Skip to main content
SpringerLink
Log in

Origins of Glutamate Release in Ischaemia

  • Conference paper
Book cover Mechanisms of Secondary Brain Damage in Cerebral Ischemia and Trauma

Part of the book series: Acta Neurochirurgica ((NEUROCHIRURGICA,volume 66))

Summary

Using microdialysis coupled to on-line detection of glutamate, and recording electrical activity and field potential at the same tissue site, we have shown that the increase in extracellular glutamate under global penumbral conditions is minor. However, in the border of the ischaemic core, recurrent spreading depression is presumably associated with transient vesicular release of glutamate (exocytosis). With ischaemic insults severe enough to provoke anoxic depolarization, such as in the ischaemic core, exocytosis only occurred for a few minutes because it requires ATP hydrolysis, and the magnitude of this release was minor in comparison with that of the total glutamate efflux. Subsequent experiments with a selective inhibitor of high-affinity glutamate transporters suggested that reversal of glutamate uptake may not be a major contributor to the sustained release of glutamate in this condition.

These results, and other considerations, do not favour the view that presynaptic glutamate release and reversed glutamate uptake are suitable targets for neuroprotection in ischaemia. Acting post-synaptically to inhibit recurrent spreading depression (NMDA-receptor antagonists) or to modulate long-lasting enhancement of synaptic efficiency (‘anoxia-induced long-term potentiation’) appear to be more rational strategies.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Astrup J, Siesjö BK, Symon L (1981) Threshold in cerebral ischemia-the ischemic penumbra. Stroke 12: 723–725

    Article  PubMed  CAS  Google Scholar 

  2. Benveniste H, Hüttemeier PC (1990) Microdialysis-theory and application. Prog Neurobiol 35: 195–215

    Article  PubMed  CAS  Google Scholar 

  3. Blasi J, Chapman ER, Link E, Binz T, Yamasaki S, De Camilli P, SüdhofTC, Niemann H, Jahn R (1993) Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 365: 160–163

    CAS  Google Scholar 

  4. Bradford HF, Young AMJ, Crowder JM (1987) Continuous leakage from brain cells is balanced by compensatory high-affinity reuptake transport. Neurosci Lett 81: 296–302

    Article  PubMed  CAS  Google Scholar 

  5. Buchan A, Li H, Pulsinelli WA (1991) The N-methyl-D-aspartate antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adult rats. J Neurosci 11: 1049–1056

    PubMed  CAS  Google Scholar 

  6. Crépel V, Hammond C, Krnjevic K, Chinestra P, Ben-Ari Y (1993) Anoxia-induced LTP of isolated NMDA receptor-mediated synaptic responses. J Neurophysiol 69: 1774–1778

    Google Scholar 

  7. Didier M, Héaulme M, Gonalons N, Soubrié P, Bockaert J, Pin JP (1993) M K’-stimulated a“Ca2, uptake in cerebellar granule cell cultures mainly results from NMDA receptor activation. Eur J Pharmacol 244: 57–65

    Google Scholar 

  8. Erecinska M, Silver IA (1994) Ions and energy in mammalian brain. Prog Neurobiol 43: 37–71

    Article  PubMed  CAS  Google Scholar 

  9. Fabricius M, Hensen LH, Lauritzen M (1993) Microdialysis of interstitial amino acids during spreading depression and anoxic depolarization in rat neocortex. Brain Res 612: 61–69

    Article  PubMed  CAS  Google Scholar 

  10. Fleischer JE, Tateishi A, Drummond JC, Scheller MS, Grafe MR, Zornow MH, Shearman GT, Shapiro HM (1989) MK-801, an excitatory amino acid antagonist, does not improve neurologic outcome following cardiac arrest in cats. J Cereb Blood Flow Metab 9: 795–804

    Article  PubMed  CAS  Google Scholar 

  11. Garthwaite G, Williams GD, Garthwaite J (1992) Glutamate toxicity: an experimental and theoretical analysis. Eur J Neurosci 4: 353–360

    Article  PubMed  Google Scholar 

  12. Griffiths R, Dunlop J, Gorman A, Senior J, Grieve A (1994) Ltrans-pyrrolidine-2, 4-dicarboxylate and cis-1-aminocyclo- butane-1,3-dicarboxylate behave as transportable, competitive inhibitors of the high-affinity glutamate transporters. Biochem Pharmacol 47: 267–274

    Article  PubMed  CAS  Google Scholar 

  13. Hansen AJ (1985) Effects of anoxia on ion distribution in the brain. Physiol Rev 65: 101–148

    PubMed  CAS  Google Scholar 

  14. Iijima T, Mies G, 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

    Article  PubMed  CAS  Google Scholar 

  15. Jing J, Aitken PG, Somjen GG (1993) Role of calcium channels in spreading depression in rat hippocampal slices. Brain Res 604: 251–259

    Article  PubMed  CAS  Google Scholar 

  16. Kanai Y, Smith CP, Hediger MA (1993) The elusive transporters with a high-affinity for glutamate. Trends Neurosci 16: 365–370

