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Almitrine prevents some hypoxia-induced metabolic injury in rat astrocytes

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Molecular and Chemical Neuropathology

Abstract

During reperfusion of ischemic brain tissue, the production of reactive oxygen species initiates several modifications of the astroglial functional and ultrastructural integrity. During 24 h after ischemic treatment, modification of cellular superoxide free radical scavenging systems have been observed in primary culture of rat astroglial cell. Mitochondrial Mn superoxide dismutase activity (Mn-SOD) gradually decreases, whereas that of the cytosolic Cu,Zn form of the enzyme remains unaffected. We observed in parallel a significant decrease of glutamine synthetase (GS), an astrocyte specifically located enzyme. Addition of almitrine (dialylamine-4′,6′-triazinyl 2′)-l-(bis-parafluorobenzydryl)-4-piperazine or dibucaine (a phospholipase A2 inhibitor) antagonizes the decrease of Mn-SOD activity, but does not affect modification of GS activity. Combined effects are observed by simultaneous addition of both drugs. Our data demonstrate that almitrine may increase the synthesis of some mitochondrial proteins, like Mn-SOD, and provide support for further study on the therapeutic potential of almitrine in ischemic astroglial cell injury.

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References

  • Akai F., Maeda M., Suzuki K., Inagaki S., Takagi H., and Taniguchi N. (1990) Immunocytochemical localization of manganese superoxide dismutase (Mn+ +-SOD) in the hippocampus of the rat.Neurosci. Lett. 115, 19–23.

    Article  PubMed  CAS  Google Scholar 

  • Armstead W. M., Mirro R., Busija D. W., and Leffler C. W. (1988) Postischemic generation of superoxide anion by newborn pig brain.Am. J. Physiol. 255, H401-H403.

    PubMed  CAS  Google Scholar 

  • Arrigoni E. and Cohadon F. (1991) Calcium activated neutral protease activities in brain trauma.Neurochem. Res. 16, 483–487.

    Article  PubMed  CAS  Google Scholar 

  • Benzi G. O., Pastoris O., Villa R. F., and Giuffrida A. A. (1985) Influence of aging and exogenous substances on cerebral energy metabolism in post-hypoglycemic recovery.Biochem. Pharmacol. 34, 1477–1485.

    Article  PubMed  CAS  Google Scholar 

  • Benzi G., Pastoris O., Marzatico F., and Dagani F. (1990) Influence of aging and drug treatment on the bioenergetics of hypoxic brain.Neurochem. Res. 15, 659–665.

    Article  PubMed  CAS  Google Scholar 

  • Benzi G., Curti D., Pastoris O., Marzatico F., Villa R. F., and Dagani F. (1991) Sequential damage in mitochondrial complexes by peroxidative stress.Neurochem. Res. 16, 1295–1302.

    Article  PubMed  CAS  Google Scholar 

  • Borzeix M. G. and Caun J. (1987) Experimental approach of treatment of cerebral ischemia by a combination of raubasine and almitrine.Arzneimittelforschung 37, 491–494.

    PubMed  CAS  Google Scholar 

  • Chan P. H., Fishman R. A., Longar S., Chen S., and Yu A. (1985) Cellular and molecular effects of polyunsaturated fatty acids in brain ischemia and injury.Prog. Brain Res. 63, 227–235.

    Article  PubMed  CAS  Google Scholar 

  • Chan P. H., Chen S. F., and Yu A. CH. (1988a) Induction of intracellular superoxide radical formation by arachidonic acid and by polyunsaturated fatty acids in primary astrocytic cultures.J. Neurochem. 50, 1185–1193.

    Article  PubMed  CAS  Google Scholar 

  • Chan P. H., Chu L., and Fishman R. A. (1988b) Reduction of activities of superoxide dismutase but not of glutathione peroxidase in rat brain regions following decapitation ischemia.Brain Res. 439, 388–390.

    Article  PubMed  CAS  Google Scholar 

  • Choi D. W. (1990) Cerebral hypoxia: some new approaches and unanswered questions.J. Neurosci. 10, 2493–2501.

    PubMed  CAS  Google Scholar 

  • Deby C. and Goutier R. (1990) New perspectives on the biochemistry of superoxide anion and the efficiency of superoxide dismutase.Biochem. Pharmacol. 39, 399–405.

    Article  PubMed  CAS  Google Scholar 

  • Deloulme J. C., Janet T., Au D., Storm D. R., Sensenbrenner M., and Baudier J. (1990) Neuromodulin (GAP 43), a neuronal protein kinase C substrate is also present in O-2 glial lineage: characterization of neuromodulin in secondary cultures of oligodendrocytes and comparison with the neuronal antigen.J. Cell Biol. 111, 1559–1569.

    Article  PubMed  CAS  Google Scholar 

  • Gaudert R. J., Alam I., and Levine L. (1980) Accumulation of cyclooxygenase products of arachidonic acid metabolism in gerbil brain during reperfusion after bilateral common carotid artery occlusion.J. Neurochem. 35, 653–658.

    Article  Google Scholar 

  • Halliwell B. and Gutteridge J. M. C. (1985) Oxygen radicals and the nervous system.Trends Neurosci. 2, 22–26.

