Dantrolene prevents glutamate cytotoxicity and Ca2+ release from intracellular stores in cultured cerebral cortical neurons.
Using primary cultures of cerebral cortical neurons, it has been demonstrated that the antihyperthermia drug dantrolene completely protects against glutamate-induced neurotoxicity. Furthermore, in the presence of extracellular calcium, dantrolene reduced the glutamate-induced increase in the intracellular calcium concentration by 70%. In the absence of extracellular calcium, this glutamate response was completely blocked by dantrolene. Dantrolene did not affect the kinetics of [3H]glutamate binding to membranes prepared from similar cultures. These results indicate that release of calcium from intracellular stores is essential for the propagation of glutamate-induced neuronal damage. Because it is likely that glutamate is involved in neuronal degeneration associated with ischemia and hypoxia, the present findings might suggest that dantrolene and possibly other drugs affecting intracellular calcium pools might be of therapeutic interest.
Frandsen
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PharmaBiotec Research Center, Department of Biology B, Royal Danish School of Pharmacy, Copenhagen, Denmark.
Schousboe
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D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D003620:Dantrolene / Q000494:pharmacology*; D005971:Glutamates / Q000633:toxicity*; D018698:Glutamic Acid; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology
D005971:Glutamates; D018698:Glutamic Acid; D011189:Potassium Chloride; D003620:Dantrolene; D002118:Calcium