Acute Brain Injury, NMDA Receptors, and Hydrogen Ions: Observations in Cortical Cell Cultures

  • Dennis W. Choi
  • Hannelore Monyer
  • Rona G. Giffard
  • Mark P. Goldberg
  • Chadwick W. Christine
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 268)


Excess stimulation of NMDA receptors by endogenous glutamate likely contributes to the neuronal cell loss associated with several types of acute brain injury in vivo (Meldrum, 1985; Rothman and Olney, 1987, Choi, 1988), including ischemia (Simon et al., 1984), hypoglycemia (Wieloch, 1985), epilepsy (Labuyere et al., 1986) and trauma (Faden and Simon, 1988). Among the experiments supporting this statement are those studying the controlled delivery of insults to dispersed neuronal and glial cells in primary culture. Demonstration that a given pharmacological manipulation is neuroprotective in such cultures establishes that a beneficial effect can be produced directly on brain parenchyma, without involvement of systemic metabolism or alterations in blood flow. While organizational features of the intact nervous system are not expressed in cell culture, many intrinsic aspects of neuronal and glial cell behavior do appear to be qualitatively preserved. In particular, basic mechanisms relevant to glutamate transmission and glutamate neurotoxicity are present in cultured brain cells.


NMDA Receptor Neuronal Injury NMDA Antagonist Glucose Deprivation Acute Brain Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Auer, R.N., and Siesjo, B.K., 1988, Biological differences between ischemia, hypoglycemia, and epilepsy, Ann. Neurol, 24: 699.PubMedCrossRefGoogle Scholar
  2. Bradford, H.F., Ward, H.K., and Thomas, A.J., 1978, Glutamine - A major substrate for nerve endings, J. Neurochem, 30: 1453.PubMedCrossRefGoogle Scholar
  3. Choi, D.W., 1987, Ionic dependence of glutamate neurotoxicity in cortical cell culture, J. Neurosci, 7: 369.PubMedGoogle Scholar
  4. Choi, D.W., 1988, Glutamate neurotoxicity and diseases of the nervous system, Neuron, 1: 623.PubMedCrossRefGoogle Scholar
  5. Dunwiddie, T.V., 1985, The physiological role of adenosine in the central nervous system, Int. Rev. Neurobiol, 27: 63.PubMedCrossRefGoogle Scholar
  6. Evans, M.C., Swan, J.H., and Meldrum, B.S., 1988, An adenosine analogue, 2-chloroadenosine, protects against long term development of ischaemic cell loss in the rat hippocampus, Neurosci. Lett, 83: 287.CrossRefGoogle Scholar
  7. Faden, A.I., Demediuk, P., Panter, S.S., Vink, R., 1989, The role of excitatory amino acids and NMDA receptors in traumatic brain injury, Science, 244: 798.PubMedCrossRefGoogle Scholar
  8. Faden, A.I., and Simon, R.P., 1988, A potential role for excitotoxins in the pathophysiology of spinal cord injury, Ann. Neurol, 23: 623.PubMedCrossRefGoogle Scholar
  9. Giffard, R.G., Monyer, H., Christine, C.W., and Choi, D.W., 1989, Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures, Brain Res., in press.Google Scholar
  10. Goldberg, M.P., Monyer, H., and Choi, D.W., 1988a, Hypoxic neuronal injury in vitro depends on extracellular glutamine, Neurosci. Lett, 94: 52.PubMedCrossRefGoogle Scholar
  11. Goldberg, M.P., Monyer, H., and Choi, D.W., 1988b, Cortical neuronal injury in vitro following combined glucose and oxygen deprivation: ionic dependence and delayed protection by NMDA antagonists, Soc. Neurosci. Abstr, 14: 745.Google Scholar
  12. Goldberg, M.P., Monyer, H., Weiss, J.W., and Choi, D.W., 1988c, Adenosine reduces cortical neuronal injury induced by oxygen or glucose deprivation in vitro, Neurosci. Lett, 89: 323.PubMedCrossRefGoogle Scholar
  13. Goldberg, M.P., Pham, P.C., and Choi, D.W., 1987a, Dextrorphan and dextromethorphan attenuate hypoxic injury in neuronal culture, Neurosci. Lett, 80: 11.PubMedCrossRefGoogle Scholar
