Skip to main content
SpringerLink
Log in

Astrocytic swelling in traumatic-hypoxic brain injury

Beneficial effects of an inhibitor of anion exchange transport and glutamate uptake in glial cells

  • Original Articles
  • Published:
Molecular and Chemical Neuropathology

Abstract

Swelling of brain slices is shown to occur in response to elevated potassium levels or glutamate, which is accompanied by astrocytic swelling. Cl−/HCO −3 anion exchange inhibitors, such as SITS (4-acetamido-4′-isothiocyanostilbene-2,2′-disulfonic acid) or furosemide, but not the specific cotransport inhibitor bumetanide, inhibit swelling or increased ion uptake in rat brain slices caused by elevated potassium although there were marked species differences in sensitivity. A novel anion exchange inhibitor,l-644,711, inhibits swelling and increased ion uptake caused by glutamate in rat and cat brain slices, as well as inhibiting [3H]glutamate uptake in primary rat astrocyte cultures. Possible mechanisms of action of the inhibitors are discussed.l-644,711 was also found to be effective in promoting recovery from a trauma plus hypoxia head injury model in cats. Marked perivascular astrocytic swelling is associated with this head injury model, andl-644,711 also inhibited such astroglial swelling as determined ultrastructurally. The significance of these findings in relation to possible connections between astrocytic swelling and brain pathology is discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bakay L. and Lee J. C. (1968) The effect of acute hypoxia and hypercapnia on the ultrastructure of the central nervous system.Brain 91, 697–706.

    Article  PubMed  CAS  Google Scholar 

  • Bakay L., Lee J. C., Lee G. C., and Peng J.-R. (1977) Experimental cerebral concussion. Part I. An electron microscopic study.J. Neurosurg. 47, 525–531.

    Article  PubMed  CAS  Google Scholar 

  • Barron K. D., Dentinger M. P., Kimelberg H. K., Nelson L. R., Bourke R. S., Keegan S., Mankes R., and Cragoe E. J., Jr. (1988) Ultrastructural features of a brain injury model in cat. 1. Vascular and neuroglial changes and the prevention of astroglial swelling by a fluorenyl (aryloxy)alkanoic acid derivative (l-644,711).Acta Neuropath. (Berlin)75, 295–307.

    Article  CAS  Google Scholar 

  • Bevan S., Chiu S. Y., Gray P. T. A., and Ritchie J. M. (1985) The presence of voltage-gated sodium, potassium and chloride channels in rat cultured astrocytes.Proc. R. Soc. Lond. B. 225, 299–313.

    Article  PubMed  CAS  Google Scholar 

  • Bonting S. L. (1970) Na+−K+ activated ATPase and cation transport,Membranes and Ion Transport, vol. I (Bittar E. E., ed.), pp. 258–263, Wiley, New York.

    Google Scholar 

  • Bourke R. S. and Tower D. B. (1966) Fluid compartmentation and electrolytes of cat cerebral cortexin vitro. II. Sodium, potassium and chloride of mature cortex.J. Neurochem. 13, 1099–1117.

    Article  PubMed  CAS  Google Scholar 

  • Bourke R. S., Kimelberg H. K., Daze M. A., and Popp A. J. (1979) Studies on the formation of astroglial swelling and its inhibition by clinically useful agents,Neural Trauma (Popp A. J., Nelson L. R., Bourke, R. S., and Kimelberg, H. K., eds.), pp. 95–113, Raven, New York.

    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.

    Article  PubMed  CAS  Google Scholar 

  • Bowman C. L. and Kimelberg H. K. (1984) Excitatory amino acids directly depolarize rat brain astrocytes in primary culture.Nature 311, 656–659.

    Article  PubMed  CAS  Google Scholar 

  • Brazy P. C. and Gunn R. B. (1976) Furosemide inhibition of chloride transport in human red blood cells.J. Gen. Physiol. 68, 583–599.