    Article  PubMed  CAS  Google Scholar 

  17. Kanner BI, Bendahan A (1982) Binding order of substrates to the sodium and potassium ion coupled L-glutamic acid transporter from rat brain. Biochem 21: 6327–6330

    Article  CAS  Google Scholar 

  18. Kempski O, Staub F, Jansen M, Schödel F, Baethmann A (1988) Glial swelling during extracellular acidosis in vitro. Stroke 19: 385–392

    Article  PubMed  CAS  Google Scholar 

  19. Kempski O, Zimmer M, Neu A, v Rosen F, Jansen M, Baethmann A (1987) Control of glial cell volume in anoxia: In vitro studies on ischemic cell swelling. Stroke 18: 623–628

    Article  PubMed  CAS  Google Scholar 

  20. Kimelberg HK, Goderie SK, Higman S, Pang S, Waniewski RA (1990) Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J Neurosci 10: 1583–1591

    PubMed  CAS  Google Scholar 

  21. Kimelberg HK, Rose JW, Barron KD, Waniewski RA, Cragoe EJ (1989) Astrocytic swelling in traumatic-hypoxic brain injury. Beneficial effects of an inhibitor of anion exchange transport and glutamate uptake in glial cells. Molecul Chem Neuropathol 11: 1–31

    Article  CAS  Google Scholar 

  22. Korf J, Postema F (1988) Rapid shrinkage of rat striatal extracellular space after local kainate application and ischemia as recorded by impedance. J Neurosci Res 19: 504–510

    Article  PubMed  CAS  Google Scholar 

  23. Lauritzen M (1994) Pathophysiology of the migraine aura: the spreading depression theory. Brain 117: 199–210

    Article  PubMed  Google Scholar 

  24. Lowry OH, Passonneau JV, Hasselberger FX, Schultz D (1964) Effects of ischemia on known substrates and cofactors of the glycolytic pathway in brain. J Biol Chem 239: 18–30

    PubMed  CAS  Google Scholar 

  25. Maycox PR, Hell JW, Jahn R (1990) Amino acid neurotransmission: spotlight on synaptic vesicles. Trends Neurosci 13: 83–87

    Article  PubMed  CAS  Google Scholar 

  26. McCulloch J, Ozyurt E, Park CK, Nehls DG, Teasdale GM, Graham DI (1993) Glutamate receptor antagonists in experimental focal cerebral ischaemia. In: Baethmann A, Kempski O, Schürer L (eds) Mechanisms of secondary brain damage -current state. Acta Neurochir Wien [Suppl] 57: 73–79

    Google Scholar 

  27. McMahon HT, Foran P, Dolly JO, Verhage M, Wiegant VM, Nicholls DG (1992) Tetanus toxin and botulinum toxins A and B inhibit glutamate, gamma-aminobutyric acid, aspartate, and metenkephalin release from synaptosomes. Clues to the locus of action. J Biol Chem 267: 21338–21343

    PubMed  CAS  Google Scholar 

  28. Meldrum BS, Millan MH, Obrenovitch TP (1993) Injury induced excitatory amino acid release. In: Globus MYT, Dietrich WD (eds) The role of neurotransmitters in brain injury. Plenum, New York, pp l-7

    Google Scholar 

  29. Nicholls DG, Attwell D (1990) The release and uptake of excitatory amino acids. Trends Neurosci 11: 462–468

    Google Scholar 

  30. Nicholls DG, Sihra T (1986) Synaptosomes possess an exocytotic pool of glutamate. Nature 321: 772–773

    Article  PubMed  CAS  Google Scholar 

  31. Obrenovitch TP, Garofalo O, Harris RJ, Bordi L, Ono M, Momma F, Bachelard HS, Symon L (1988) Brain tissue concentration of ATP, phosphocreatine, lactate, and tissue pH in relation to reduced cerebral blood flow following experimental acute middle cerebral artery occlusion. J Cereb Blood Flow Metab 8: 866–874

    Article  PubMed  CAS  Google Scholar 

  32. Obrenovitch TP, Richards DA (1995) Neurotransmitter changes in the extracellular fluid in cerebral ischaemia. Cerebrovasc Brain Metabol Rev 7: 1–54

    CAS  Google Scholar 

  33. Obrenovitch TP, Richards DA, Sarna GS, Symon L (1993a) Combined intracerebral microdialysis and electrophysiological recording: methodology and applications. J Neurosci Meth 47: 139–145

    Article  CAS  Google Scholar 

  34. Obrenovitch TP, Sarna, GS, Millan MH, Lok S-Y, Kawauchi M, Ueda Y, Symon L (1990a) Intracerebral dialysis with on-line enzyme fluorometric detection: a novel method to investigate the changes in the extracellular concentration of glutamic acid. In: Krieglstein J, Oberpichler H (eds) Pharmacology of cerebral ischemia 1990. Thieme, Stuttgart, pp 23–31

    Google Scholar 

  35. Obrenovitch TP, Scheller D, Matsumoto T, Tegtmeier F, Höller M, Symon L (1990b) A rapid redistribution of hydrogen ions is associated with depolarization and repolarization subsequent to cerebral ischaemia/reperfusion. J Neurophysiol 64: 1125–1133

