Glutamate: a potential mediator of inorganic mercury neurotoxicity.

Exposure to mercury vapor (Hg0) produces neurotoxic effects which are for the most part subsequent to its biotransformation in brain to the mercuric cation (Hg2 +), which has an exceptionally strong affinity towards the SH groups in proteins. However, neurologic symptoms are often encountered in subjects in which Hg+ concentration in the brain remains in the submicromolar range, markedly below the anticipated threshold for direct inhibition of cerebral metabolism and function. In this report we review biochemical and morphological evidence obtained in this and other laboratories in tissue culture studies suggesting that in such instances mercury neurotoxicity may be mediated by excitotoxic activity of glutamate (GLU). Mercuric chloride (MC) at 1 microM concentration (or less) inhibits GLU uptake and stimulates GLU release in cultured astrocytes, which in vivo is likely to result in excessive GLU accumulation in the extracellular space of the CNS. Inhibition of GLU uptake and stimulation of GLU release by MC may be attenuated by addition to the cultures of a cell membrane-penetrating agent dithiothreitol (DTT) but not of glutathione (GSH), which is not transported to the inside of the cells. However, MC-stimulated release of GLU is suppressed when the intracellular GSH levels are increased by metabolic manipulation. The results indicate that the MC-vulnerable SH groups critical for GLU transport are located within the astrocytic membranes. Ultrastructural evidence for GLU-mediated MC neurotoxicity came from studies in an organotypic culture of rat cerebellum. We have shown that: 1) 1 microM MC lowers the threshold of GLU neurotoxicity, 2) the combined neurotoxic effect of GLU plus MC is attenuated by DTT but not by GSH, which is consistent with the involvement of impaired astrocytic GLU transport, and 3) neuronal damage induced by GLU plus MC becomes less accentuated in a medium with dizocilpine (MK-801), a noncompetitive NMDA receptor antagonist.