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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1992 Apr 1;89(7):2590–2594. doi: 10.1073/pnas.89.7.2590

Mobilization of dantrolene-sensitive intracellular calcium pools is involved in the cytotoxicity induced by quisqualate and N-methyl-D-aspartate but not by 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate and kainate in cultured cerebral cortical neurons.

A Frandsen 1, A Schousboe 1
PMCID: PMC48707  PMID: 1372982

Abstract

By using primary cultures of cerebral cortical neurons, it has been demonstrated that the antihyperthermia drug dantrolene protects against cytotoxicity induced by the excitatory amino acids quisqualate (QA) and N-methyl-D-aspartate (NMDA), whereas no effect was observed on cell damage mediated by kainate (KA) or 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionate (AMPA). In parallel it was shown that KA and AMPA increased the concentration of intracellular free calcium ([Ca2+]i) mainly by influx, whereas the increase in [Ca2+]i stimulated by NMDA and QA predominantly was caused by release of Ca2+ from intracellular stores, which for NMDA seemed to be mediated at least partly by Ca2+ influx. In accordance with the effects on cytotoxicity, dantrolene blocked the increase in [Ca2+]i elicited by QA and NMDA leaving the increase induced by KA and AMPA unaffected. The finding that 2-amino-3-[3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionate, which regarding toxicity is a selective KA antagonist, only reduced the KA-stimulated increase in [Ca2+]i by 30% may suggest that the elevation of [Ca2+]i is not the only element in KA-induced cytotoxicity. On the other hand, the present study underlines the importance of Ca2+ for cytotoxicity induced by some excitatory amino acids (glutamate, NMDA, and QA) and supports the current proposal that multiple mechanisms are operating, even concerning calcium homeostasis. Because excitatory amino acid-induced cytotoxicity is thought to be involved in neuropathological conditions such as ischemia, it is possible that dantrolene might be of therapeutic interest.

