In vitro evidence for the role of glutamate in the CNS toxicity of mercury.
Intoxication with elemental mercury vapor or with methylmercury results in the accumulation of mercuric mercury (Hg2+) in the brain. Submicromolar concentrations of Hg2+ were shown previously to inhibit glutamate uptake in astrocyte cultures selectively and reversibly. This finding suggests that blockade of the inactivation of synaptically released glutamate is a potential mechanism of the CNS toxicity of Hg2+. The present study shows further that Hg2+ (< or = 1 microM): (i) markedly inhibits the clearance of extracellular glutamate both by astrocyte cultures and by spinal cord cultures; (ii) reduces glutamine content and export in astrocyte cultures; (iii) has little effect on neuronal viability in spinal cord cultures in the absence of excitotoxic accumulations of glutamate; (iv) does not impair the sensitivity of neurons to the excitotoxic action of glutamate. Also, it is noted that Hg2+ (< or = 1 microM) has not been shown to impair transmitter release acutely in existing studies of presynaptic actions. Thus, the available evidence from in vitro studies is consistent with the hypothesis that low concentrations of mercuric mercury in the brain can cause neurotoxicity by selectively inhibiting the uptake of synaptically released glutamate, with consequent elevation of glutamate levels in the extracellular space.
Brookes
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Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000139:chemically induced*; D003847:Deoxyglucose / Q000493:pharmacokinetics; D005110:Extracellular Space / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism / Q000493:pharmacokinetics / Q000502:physiology*; D018698:Glutamic Acid; D005973:Glutamine / Q000378:metabolism; D008628:Mercury / Q000633:toxicity*; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010784:Photomicrography; D016622:Silver Staining; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium
D005971:Glutamates; D005973:Glutamine; D014316:Tritium; D018698:Glutamic Acid; D003847:Deoxyglucose; D008628:Mercury