    PubMed  CAS  Google Scholar 

  36. Obrenovitch TP, Urenjak J, Richards DA, Ueda Y, Curzon G, Symon L (1993b) Extracellular neuroactive amino acids in the rat brain striatum during moderate and severe transient ischemia. J Neurochem 61: 178–186

    Article  PubMed  CAS  Google Scholar 

  37. Obrenovitch TP, Zilkha E (1995) Changes in extracellular glutamate concentration associated with propagating cortical spreading depression. In: Olesen J, Moskowitz MA (eds) Experimental headache models in animal and man. Raven, New York, pp 113–117

    Google Scholar 

  38. Obrenovitch TP, Zilkha E, Urenjak J (1995) Intracerebral microdialysis: electrophysiological evidence of a critical pitfall. J Neurochem 64: 1884–1887

    Article  PubMed  CAS  Google Scholar 

  39. Pin J-P, Bockaert J (1989) Two distinct mechanisms differentially affected by excitatory amino acids trigger gammaaminobutyric acid release from striatal neurones in primary cultures. J Neurosci 9: 648–656

    PubMed  CAS  Google Scholar 

  40. Scheller D, Heister U, Kolb J, Tegtmeier F (1993) On the role of excitatory amino acids during generation and propagation of spreading depression. In: Lemenkühler A, Grotemeyer KH, Tegtmeier F (eds) Migraine: basic mechanisms and treatments. Urban and Schwarzenberg, München, pp 355–356

    Google Scholar 

  41. Söllner T, Rothman JE (1994) Neurotransmission: harnessing fusion machinery at the synapse. Trends Neurosci 17: 344–349

    Article  PubMed  Google Scholar 

  42. Storm-Mathisen J, Leknes AK, Bore AT, Waaland JL, Edminson P, Haug F-MS, Ottersen OP (1983) First visualization of glutamate and GABA in neurones by immunocytochemistry. Nature 301: 517–520

    Article  PubMed  CAS  Google Scholar 

  43. Szatkowski M, Attwell D (1994) Triggering and execution of neuronal death in brain ischaemia: two phases of glutamate release by different mechanisms. Trends Neurosci 17: 359–365

    Article  PubMed  CAS  Google Scholar 

  44. Szatkowski M, Barbour B, Attwell D (1990) Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature 348: 443–446

    Article  PubMed  CAS  Google Scholar 

  45. Tyson GW, Teasdale GM, Graham DI, McCulloch J (1984) Focal cerebral ischemia in the rat: topography of hemodynamic and histopathological changes. Ann Neurol 15: 559–567

    Article  PubMed  CAS  Google Scholar 

  46. Van-Vliet BJ, Sebben M, Dumuis A, Gabrion J, Bockaert J, Pin JP (1989) Endogenous amino acid release from cultured cerebellar neuronal cells: effect of tetanus toxin on glutamate release. J Neurochem 52: 1229–1239

    Article  PubMed  CAS  Google Scholar 

  47. Wahl F, Obrenovitch TP, Hardy AM, Plotkine M, Boulu R, Symon L (1994) Extracellular glutamate during focal cerebral ischaemia in rats: Time course and calcium-dependency. J Neurochem 63: 1003–1011

    Article  PubMed  CAS  Google Scholar 

  48. Waldmeier PC, Wicki P, Feldtrauer J-J (1993) Release of endogenous glutamate from rat cortical slices in presence of the glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid. Naunyn Schmiedeberg’s Arch Pharmacol 348: 478–485

    Article  CAS  Google Scholar 

  49. Zilkha E, Obrenovitch TP, Koshi A, Kusakabe H, Bennetto HP (1995) Extracellular glutamate: on-line monitoring using microdialysis coupled to enzyme-amperometric analysis. J Neurosci Meth 60: 1–9

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Gough-Cooper Department of Neurological Surgery, Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    T. P. Obrenovitch Ph.D.

Authors
  1. T. P. Obrenovitch Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institut für Chirurgische Forschung, Klinikum Grosshadern, Ludwig-Maximilians-Universität, München, Federal Republic of Germany

    Alexander Baethmann  & Nikolaus Plesnila  & 

  2. Institut für Neurochirurgische Pathophysiologie, Johannes-Gutenberg-Universität, Mainz, Federal Republic of Germany

    Oliver S. Kempski

  3. Klinik für Neurochirurgie, Universität zu Köln, Köln, Federal Republic of Germany

    Frank Staub

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Springer-Verlag

About this paper

Cite this paper

Obrenovitch, T.P. (1996). Origins of Glutamate Release in Ischaemia. In: Baethmann, A., Kempski, O.S., Plesnila, N., Staub, F. (eds) Mechanisms of Secondary Brain Damage in Cerebral Ischemia and Trauma. Acta Neurochirurgica, vol 66. Springer, Vienna. https://doi.org/10.1007/978-3-7091-9465-2_9

Download citation

  • DOI: https://doi.org/10.1007/978-3-7091-9465-2_9

  • Publisher Name: Springer, Vienna

  • Print ISBN: 978-3-7091-9467-6

  • Online ISBN: 978-3-7091-9465-2

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation