Oxidative stress accelerates synaptic glutamate dyshomeostasis and NMDARs disorder during methylmercury‐induced neuronal apoptosis in rat cerebral cortex

Methylmercury (MeHg) is a potent neurotoxin,which leads to a wide range of intracellular effects. The molecular mechanismsassociated to MeHg‐induced neurotoxicity have not been fully understood.Oxidative stress, as well as synaptic glutamate (Glu) dyshomeostasis have beenidentified as two critical mechanisms during MeHg‐mediated cytotoxicity. Here,we developed a rat model of MeHg poisoning to evaluate its neurotoxic effectsby focusing on cellular oxidative stress and synaptic Glu disruption. Inaddition, we investigated the neuroprotective role of alpha‐lipoic acid (α‐LA), a natural antioxidant, todeeply explore the underlying interaction between them. Fifty‐six rats wererandomly divided into four groups: saline control, MeHg treatment (4 or 12μmol/kg MeHg), and α‐LApre‐treatment (35 μmol/kg α‐LA+12μmol/kg MeHg). Rats exposed to 12 μmol/kg MeHg induced neuronal oxidativestress, with ROS accumulation and cellular antioxidant system impairment. Nrf2 andxCT pathways were activated with MeHg treatment. The enzymatic or non‐enzymaticof cellular GSH synthesis were also disrupted by MeHg. On the other hand, the abnormalactivities of GS and PAG disturbed the “Glu‐Gln cycle”, leading to NMDARsover‐activation, Ca2+ overload, and the calpain activation, which acceleratedNMDARs degradation. Meanwhile, the high expressions of phospho‐p44/42 MAPK,phospho‐p38 MAPK, phospho‐CREB, and the high levels of caspase 3 and Bax/Bcl‐2 finallyindicated the neuronal apoptosis after MeHg exposure. Pre‐treatment with α‐LA significantly preventedMeHg‐induced neurotoxicity. In conclusion, the oxidative stress and synapticGlu dyshomeostasis contributed to MeHg‐induced neuronal apoptosis. Alpha‐LAattenuated these toxic effects through mechanisms of anti‐oxidation andindirect Glu dyshomeostasis prevention