    Article  PubMed  CAS  Google Scholar 

  • Cabantchik Z. I., Knauf P. A., and Rothstein A. (1978) The anion transport system of the red blood cell. The role of membrane protein evaluated by the use of probes.Biochim. Biophys. Acta 515, 239–302.

    PubMed  CAS  Google Scholar 

  • Casper D. S., Trelstad R. L., and Reif-Lehrer L. (1982) Glutamate-induced cellular injury in isolated chick embryo retina: Muller cell localization of initial effects.J. Comp. Neurol. 209, 79–90.

    Article  PubMed  CAS  Google Scholar 

  • Chan P. H., Yurko M., and Fishman R. A. (1982) Phospholipid degradation and cellular edema induced by free radicals in brain cortical slices.J. Neurochem. 38, 525–531.

    Article  PubMed  CAS  Google Scholar 

  • Chan P. H., Yu A. C. H., and Fishman R. A. (1988) Free fatty acids and excitatory neurotransmitter amino acids as determinants of pathological swelling of astrocytes in primary culture,The Biochemical Pathology of Astrocytes (Norenberg M. D., Hertz L., and Schousboe A., eds.), pp. 327–335, Liss, New York.

    Google Scholar 

  • Coles J. A., Tsacopoulos M., Rabineau P., and Gardner-Medwin A. R. (1981) Movement of potassium into glial cells in the retina of the drone, Apis mellifera, during photostimulation,Ion-selective Microelectrodes and Their Use in Excitable Tissues (Sykova E., Hnik P., and Vyklicky, eds.), pp. 345–349, Plenum, New York.

    Google Scholar 

  • Cragoe E. J., Jr., Gould N. P., and Woltersdorf O. W., Jr., Ziegler C., Bourke R. S., Nelson L. R., Kimelberg H. K., Waldman J. B., Popp A. J., and Sedransk N. (1982) Agents for the treatment of brain injury. 1. (Aryloxy)alkanoic acids.J. Med. Chem. 25, 567–579.

    Article  PubMed  CAS  Google Scholar 

  • Cragoe E. J., Jr., Woltersdorf O. W., Jr., Gould N. P., Pietruszkiewicz A. M., Ziegler C., Sakurai Y., Stokker G. E., Anderson P. S., Bourke R. S., Kimelberg H. K., Nelson L. R., Barron K. D., Rose J. R., Szarowski D., Popp A. J., and Waldman J. B. (1986) Agents for the treatment of brain edema. 2. [(2,3,9,9a-tetrahydro-3-oxo-substituted-1 H-fluoren-7-yl)oxy] alkanoic acids and some of their analogues.J. Med. Chem. 29, 825–841.

    Article  PubMed  CAS  Google Scholar 

  • Dietzel I., Heinemann U., Hofmeier G., and Lux H. D. (1980) Transient changes in the size of the extracellular space in the sensorimotor cortex of cats in relation to stimulus-induced changes in potassium concentration.Exp. Brain Res. 40, 432–439.

    Article  PubMed  CAS  Google Scholar 

  • Duffy P. E. (1983)Astrocytes: Normal, Reactive and Neoplastic, Raven, New York.

    Google Scholar 

  • Franck G., Grisar T., and Moonen G. (1983) Glial and neuronal Na+, K+ pump.Advances in Cellular Neurobiology 4, 133–159.

    Google Scholar 

  • Frangakis M. V. and Kimelberg H. K. (1984) Dissociation of neonatal rat brain by dispase for preparation of primary astrocyte cultures.Neurochem. Res. 9, 1685–1693.

    Article  Google Scholar 

  • Frelin C., Chassande O., and Lazdunski M. (1986) Biochemical characterization of the Na+/K+/Cl− co-transport in chick cardiac cells.Biochem. Biophys. Res. Commun. 134, 326–331.

    Article  PubMed  CAS  Google Scholar 

  • Garay R. P., Hannaert P. R., Nazaret C., and Cragoe E. J., Jr. (1986) The significance of the relative effects of loop diuretics and anti-brain edema agents on the Na+, K+, Cl− cotransport system and the Cl−/NaCO −3 anion exchanger.Naunyn-Schmiedeberg’s Arch. Pharmacol. 334, 202–209.

    Article  CAS  Google Scholar 

  • Garcia J. H. and Lossinsky A. S. (1979) Brain edema: Introduction,Cerebrovascular Diseases (Price T. R. and Nelson, E., eds.), pp. 125–130, Raven, New York.

    Google Scholar 

  • Garcia J. H., Kalimo H., Kamijyo Y., and Trump B. F. (1977) Cellular events during partial cerebral ischemia. I. Electron microscopy of feline cerebral cortex after middle cerebral artery occlusion.Virchows Arch. B. Cell. Path. 25, 191–206.

    CAS  Google Scholar 

  • Gray P. T. A. and Ritchie J. M. (1986) A voltage-gated chloride conductance in rat cultured astrocytes.Proc. R. Soc. Lond. B. 228, 267–288.

    Article  PubMed  CAS  Google Scholar 

  • Griffiths D. R., Burns N., and Crawford A. R. (1978) Early vascular changes in the spinal gray matter following impact injury.Acta Neuropathol. (Berlin)41, 33–39.

    Article  CAS  Google Scholar 

  • Herndon R. M., Coyle J. T., and Addicks E. (1980) Ultrastructural analysis of kainic acid lesion to cerebellar cortex.Neuroscience 5, 1015–1026.

    Article  PubMed  CAS  Google Scholar 

  • Hertz J. (1979) Functional interactions between neurons and astrocytes. I. Turnover and metabolism of putative amino acid transmitters.Prog. in Neurobiol. 13, 277–323.

    Article  CAS  Google Scholar 

  • Hirano A. (1981) Astrocytes,A Guide to Neuropathology, pp. 204–224, Igaku Shoin, Tokyo.

    Google Scholar 

  • Hirata H., Slater N. T., and Kimelberg H. K. (1983) Alpha-adrenergic receptor-mediated depolarization of rat neocortical astrocytes in primary culture.Brain Res. 270, 358–362.

    Article  PubMed  CAS  Google Scholar 

  • Hodgkin A. L. and Horowicz P. (1959) The influence of potassium and chloride ions on the membrane potential of single muscle fibres.J. Physiol. 148, 127–160.

    PubMed  CAS  Google Scholar 

  • Jenkins L. W., Povlishock J. T., Becker D. P., Miller J. D., and Sullivan H. G. (1979) Complete cerebral ischemia. An ultrastructural study.Acta Neuropathol. (Berlin)48, 113–125.

    Article  CAS  Google Scholar 

  • Jenkins L. W., Becker D. P., and Coburn T. H. (1984) A quantitative analysis of glial swelling and ischemic neuronal injury following complete cerebral ischemia.Recent Progress in the Study and Therapy of Brain Edema (Go T. G. and Baethmann A., eds.), pp. 523–537, Plenum, New York.

    Google Scholar 

  • Kalimo H., Rehncrona S., Soderfeldt B., Olsson Y., and Siesjö, B. K. (1981) Brain lactic acidosis and ischemic cell damage. 2. Histopathology.J. Cerebr. Blood Flow Metab. 1, 313–327.

    CAS  Google Scholar 

  • Kimelberg H. K. (1979) Glial enzymes and ion transport in brain swelling,Neural Trauma (Popp A. J., Bourke R. S., Nelson L. R., and Kimelberg, H. K., eds.), pp. 137–153, Raven, New York.

    Google Scholar 

  • Kimelberg H. K. (1981) Active accumulation and exchange transport of chloride in stroglial cells in culture.Biochim. Biophys. Acta 646, 179–184.

    Article  PubMed  CAS  Google Scholar 

  • Kimelberg H. K. (1987) Anisotonic media and glutamate-induced ion transport and volume responses in primary astrocyte cultures.J. Physiol. (Paris)82, 294–303.

    CAS  Google Scholar 

  • Kimelberg H. K. and Bourke R. S. (1982) Anion transport in the nervous system,Handbook of Neurochemistry (Lajtha, A., ed.), pp. 31–67, Plenum, New York.

    Google Scholar 

  • Kimelberg H. K. and Frangakis M. V. (1985) Furosemide- and bumetanide-sensitive ion transport and volume control in primary astrocyte cultures from rat brain.Brain Res. 361, 125–134.

    Article  PubMed  CAS  Google Scholar 

  • Kimelberg H. K. and Frangakis M. V. (1986) Volume regulation in primary astrocyte cultures.Advances in the Biosciences 61, 177–186.

    Google Scholar 

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

    Google Scholar 

  • Kimelberg H. K., Biddelcome S., and Bourke R. S. (1979) SITS-inhibitable Cl− transport and Na+-dependent H+ production in primary astroglial cultures.Brain Res. 173, 111–124.

    PubMed  CAS  Google Scholar 

  • Kimelberg H. K., Bowman C. L., and Hirata H. (1986) Anion transport in astrocytes.Ann. NY Acad. Sci. 481, 334–353.

    Article  PubMed  CAS  Google Scholar 

  • Kimelberg H. K., Pang S., and Treble D. H. (1989a) Excitatory amino-acid stimulated uptake of22Na+ in primary astrocyte cultures.J. Neurosci. 9, 1141–1149.

    PubMed  CAS  Google Scholar 

  • Kimelberg H. K., Goderie S., and Waniewski, R. A. Hypoosmotic media-induced release of amino acids from astrocytes.Soc. Neurosci. Abst. (in press).

  • Kimelberg H. K., Bowman C., Biddlecome S., and Bourke R. S. (1979b) Cation transport and membrane potential properties of primary astroglial cultures from neonatal rat brains.Brain Res. 177, 533–550.

    Article  PubMed  CAS  Google Scholar 

  • Kimelberg H. K., Bourke R. S., Stieg P. E., Barron K. D., Hirata H., Pelton E. W., and Nelson L. R. (1982) Swelling of astroglia after injury to the central nervous system: Mechanisms and consequences,Head Injury: Basic and Clinical Aspects (Grossman R. G. and Gildenberg P. L., eds.), pp. 31–44, Raven, New York.

    Google Scholar 

  • Kimelberg H. K., Cragoe E. J., Jr., Nelson L. R., Popp A. J., Szarowski D., Rose J. W., Woltersdorf O. W., Jr., and Pietruszkiewicz A. M. (1987) Improved recovery from a traumatic-hypoxic brain injury in cats by intracisternal injection of an anion transport inhibitor.Central Nervous System Trauma 4, 3–14.

    PubMed  CAS  Google Scholar 

  • Klatzo I. (1967) Neuropathological aspects of brain edema.J. Neuropathol. Exp. Neurol. 26, 1–13.

    Article  PubMed  CAS  Google Scholar 

  • Klatzo I., Chui E., Fujiwara K., and Spatz M. (1980) Resolution of vasogenic brain edema (VBE),Brain Edema, Advances in Neurology, vol. 28, (Cervos-Navarro J. and Ferszt R., eds.), pp. 359–374, Raven, New York.

    Google Scholar 

  • Klatzo I., Suszuki R., Orzi F., Schuier F., and Nitsch C. (1984) Pathomechanisms of ischemic brain edema,Recent Progress in the Study and Therapy of Brain Edema (Go T. G. and Baethmann, A., eds.), pp. 1–10, Plenum, New York.

    Google Scholar 

  • Kletzien R. F., Pariza M. W., Becker J. E., and Potter V. R. (1975) A method using 3-0-methyl-d-glucose and phloretin for the determination of intracellular water space of cells in monolayer culture.Anal. Biochem. 68, 537–544.

