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.
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.
Frandsen
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Department of Biological Sciences, Royal Danish School of Pharmacy, Copenhagen.
Schousboe
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D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D003620:Dantrolene / Q000494:pharmacology*; D005971:Glutamates / Q000494:pharmacology; D018698:Glutamic Acid; D007051:Ibotenic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity*; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity*; D009498:Neurotoxins / Q000633:toxicity*; D016318:Quisqualic Acid / Q000633:toxicity*; D014700:Verapamil / Q000494:pharmacology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D005971:Glutamates; D009498:Neurotoxins; D007051:Ibotenic Acid; D018698:Glutamic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D016318:Quisqualic Acid; D014700:Verapamil; D003620:Dantrolene; D007608:Kainic Acid; D002118:Calcium