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Attenuation of Glutamate‐Induced Neurotoxicity in Chronically Ethanol‐Exposed Cerebellar Granule Cells by NMDA Receptor Antagonists and Ganglioside GM 1
Author(s) -
Hoffman Paula L.,
Lorio Karen R.,
Snell Lawrence D.,
Tabakoff Boris
Publication year - 1995
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.1995.tb01573.x
Subject(s) - nmda receptor , excitotoxicity , glutamate receptor , neurotoxicity , ganglioside , pharmacology , chemistry , downregulation and upregulation , cerebellum , receptor , toxicity , biochemistry , endocrinology , biology , gene , organic chemistry
Ethanol, acutely, is a potent inhibitor of the function of the N ‐methyl‐D‐aspartate (NMDA) subtype of glutamate receptor. After chronic exposure of animals to ethanol, however, the NMDA receptor in brain is upregulated. This upregulation is associated with the occurrence of ethanol withdrawal seizures. When cultured cerebellar granule neurons are exposed chronically to ethanol, the resulting upregulation of NMDA receptor function renders the cells more susceptible to glutamate‐induced neurotoxicity. The present studies show that chronic ethanol exposure produces an increase in NMDA receptor number in the cells, measured by ligand binding to intact cells. Glutamate‐induced excitotoxicity, both in control and ethanol‐exposed cells, is blocked by the same NMDA receptor antagonists previously shown to block ethanol withdrawal seizures in animals. In addition, glutamate neurotoxicity is blocked by acute (2‐hr) pretreatment of cells with ganglioside GM., or by chronic (3 days) treatment with the ganglioside. Acute ganglioside treatment does not interfere with the initial rise in intracellular calcium caused by glutamate, whereas this response is downregulated after chronic ganglioside treatment. These results suggest that therapeutic agents can be developed to block both ethanol withdrawal signs and the neuronal damage that accompanies ethanol withdrawal. Furthermore, chronic ganglioside treatment during ethanol exposure has the potential to prevent changes in the NMDA receptor that lead to withdrawal seizures and enhanced susceptibility to excitotoxicity.