  14. Goldberg, M.P., Viseskul, V., and Choi, D.W., 1988d, Phencyclidine receptor ligands attenuate cortical neuronal injury following N-methyl-D-aspartate exposure or hypoxia, J. Pharmacol. Exp. Therap, 245: 1081.Google Scholar
  15. Goldberg, M.P., Weiss, J.W., Pham, P.C., and Choi, D.W., 1987b, N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture, J. Pharmacol. Exp. Therap, 243: 784.Google Scholar
  16. Hamberger, A.C., Chiang, G.H., Nylen, E.S., Scheff, S.W., and Cotman, C.W., 1979, Glutamate as a CNS transmitter. I.Evaluation of glucose and glutamine as precursors for the synthesis of preferentially released glutamate, Brain Res., 168: 513.PubMedCrossRefGoogle Scholar
  17. Hayes, R.L., Jenkins, L.W., Lyeth, B.G., Balster, R.L., Robinson, S.E., Clifton, G.L., Stubbins, J.F., Young, H.F., 1988, Pretreatment with phencyclidine, an N-methyl-D-aspartate antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury, J. Neurotrauma, 5: 259.PubMedCrossRefGoogle Scholar
  18. Labuyere, J., Fuller, T.A., Olney, J.W., Price, M.T., Zorumski, C., Clifford, D., 1986, Phencyclidine and ketamine protect against kainic acid-induced seizures and seizure-related brain damage, Soc. Neurosci. Abstr, 12: 344.Google Scholar
  19. McIntosh, T., Soares, H., Hayes, R., Simon, R., 1988, The NMDA receptor antagonist MK-801 prevents edema and restores magnesium homeostasis after traumatic brain injury in rats, in: “Frontiers in Excitatory Amino Acid Research,” E.A. Calalheiro, J. Lehmann, and L. Turski, eds., Alan R. Liss, New York.Google Scholar
  20. Meldrum, B., 1985, Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters, Clin. Sci, 68: 113.PubMedGoogle Scholar
  21. Monyer, H., Goldberg, M.P., Choi, D.W., 1989, Glucose deprivation neuronal injury in cortical culture, Brain Res., 483: 347.PubMedCrossRefGoogle Scholar
  22. Monyer, H., and Choi, D.W., 1989, Glucose deprivation neuronal injury in vitro is modified by withdrawal of extracellular glutamine, J. Cereb. Blood Flow Metab, accepted.Google Scholar
  23. Morad, M., Dichter, M., and Tang, C.M., 1988, The NMDA activated current in hippocampal neurons is highly sensitive to [H+] Soc. Neurosci. Abstr. 14: 791.Google Scholar
  24. Rothman, S., 1984, Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death, J. Neurosci, 4: 1884.PubMedGoogle Scholar
  25. Rothman, S.M., and Olney, J.W. 1987, Excitotoxicity and the NMDA receptor, Trends Neurosci., 10: 299.CrossRefGoogle Scholar
  26. Schurr, A., Dong, W.Q., Reid, K.H., West, C.A., and Rigor, B.M., 1988, Lactic acidosis and recovery of neuronal function following cerebral hypoxia in vitro, Brain Res., 438: 311.PubMedCrossRefGoogle Scholar
  27. Simon, R.P., Swan, J.H., Griffiths, T., and Meldrum, B.S., 1984, Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain, Science, 226: 850.PubMedCrossRefGoogle Scholar
  28. Tecoma, E.S., Monyer, H., Goldberg, M.P., and Choi, D.W., 1989, Traumatic neuronal injury in vitro is attenuated by NMDA antagonists, Neuron, 2: 1541.PubMedCrossRefGoogle Scholar
  29. Von Lubitz, D.K., Dambrosia, J.M., Kempski, O., and Redmond, D.J., 1988, Cyclohexyl adenosine protects against neuronal death following ischemia in the CAI region of gerbil hippocampus, Stroke, 19: 1133.CrossRefGoogle Scholar
  30. Weiss, J., Goldberg, M.P., and Choi, D.W., 1986, Ketamine protects culturedneocortical neurons from hypoxic injury, Brain Res., 380: 186.PubMedCrossRefGoogle Scholar
  31. Wieloch, T., 1985, Hypoglycemia-induced neuronal damage prevented by an N-methyl-Daspartate antagonist, Science, 230: 681.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1990

Authors and Affiliations

  • Dennis W. Choi
    • 1
  • Hannelore Monyer
    • 1
  • Rona G. Giffard
    • 2
  • Mark P. Goldberg
    • 1
  • Chadwick W. Christine
    • 1
  1. 1.Department of NeurologyStanford University Medical CenterStanfordUSA
  2. 2.Department of AnesthesiaStanford University Medical CenterStanfordUSA

Personalised recommendations