Glutathione-Mediated Neuroprotection Against Methylmercury Neurotoxicity in Cortical Culture is Dependent on MRP1

Authors

Travis Rush, Marquette University
Xiaoqian Liu, Marquette UniversityFollow
Andrew B. Nowakowski, University of Wisconsin - Milwaukee
David H. Petering, University of Wisconsin - Milwaukee
Doug Lobner, Marquette UniversityFollow

Document Type

Article

Language

eng

Format of Original

6 p.

Publication Date

6-2012

Publisher

Elsevier

Source Publication

Neurotoxicology

Source ISSN

0161-813X

Original Item ID

doi: 10.1016/j.neuro.2012.03.004

Abstract

Methylmercury (MeHg) exposure at high concentrations poses significant neurotoxic threat to humans worldwide. The present study investigated the mechanisms of glutathione-mediated attenuation of MeHg neurotoxicity in primary cortical culture. MeHg (5 μM) caused depletion of mono- and disulfide glutathione in neuronal, glial and mixed cultures. Supplementation with exogenous glutathione, specifically glutathione monoethyl ester (GSHME) protected against the MeHg induced neuronal death. MeHg caused increased reactive oxygen species (ROS) formation measured by dichlorodihydrofluorescein (DCF) fluorescence with an early increase at 30 min and a late increase at 6 h. This oxidative stress was prevented by the presence of either GSHME or the free radical scavenger, trolox. While trolox was capable of quenching the ROS, it showed no neuroprotection. Exposure to MeHg at subtoxic concentrations (3 μM) caused an increase in system x_c⁻ mediated ¹⁴C-cystine uptake that was blocked by the protein synthesis inhibitor, cycloheximide (CHX). Interestingly, blockade of the early ROS burst prevented the functional upregulation of system x_c⁻. Inhibition of multidrug resistance protein-1 (MRP1) potentiated MeHg neurotoxicity and increased cellular MeHg. Taken together, these data suggest glutathione offers neuroprotection against MeHg toxicity in a manner dependent on MRP1-mediated efflux.

Comments

Accepted version. NeuroToxicology, Vol. 33, No. 3 (June 2012): 476-481. DOI. © 2012 Elsevier Inc. Used with permission.

Recommended Citation

Rush, Travis; Liu, Xiaoqian; Nowakowski, Andrew B.; Petering, David H.; and Lobner, Doug, "Glutathione-Mediated Neuroprotection Against Methylmercury Neurotoxicity in Cortical Culture is Dependent on MRP1" (2012). Biomedical Sciences Faculty Research and Publications. 34.
https://epublications.marquette.edu/biomedsci_fac/34