    Article  Google Scholar 

  • Halliwell B. and Gutteridge J. M. (1986) Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts.Arch. Biochem. Biophys. 246, 501–514.

    Article  PubMed  CAS  Google Scholar 

  • Hansen A. J. (1985) Effect of anoxia on ion distribution in brain.Physiol. Rev. 65, 101–148.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Hillered L., Siesjö B. K., and Arfors K. E. (1984) Mitochondrial response to transient forebrain ischemia and recirculation in the rat.J. Cereb. Blood Row Metab. 4, 438–446.

    CAS  Google Scholar 

  • Kimelberg H. K. and Ransom B. R. (1986) Physiological and pathological aspects of astrocytic swelling, inAstrocytes, vol. 3 (Fedoroff S. and Vernadakis A., eds.), pp. 129–166, Academic, Orlando, FL.

    Google Scholar 

  • Kim-Lee M. H., Stokes B. T., and Yates A. J. (1992) Reperfusion paradox: a novel mode of glial cell injury.Glia 5, 56–64.

    Article  PubMed  CAS  Google Scholar 

  • Kukreja R. C., Kontos H. A., Hess M. L., and Ellis E. F. (1986) PGH synthase and lipoxygenase generate superoxide in the presence of NADH and NADPH.Circ. Res. 59, 612–619.

    PubMed  CAS  Google Scholar 

  • Laubie M. (1982) Current concepts on almitrine bismesylate: mechanism of action.Bull. Europ. Physiopathol. Resp. 18, 299–306.

    Google Scholar 

  • Lowry O. H., Rosebrough W. J., Farr A. L., and Randall R. J. (1951) Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193, 265–275.

    PubMed  CAS  Google Scholar 

  • Malis C. D. and Bonventre J. V. (1986) Mechanism of calcium potentiation of oxygen free radical injury to renal mitochondria. A model for post-ischemic and toxic mitochondrial damage.J. Biol. Chem. 261, 14,201–14,208.

    CAS  Google Scholar 

  • Mehrotra S., Kakkar P., and Uiswanathan P. N. (1991) Mitochondrial damage by active oxygen species in vitro.Free Radical Biol. Med. 10, 277–285.

    Article  CAS  Google Scholar 

  • Mishra O. P., Delivoria-Papadopoulos M., and Wagerle L. C. (1990) Anti-oxydant enzymes in the brain of newborn piglets during ischemia followed by reperfusion.Neuroscience 35, 211–215.

    Article  PubMed  CAS  Google Scholar 

  • Morii H., Takeuchi Y., and Watanabe Y. (1991) Selective inhibition of NADH-Co Q oxidoreductase (complex I) of rat brain mitochondria by arachidonic acid.Biochem. Biophys. Res. Commun. 178, 1120–1126.

    Article  PubMed  CAS  Google Scholar 

  • Oberley L. W., St. Clair D. K., Autor A. P., and Oberley T. D. (1987) Increase in manganese superoxide dismutase activity in the mouse heart after X-irradiation.Arch. Biochem. Biophys. 254, 69–80.

    Article  PubMed  CAS  Google Scholar 

  • Oliver C. N., Starke-Reed P. E., Stadtman E. R., Liv G. J., Carney J. M., and Floyd R. A. (1990) Oxidative damage to brain proteins, loss of glutamine synthetase activity, and production of free radicals during ischemia-reperfusion induced injury to gerbil brain.Proc. Natl. Acad. Sci. USA 87, 5144–5147.

    Article  PubMed  CAS  Google Scholar 

  • Paoletti F., Aldinucci D., Mocali A., and Capparrini A. (1986) A sensitive spectrophotometric method for the determination of superoxide dismutase activity in tissue extract.Anal. Biochem. 154, 536–541.

    Article  PubMed  CAS  Google Scholar 

  • Patt A., Harken R. H., Burton L. K., Rodell T. C., Piermattei D., Schorr W. J., Parker N. B., Berger E. M., Horesh I. R., Terade L. S., Linas S. L., Cheronis J. C., and Repine J. I. (1988) Xanthine oxidase derived hydrogen peroxide contributes to ischemia-reperfusion induced edema in gerbil brain.J. Clin. Invest. 81, 1556–1562.

    Article  PubMed  CAS  Google Scholar 

  • Petito C. K., Juurlink B. H. J., and Hertz L. (1991) In vitro models differentiating between direct and indirect effects of ischemia on astrocytes.Exp. Neurol. 113, 364–372.

    Article  PubMed  CAS  Google Scholar 

  • Sakamoto A., Ohnishi S. T., Ohnishi T., and Ogawa R. (1991) Relationship between free radical production and lipid peroxidation during ischemiareperfusion injury in the rat brain.Brain Res. 554, 186–192.

    Article  PubMed  CAS  Google Scholar 

  • Schmidt-Kastner S., Szymas J., and Hossmann K. A. (1990) Immunohistochemical study of glial reaction and serum-protein extrovasation in relation to neuronal damage in rat hippocampus after ischemia.Neuroscience 38, 527–540.

