The molecular mechanisms mediating mercury-induced neurotoxicity are not yet completely understood. Thus, the aim of this study was to investigate whether the severity of MeHg-and HgCl2-mediated cytotoxicity to SH-SY5Y human dopaminergic neurons can be attenuated by regulating glutamate-mediated signal-transmission through caffeine and interferon-gamma (IFN-gamma). The SH-SY5Y cells were exposed to 1, 2 and 5 mu M of either MeHgCl2 or HgCl2 in the presence or absence of L-glutamine. To examine the effect of adenosine receptor antagonist, the cells were treated with 10 and 20 mu M caffeine. The total mitochondrial metabolic activity and oxidative stress intensity coefficient were determined in the 1 ng/ml IFN-gamma-and glutamate-stimulated SH-SY5Y cells. Following exposure to mercury, the concentration-dependent decrease in mitochondrial metabolic activity inversely correlated with oxidative stress intensity. MeHg was more toxic than HgCl2. Mercury-induced neuronal death was dependent on glutamate-mediated excitotoxicity. Caffeine reduced the mercury-induced oxidative stress in glutaminecontaining medium. IFN-gamma treatment decreased cell viability and increased oxidative stress in glutamine-free medium, despite caffeine supplementation. Although caffeine exerted a protective effect against MeHg-induced toxicity with glutamate transmission, under co-stimulation with glutamine and IFN-gamma, caffeine decreased the MeHg-induced average oxidative stress only by half. Thereby, our data indicate that the IFN-gamma stimulation of mercury-exposed dopaminergic neurons in neuroinflammatory diseases may diminish the neuroprotective effects of caffeine.