Role of glutathione in determining the differential sensitivity between the cortical and cerebellar regions towards mercury-induced oxidative stress

Abstract: Certain discrete areas of the CNS exhibit enhanced sensitivity towards MeHg. To determine whether GSH is responsible for this particular sensitivity, we investigated its role in MeHg-induced oxidative insult in primary neuronal and astroglial cell cultures of both cerebellar and cortical origins. For this purpose, ROS and GSH were measured with the fluorescent indicators, CMH2DCFDA and MCB. Cell associated-MeHg was measured with 14C-radiolabeled MeHg. The intracellular GSH content was modified by pretreatment with NAC or DEM. For each of the dependent variables (ROS, GSH, and MTT), there was an overall significant effect of cellular origin, MeHg and pretreatment in all the cell cultures. A trend towards significant interaction between origin×MeHg×pretreatment was observed only for the dependent variable, ROS (astrocytes p =0.056; neurons p =0.000). For GSH, a significant interaction between origin×MeHg was observed only in astrocytes (p =0.030). The cerebellar cell cultures were more vulnerable (astrocytesmean =223.77; neuronsmean =138.06) to ROS than the cortical cell cultures (astrocytesmean =125.18; neuronsmean =107.91) for each of the tested treatments. The cell associated-MeHg increased when treated with DEM, and the cerebellar cultures varied significantly from the cortical cultures. Non-significant interactions between origin×MeHg×pretreatment for GSH did not explain the significant interactions responsible for the increased amount of ROS produced in these cultures. In summary, although GSH modulation influences MeHg-induced toxicity, the difference in the content of GSH in cortical and cerebellar cultures fails to account for the increased ROS production in cerebellar cultures. Hence, different approaches for the future studies regarding the mechanisms behind selectivity of MeHg have been discussed. [Copyright &y& Elsevier]