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Selected References

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  1. Bouchelouche P., Belhage B., Frandsen A., Drejer J., Schousboe A. Glutamate receptor activation in cultured cerebellar granule cells increases cytosolic free Ca2+ by mobilization of cellular Ca2+ and activation of Ca2+ influx. Exp Brain Res. 1989;76(2):281–291. doi: 10.1007/BF00247888. [DOI] [PubMed] [Google Scholar]
  2. Choi D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988 Oct;1(8):623–634. doi: 10.1016/0896-6273(88)90162-6. [DOI] [PubMed] [Google Scholar]
  3. Davies J., Francis A. A., Jones A. W., Watkins J. C. 2-Amino-5-phosphonovalerate (2APV), a potent and selective antagonist of amino acid-induced and synaptic excitation. Neurosci Lett. 1981 Jan 1;21(1):77–81. doi: 10.1016/0304-3940(81)90061-6. [DOI] [PubMed] [Google Scholar]
  4. Dichter M. A. Rat cortical neurons in cell culture: culture methods, cell morphology, electrophysiology, and synapse formation. Brain Res. 1978 Jun 30;149(2):279–293. doi: 10.1016/0006-8993(78)90476-6. [DOI] [PubMed] [Google Scholar]
  5. Drejer J., Honoré T., Schousboe A. Excitatory amino acid-induced release of 3H-GABA from cultured mouse cerebral cortex interneurons. J Neurosci. 1987 Sep;7(9):2910–2916. doi: 10.1523/JNEUROSCI.07-09-02910.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ellrén K., Lehmann A. Calcium dependency of N-methyl-D-aspartate toxicity in slices from the immature rat hippocampus. Neuroscience. 1989;32(2):371–379. doi: 10.1016/0306-4522(89)90085-7. [DOI] [PubMed] [Google Scholar]
  7. Frandsen A., Andersen C. F., Schousboe A. Possible role of cGMP in excitatory amino acid induced cytotoxicity in cultured cerebral cortical neurons. Neurochem Res. 1992 Jan;17(1):35–43. doi: 10.1007/BF00966863. [DOI] [PubMed] [Google Scholar]
  8. Frandsen A., Drejer J., Schousboe A. Direct evidence that excitotoxicity in cultured neurons is mediated via N-methyl-D-aspartate (NMDA) as well as non-NMDA receptors. J Neurochem. 1989 Jul;53(1):297–299. doi: 10.1111/j.1471-4159.1989.tb07327.x. [DOI] [PubMed] [Google Scholar]
  9. Frandsen A., Drejer J., Schousboe A. Glutamate-induced 45Ca2+ uptake into immature cerebral cortex neurons shows a distinct pharmacological profile. J Neurochem. 1989 Dec;53(6):1959–1962. doi: 10.1111/j.1471-4159.1989.tb09268.x. [DOI] [PubMed] [Google Scholar]
  10. Frandsen A., Krogsgaard-Larsen P., Schousboe A. Novel glutamate receptor antagonists selectively protect against kainic acid neurotoxicity in cultured cerebral cortex neurons. J Neurochem. 1990 Nov;55(5):1821–1823. doi: 10.1111/j.1471-4159.1990.tb04976.x. [DOI] [PubMed] [Google Scholar]
  11. Frandsen A., Quistorff B., Schousboe A. Phenobarbital protects cerebral cortex neurones against toxicity induced by kainate but not by other excitatory amino acids. Neurosci Lett. 1990 Mar 26;111(1-2):233–238. doi: 10.1016/0304-3940(90)90374-i. [DOI] [PubMed] [Google Scholar]
  12. Frandsen A., Schousboe A. Dantrolene prevents glutamate cytotoxicity and Ca2+ release from intracellular stores in cultured cerebral cortical neurons. J Neurochem. 1991 Mar;56(3):1075–1078. doi: 10.1111/j.1471-4159.1991.tb02031.x. [DOI] [PubMed] [Google Scholar]
  13. Frandsen A., Schousboe A. Development of excitatory amino acid induced cytotoxicity in cultured neurons. Int J Dev Neurosci. 1990;8(2):209–216. doi: 10.1016/0736-5748(90)90013-r. [DOI] [PubMed] [Google Scholar]
  14. Honoré T., Davies S. N., Drejer J., Fletcher E. J., Jacobsen P., Lodge D., Nielsen F. E. Quinoxalinediones: potent competitive non-NMDA glutamate receptor antagonists. Science. 1988 Aug 5;241(4866):701–703. doi: 10.1126/science.2899909. [DOI] [PubMed] [Google Scholar]
  15. Koh J. Y., Choi D. W. Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay. J Neurosci Methods. 1987 May;20(1):83–90. doi: 10.1016/0165-0270(87)90041-0. [DOI] [PubMed] [Google Scholar]
  16. Kojima I., Kojima K., Kreutter D., Rasmussen H. The temporal integration of the aldosterone secretory response to angiotensin occurs via two intracellular pathways. J Biol Chem. 1984 Dec 10;259(23):14448–14457. [PubMed] [Google Scholar]
  17. Minta A., Kao J. P., Tsien R. Y. Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J Biol Chem. 1989 May 15;264(14):8171–8178. [PubMed] [Google Scholar]
  18. Nicoletti F., Wroblewski J. T., Novelli A., Guidotti A., Costa E. Excitatory amino acid signal transduction in cerebellar cell cultures. Funct Neurol. 1986 Oct-Dec;1(4):345–349. [PubMed] [Google Scholar]
  19. Rothman S. M., Thurston J. H., Hauhart R. E. Delayed neurotoxicity of excitatory amino acids in vitro. Neuroscience. 1987 Aug;22(2):471–480. doi: 10.1016/0306-4522(87)90347-2. [DOI] [PubMed] [Google Scholar]
  20. Schousboe A., Drejer J., Hansen G. H., Meier E. Cultured neurons as model systems for biochemical and pharmacological studies on receptors for neurotransmitter amino acids. Dev Neurosci. 1985;7(5-6):252–262. doi: 10.1159/000112294. [DOI] [PubMed] [Google Scholar]
  21. Siesjö B. K., Bengtsson F., Grampp W., Theander S. Calcium, excitotoxins, and neuronal death in the brain. Ann N Y Acad Sci. 1989;568:234–251. doi: 10.1111/j.1749-6632.1989.tb12513.x. [DOI] [PubMed] [Google Scholar]
  22. Sladeczek F., Pin J. P., Récasens M., Bockaert J., Weiss S. Glutamate stimulates inositol phosphate formation in striatal neurones. Nature. 1985 Oct 24;317(6039):717–719. doi: 10.1038/317717a0. [DOI] [PubMed] [Google Scholar]
  23. Wahl P., Schousboe A., Honoŕe T., Drejer J. Glutamate-induced increase in intracellular Ca2+ in cerebral cortex neurons is transient in immature cells but permanent in mature cells. J Neurochem. 1989 Oct;53(4):1316–1319. doi: 10.1111/j.1471-4159.1989.tb07430.x. [DOI] [PubMed] [Google Scholar]
  24. Ward A., Chaffman M. O., Sorkin E. M. Dantrolene. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in malignant hyperthermia, the neuroleptic malignant syndrome and an update of its use in muscle spasticity. Drugs. 1986 Aug;32(2):130–168. doi: 10.2165/00003495-198632020-00003. [DOI] [PubMed] [Google Scholar]
  25. Weiss J. H., Hartley D. M., Koh J., Choi D. W. The calcium channel blocker nifedipine attenuates slow excitatory amino acid neurotoxicity. Science. 1990 Mar 23;247(4949 Pt 1):1474–1477. doi: 10.1126/science.247.4949.1474. [DOI] [PubMed] [Google Scholar]

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