    Article  PubMed  CAS  Google Scholar 

  • Koechel D. A. (1981) Ethacrynic acid and related diuretics: Relationship of structure to beneficial and detrimental actions.Ann. Rev. Pharmacol. Toxicol. 21, 265–293.

    Article  CAS  Google Scholar 

  • Kraig R. P., Pulsinelli W. A., and Plum F. (1985a) Hydrogen ion buffering during complete brain ischemia.Brain Res. 342, 281–290.

    Article  PubMed  CAS  Google Scholar 

  • Kraig R. P., Pulsinelli W. A., and Plum F. (1985b) Heterogeneous distribution of hydrogen and bicarbonate ions during complete brain ischemia.Prog. Brain. Res. 63, 155–166.

    Article  PubMed  CAS  Google Scholar 

  • Kregenow F. M. (1981) Osmoregulatory salt transport mechanisms: Control of cell volume in anisotonic media.Ann. Rev. Physiol. 43, 493–505.

    Article  CAS  Google Scholar 

  • Lowe A. G. and Lambert A. (1983) Chloride-bicarbonate exchange and related transport processes.Biochim. Biophys. Acta 694, 353–374.

    Google Scholar 

  • Lund-Anderson H. and Hertz L. (1970) Effects of potassium and of glutamate on swelling and on sodium and potassium content in brain cortex slices from adult rats.Exp. Brain Res. 11, 199–212.

    Google Scholar 

  • Martin D. L. and Shain W. (1979) High affinity transport of taurine and beta-alanine and low affinity transport of gamma-aminobutyric acid by a single transport system in cultured glioma cells.J. Biol. Chem. 254, 7076–7084.

    PubMed  CAS  Google Scholar 

  • Matyja E. (1986) Morphologic evidence of a primary response of glia to kainic acid administration into the rat neostriatum; studiedin vivo andin vitro.Expt. Neurol. 92, 609–623.

    Article  CAS  Google Scholar 

  • Matakas F., Birkle J., and Cervos-Navarro J. (1978) The effect of prolonged experimental hypercapnia on the brain.Acta Neuropathol. (Berlin)41, 207–210.

    Article  CAS  Google Scholar 

  • Nelson L. R., Bourke R. S., Popp A. J., Cragoe E. J., Jr., Signorelli A., Foster V. V., and Creel W. (1979) Evaluation of treatment modalities in severe head injuries using an animal model,Neural Trauma (Popp A. J., Bourke R. S., Nelson L. R., and Kimelberg H. K., eds.), pp. 297–313, Raven, New York.

    Google Scholar 

  • Nelson L. R., Auen E. L., Bourke R. S., Barron K. D., Malik A. B., Cragoe E. J., Jr., Waldman J. B., Kimelberg H. K., Foster V. V., Creel W., and Schuster L. (1982) A comparison of animal head injury models developed for treatment modality evaluation,Head Injury: Basic and Clinical Aspects, (Grossman R. G. and Gildenberg, P. J., eds.), pp. 117–127, Raven, New York.

    Google Scholar 

  • Norenberg M. D. (1986) Hepatic encephalopathy: A disorder of astrocytes,Astrocytes, vol 3 (Fedoroff S. and Vernadakis A., eds.), pp. 425–460, Academic, New York.

    Google Scholar 

  • Norenberg M. D. and Lapham L. W. (1974) The astrocyte response in experimental portal-systemic encephalopathy: An electron microscopic study.Neuropathol. Exp. Neurol. 33, 422–435.

    Article  CAS  Google Scholar 

  • Pappius H. M. and Elliott K. A. C. (1956) Factors affecting the potassium content of incubated brain slices.Can. J. Biochem. Physiol. 34, 1053–1067.

    PubMed  CAS  Google Scholar 

  • Plum F. (1983) What causes infarction in ischemic brain?Neurology 33, 222–233.

    PubMed  CAS  Google Scholar 

  • Siesjö, B. K. (1981) Cell damage in the brain: A speculative synthesis.J. Cerebr. Blood Flow Metab. 1, 155–185.