    Article  PubMed  CAS  Google Scholar 

  • Schor N. F. (1988) Inactivation of mammalian brain glutamine synthetase by oxygen radicals.Brain Res. 456, 17–21.

    Article  PubMed  CAS  Google Scholar 

  • Shull S., Heintz N. H., Periasamy M., Manohar M., Janssen Y. M. W., Marsh J. P., and Mossman B. T. (1991) Differential regulation of antioxidant enzymes in response to oxidants.J. Biol. Chem. 266, 24,398–24,403.

    CAS  Google Scholar 

  • Siesjö B. K. (1991) Cell damage in the brain: a speculative synthesis.J. Cereb. Blood Flow Metab. 1, 155–185.

    Google Scholar 

  • Sims N. R. (1991) Selective impairment of respiration in mitochondria isolated from brain subregions following transient forebrain ischemia in the rat.J. Neurochem. 56, 1836–1844.

    Article  PubMed  CAS  Google Scholar 

  • Smith C. D., Carney J. M., Starke-Reed P. E., Oliver C. N., Stadtman E. R., Floyd R. A., and Markesbery W. R. (1991) Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.Proc. Natl. Acad. Sci. USA 88, 10,540–10,543.

    CAS  Google Scholar 

  • Strosznajder J. and Samochocki M. (1991) Ca+ +-independent, Ca+ +-dependent and carbachol mediated arachidonic acid release from rat brain cortex membrane.J. Neurochem. 57, 1198–1206.

    Article  PubMed  CAS  Google Scholar 

  • Sutherland G., Bose R., Louw D., and Pinskyt C. (1991) Global elevation of brain superoxide dismutase activity following forebrain ischemia in rat.Neurosci. Lett. 128, 169–172.

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi Y., Morii H., Tamura M., Hayaishi O., and Watanabe Y. (1991) A possible mechanism in mitochondral dysfunction during cerebral ischemia: inhibition of mitochondrial respiration activity by arachidonic acid.Arch. Biochem. Biophys. 289, 33–38.

    Article  PubMed  CAS  Google Scholar 

  • Takeuchi K. H., Saito K. I., and Nixon R. A. (1992) Immunoassay and activity of calcium-activated neutral proteinase (mCANP): distribution in soluble and membrane-associated fractions in human and mouse brain.J. Neurochem. 58, 1526–1532.

    Article  PubMed  CAS  Google Scholar 

  • Tholey G., Copin J. C., Ledig M., and Pettmann B. (1992) Almitrine antagonizes some anoxia induced effects in astrocytes.Trans. Am. Soc. Neurochem. 23, 142.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Turrens J. F., Beconi M., Barilla J., Chavez V. B., and McCord J. M. (1991) Mitochondrial generation of oxygen radicals during reoxygenation of ischemic tissue.Free Radical Res. Commun. 12–13, 681–689.

    Article  Google Scholar 

  • Vlessis A. A., Widener L. L., and Bartos D. (1990) Effect of peroxide, sodium and calcium on brain mitochondrial respiration in vitro: potential role in cerebral ischemia and reperfusion.J. Neurochem. 54, 1412–1418.

    Article  PubMed  CAS  Google Scholar 

  • Watson B. D., Busto R., Goldberg W. J., Santiso M., Yoshida S., and Ginsberg M. D. (1984) Lipid peroxidation in vivo induced by reversible global ischemia in rat brain.J. Neurochem. 42, 268–274.

    Article  PubMed  CAS  Google Scholar 

  • Wauquier A., Ashton D., and Clincke G. H. C. (1988) Brain ischemia as a target for Ca+ + entry blockers, inCalcium Antagonists (Vanhoutte P. M., Paoletti R., and Govoni S., eds.), 522, pp. 470–490, Ann. NY Acad. Sci., New York.

    Google Scholar 

  • Weibel M., Pettmann B., Daune G., Labourdette G., and Sensenbrenner M. (1984) Chemically defined medium for the rat astroglial cells in primary cultures.Int. J. Dev. Neurosci. 2, 355–366.

    Article  CAS  Google Scholar 

  • Wong G. H. W., Elwell J. H., Oberley L. W., and Goeddel D. V. (1989) Manganous superoxide dismutase is essential for cellular resistance to cytotoxicity of tumor necrosis factor.Cell 58, 923–931.

    Article  PubMed  CAS  Google Scholar 

  • Yu A. C., Gregory G. A., and Chan P. H. (1989) Hypoxia-induced dysfunction and injury of astrocytes in primary cell cultures.J. Cereb. Blood Flow Metab. 9, 20–28.

    PubMed  CAS  Google Scholar 

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  1. Laboratoire de Neurobiologie Ontogénique, Centre de Neurochimie du CNRS, 5, rue Blaise Pascal, 67084, Strasbourg Cedex, France

    Jean-Christophe Copin, Marc Ledig & Georges Tholey

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  1. Jean-Christophe Copin
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  2. Marc Ledig
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Copin, JC., Ledig, M. & Tholey, G. Almitrine prevents some hypoxia-induced metabolic injury in rat astrocytes. Molecular and Chemical Neuropathology 20, 97–109 (1993). https://doi.org/10.1007/BF02815365

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