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National Institute of Environmental Health Sciences

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Publication Detail

Title: Characterization of glutamate toxicity in cultured rat cerebellar granule neurons at reduced temperature.

Authors: Berman, F W; Murray, T F

Published In J Biochem Toxicol, (1996)

Abstract: We have defined conditions whereby glutamate becomes toxic to isolated cerebellar granule neurons in a physiologic salt solution (pH 7.4). In the presence of a physiologic Mg++ concentration, acute glutamate excitotoxicity manifests only when the temperature was reduced from 37 degrees C to 22 degrees C. In contrast to glutamate, N-methyl-D-aspartate (NMDA) was nontoxic at either temperature at concentrations as high as 1 mM. Glycine strongly potentiated both the potency and efficacy of glutamate but revealed only a modest NMDA response. The non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxalinedione (CNQX), potently protected against glutamate challenge, although the contribution of antagonism at strychnine-insensitive glycine sites could not be excluded. To further characterize the non-NMDA receptor contribution to the excitotoxic response, the promiscuity of glutamate interaction with ionotropic receptors was simulated by exposing neurons to NMDA in the presence of non-NMDA receptor agonists. NMDA toxicity was potentiated four- to sevenfold when non-NMDA receptors were coactivated by a subtoxic concentration of AMPA, kainate, or domoate. These results suggest that non-NMDA receptor activation participates in the mechanism of acute glutamate toxicity by producing neuronal depolarization (via sodium influx), which in turn promotes the release of the voltage-dependent magnesium blockade of NMDA receptor ion channels.

PubMed ID: 9029269 Exiting the NIEHS site

MeSH Terms: Animals; Cell Count; Cells, Cultured; Cerebellum/cytology; Cerebellum/drug effects*; Cold/adverse effects*; Drug Synergism; Glutamic Acid/toxicity*; Glycine/pharmacology; L-Lactate Dehydrogenase/drug effects; L-Lactate Dehydrogenase/metabolism; N-Methylaspartate/toxicity; Neurons/drug effects*; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate/drug effects; Receptors, N-Methyl-D-Aspartate/metabolism; Research Support, U.S. Gov't, P.H.S.

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