    Google Scholar 

  • Siesjö, B. K. (1984) Brain acid-base metabolism in health and disease,Cerebral Ischemia (Bes A., Braquet P., Paoletti, R., and Siesjö B. K., eds.), pp. 157–165, Elsevier, B. V., Amsterdam.

    Google Scholar 

  • Sontheimer H., Kettenmann H., Backus K. H., and Schachner, M. (1988) Glutamate opens Na+/K+ channels in cultured astrocytes.Glia 1, 328–336.

    Article  PubMed  CAS  Google Scholar 

  • Sykova E. (1983) Extracellular K+ accumulation in the central nervous system.Prog. Biophys. Molec. Biol. 42, 135–189.

    Article  CAS  Google Scholar 

  • Trachtenberg M. C. (1982) Brain cell responses to extracellular protein,Head Injury: Basic and Clinical Aspects (Grossman R. G. and Gildenberg P. L., eds.), pp. 169–178, Raven, New York.

    Google Scholar 

  • Van Harreveld A. (1982) Swelling of the Müller fibers in the chicken retina.J. Neurobiol. 13, 519–536.

    Article  PubMed  Google Scholar 

  • Van Harreveld A. and Fifkova E. (1971) Light- and electron-microcopic changes in central nervous tissue after electrophoretic injection of glutamate.Exp. Mol. Pathol. 15, 61–81.

    Article  PubMed  Google Scholar 

  • Walz W. and Hertz L. (1984) Intense furosemide-sensitive potassium accumulation in the presence of pathologically high extracellular potassium levels.J. Cerebr. Blood Flow Metab. 4, 301–304.

    CAS  Google Scholar 

  • Walz W. and Hinks E. C. (1985) Carrier-mediated KCl accumulation accompanied by water movements is involved in the control of physiological K+ levels by astrocytes.Brain Res. 343, 44–51.

    Article  PubMed  CAS  Google Scholar 

  • Waniewski R. A. and Martin D. L. (1983) Selective inhibition of glial versus neuronal uptake ofl-glutamic acid by SITS.Brain Res. 268, 390–394.

    Article  PubMed  CAS  Google Scholar 

  • Waniewski R. A. and Martin D. L. (1984) Characterization ofl-glutamic acid transport by glioma cells in culture: Evidence for sodium-independent, chloride-dependent high affinity influx.J. Neurosci. 4, 2237–2246.

    PubMed  CAS  Google Scholar 

  • Warnock D. G., Greger R., Dunham P. B., Benjamin M. A., Fizzell R. A., Field, M., Spring K. R., Ives H. E., Aronson P. S., and Seifter J. (1983) Ion transport processes in apical membrane of epithelia.Fed. Proc. 43, 2473–2487.

    Google Scholar 

  • Yu M. C., Bakay L., and Lee J. C. (1972) Ultrastructure of the central nervous system after prolonged hypoxia. I. Neuronal alterations.Acta Neuropathol. (Berlin)22, 222–234.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Neurosurgery, New York State Department of Health, 12208, Albany, NY

    H. K. Kimelberg & J. W. Rose

  2. Department of Neurology, Albany Medical College, New York State Department of Health, 12208, Albany, NY

    K. D. Barron

  3. Veterans Administration Hospital, New York State Department of Health, 12208, Albany, NY

    K. D. Barron

  4. Wadsworth Center for Laboratories and Research, New York State Department of Health, 12208, Albany, NY

    R. A. Waniewski

  5. Merck Sharp & Dohme Research Laboratories, West Point, PA

    E. J. Cragoe

Authors
  1. H. K. Kimelberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. W. Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. D. Barron
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. A. Waniewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. J. Cragoe
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kimelberg, H.K., Rose, J.W., Barron, K.D. et al. Astrocytic swelling in traumatic-hypoxic brain injury. Molecular and Chemical Neuropathology 11, 1–31 (1989). https://doi.org/10.1007/BF03160036

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03160036

Index Entries

Search

Navigation