Attenuation of low dose methylmercury and glutamate induced-cytotoxicity and tau phosphorylation by an N-methyl-D-aspartate antagonist in human neuroblastoma (SHSY5Y) cells.

Methylmercury (MeHg), a known neurotoxin, has been reported to alter glutamate homeostasis in the neuronal environment resulting in excitotoxicity. This study was conducted to investigate whether, and if so, under what conditions, that low dose MeHg would enhance the toxicity of glutamate and to what extent that blockade of NMDA receptors would alter MeHg and glutamate's toxicity in cultured neuroblastoma cells. Neuroblastoma cells (SH-SY5Y) were used in a cell culture model to study effects of MeHg, glutamate (glu), a calcium chelator (BAPTA-AM), and a noncompetitive NMDA antagonist, MK-801 on cell growth, cell survival, and phosphorylation of tau protein, as a measure of cellular events associated with tauopathies. Exposure of cells to a combination of MeHg (50 nM) and glutamate (1 mM) resulted in both a greater decrease in cell viability as well as a greater induction in tau phosphorylation, as compared to exposures with MeHg and glutamate alone. MK-801, an NMDA receptor antagonist, and the intracellular calcium chelator, BAPTA-AM, both significantly inhibited tau hyperphosphorylation and protected cells from the effects of combination exposures to glutamate and MeHg. These results may indicate that exposure to even nontoxic levels of MeHg may prime neuronal cells to be more susceptible to neuronal injury from excitotoxicants such as glutamate and thus may increase the likelihood of neurological disease states. In conclusion, low-dose MeHg-induced toxicity may be related to an increase in the cellular response to glutamate and that NMDA receptor antagonists may provide a potential treatment for MeHg-associated neurological diseases.