabe, H., Nagai, H. and Sugino, F. (1992) Action of phospholipases A2 and C on free fatty acid release during complete ischemia in rat neocortex. Effect of phospholipase C inhibitor and N-methyl-D-aspartate antagonist.J. Neurosurg. 76, 648–651.

    PubMed  CAS  Article  Google Scholar 

  • Van Bockstaele, E.J. and Colago, E.E.O. (1996) Selective distribution of the NMDA-R1 glutamate receptor in astrocytes and presynaptic axon terminals in the nucleus locus-coeruleus of the rat brain-an immunoelectron microscopic study.J. Comp. Neurol. 369, 483–496.

    PubMed  Article  Google Scholar 

  • Vanella, A., Avola, D.F., Condorelli, A., Campisi, A., Costa, A., Giufrida, A.M. and Perez-Polo, J.R. (1989) Atioxidant enzymatic resistance to oxidative stress in primary and subcultured rat astroglial cells.Int. J. Dev. Neurosci. 7, 233–241.

    PubMed  CAS  Article  Google Scholar 

  • Viviani, B., Marinovich, M. (1998) Neurotoxicity: an active role for glia?Neurosci. Res. Comm. 23, 1–12.

    CAS  Article  Google Scholar 

  • Volterra, A., Trotti, D., Cassutti, P., Tromba, C, Galimberti, R., Lecchi, P., Racagni, G. (1992) A role for the arachi-donic cascade in fast synaptic modulation: ion channels and transmitter uptake systems as target proteins.Adv. Exp. Med. Biol. 318, 147–158.

    PubMed  CAS  Google Scholar 

  • von Ktigelgen, I., Allgaier, C, Schobert, A. and Starke, K. (1994) Co-release of noradrenaline and ATP from cultured sympathetic neurons.Neuroscience 61, 199–202.

    Article  Google Scholar 

  • Walz, W., Klimaszewski, A. and Paterson, I.A. (1993) Glial swelling in ischemia: a hypothesis.Dev. Neurosci. 15, 216–225.

    PubMed  CAS  Article  Google Scholar 

  • Watson, A., Eilers, A., Lallemand, D., Kyriakis, J., Rubin, L.L. and Ham, J. (1998) Phophorylation of c-Jun is necessary for apoptosis induced by survival signal withdrawal in cerebellar granule neurons.J. Neurosci. 18, 751–762.

    PubMed  CAS  Google Scholar 

  • Wcisfo, G. and Szczyklik, C. (1997) Tumor necrosis factor (in Polish). In: Jcedrzejczak, W.W., Podolak-Dawidziak, M (Eds)Cytokines. Clinical application (Wroclaw, Volumed), pp. 187–198.

    Google Scholar 

  • Wurdig, S. and Kugler, P. (1991) Histochemistry of glutamate metabolizing enzymes in the rat cerebellar cortex.Neurosci. Lett. 130, 165–168.

    PubMed  CAS  Article  Google Scholar 

  • Yamasaki, Y., Itoyama, Y. and Kogure, K. (1996) Involvement of cytokine production in the pathogenesis of transient cerebral ischemic damage.Proceedings of the International Symposium “Ischemia, cytokines and cellular mobilization in the brain”. Tokyo, pp. 225–229.

  • Young, J.K., Garvey, J.S. and Huang, P.C. (1991) Glial immu-noreactivity for metallothionein in the rat brain.Glia 4: 602–610.

    PubMed  CAS  Article  Google Scholar 

  • Young, J.K. (1994) Glial metallothionein.Biol. Signals 3, 169–175.

    PubMed  CAS  Article  Google Scholar 

  • Yudkoff, M., Nissim, I., Hummeler, K., Medow, M. and Pleasure, D. (1986) Utilization of [15N] glutamate by cultured astrocytes.Biochem J. 234, 185–192.

    PubMed  CAS  Google Scholar 

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Correspondence to Bozena Gabryel.

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Gabryel, B., Trzeciak, H.I. Role of astrocytes in pathogenesis of ischemic brain injury. neurotox res 3, 205–221 (2001). https://doi.org/10.1007/BF03033192

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Keywords

  • Astrocytes
  • Ischemia
  • Energy metabolism
  • Glutamate
  • Adenosine
  • Calcium
  • Immediate early genes
  • Cytokines