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.

Article date: 1992/4/1

PubMed ID: 2336188

Journal name: Proceedings of the National Academy of Sciences of the United States of America (ISSN: 0027-8424)


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.

Author List: Frandsen A, Schousboe A

Publication Types: Journal Article; Research Support, Non-U.S. Gov't

Substances mentioned in the article: Glutamates; Neurotoxins; Ibotenic Acid; Glutamic Acid; N-Methylaspartate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Quisqualic Acid; Verapamil; Dantrolene; Kainic Acid; Calcium;

Mesh terms: Animals; Calcium/metabolism; Cell Survival/drug effects; Cells, Cultured; Cerebral Cortex/cytology; Dantrolene/pharmacology; Glutamates/pharmacology; Glutamic Acid; Ibotenic Acid/analogs & derivatives; In Vitro Techniques; Kainic Acid/toxicity; Mice; N-Methylaspartate/toxicity; Neurotoxins/toxicity; Quisqualic Acid/toxicity; Verapamil/pharmacology; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid;

Citations: - 1976762

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