Figure 3: Methylmercury inhibits glutathione peroxidase and leads to increased levels of hydrogen peroxide, glutamate dyshomeostasis and lipoperoxidation.

Event (a) represents the glutathione peroxidase-catalyzed reduction of hydrogen peroxide to water with the simultaneous oxidation of glutathione to its disulfide form. Event (b) represents the astrocyte glutamate uptake, which is crucial to remove glutamate from the synaptic cleft, preventing excitotoxicity. As consequence of methylmercury-induced inhibition of glutathione peroxidase (event c), increased levels of hydrogen peroxide may lead to decreased glial glutamate uptake (event d) and increased lipoperoxidation (event h). As result of decreased astrocyte glutamate uptake, the increased levels of extracellular glutamate may lead to hyperactivation of its receptors (i.e. N-methyl-D-aspartate receptor) and increase in calcium influx (event e), which may culminate in excitotoxicity (event f) and mitochondrial dyshomeostasis (event g).

GSH (reduced glutathione = γ-l-glutamyl-l-cysteinylglycine); GSSG (oxidized glutathione); Glu (glutamate); GPx (glutathione peroxidase); H₂O₂ (hydrogen peroxide); NMDA R (N-methyl-D-aspartate receptor); mGlu R (metabotropic glutamate receptors).