Methylmercury induces oxidative stress and subsequent neural hyperactivity leading to cell death through the p38 MAPK-CREB pathway in differentiated SH-SY5Y cells.

Methylmercury (MeHg) induces site-specific cerebrocortical neuronal cell death. In our previous study using an in vivo mouse model, we reported that MeHg-induced cerebrocortical neuronal cell death may be due to neural hyperactivity triggered by activation of kinase pathways. However, the detailed molecular mechanism remained to be completely understood. In this study, we analyzed detailed signaling pathways for MeHg-induced neuronal cell death using all-trans-retinoic acid (RA) differentiated SH-SY5Y cells, which show neuron-like morphological changes and express neuron/synapse markers for cerebrocortical neurons. Time course studies revealed that MeHg-induced upregulation of c-fos, a marker of neural activation, preceded neuronal cell death. These results were similar to those observed in a MeHg-intoxicated mouse model. We observed early expression of the oxidative stress marker thymidine glycol followed by activation of p44/42 mitogen-activated protein kinase (MAPK) and p38 MAPK, and an increase in cAMP response element binding protein (CREB). Investigation of the effects of specific kinase inhibitors revealed that SB203580, a specific inhibitor for p38 MAPK, significantly blocked the upregulation of c-fos and the subsequent neuronal cell death. In contrast, PD98059 and U0126, specific inhibitors for p44/p42 MAPK, showed no effects on MeHg-induced neurotoxicity. Furthermore, the antioxidants Trolox and edaravone significantly suppressed MeHg-induced thymidine glycol expression, p38 MAPK-CREB pathway activation, and neurotoxicity. Altogether, these results suggest that MeHg-induced oxidative stress and subsequent activation of the p38 MAPK-CREB pathway contribute to cerebrocortical neuronal hyperactivity and subsequent neuronal cell death.