Riluzole-Triggered GSH Synthesis via Activation of Glutamate Transporters to Antagonize Methylmercury-Induced Oxidative Stress in Rat Cerebral Cortex

Abstract

Objective. This study was to evaluate the effect of riluzole on methylmercury- (MeHg-) induced oxidative stress, through promotion of glutathione (GSH) synthesis by activating of glutamate transporters (GluTs) in rat cerebral cortex. Methods. Eighty rats were randomly assigned to four groups, control group, riluzole alone group, MeHg alone group, and riluzole + MeHg group. The neurotoxicity of MeHg was observed by measuring mercury (Hg) absorption, pathological changes, and cell apoptosis of cortex. Oxidative stress was evaluated via determining reactive oxygen species (ROS), 8-hydroxy-2-deoxyguanosine (8-OHdG), malondialdehyde (MDAs), carbonyl, sulfydryl, and GSH in cortex. Glutamate (Glu) transport was studied by measuring Glu, glutamine (Gln), mRNA, and protein of glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). Result. (1) MeHg induced Hg accumulation, pathological injury, and apoptosis of cortex; (2) MeHg increased ROS, 8-OHdG, MDA, and carbonyl, and inhibited sulfydryl and GSH; (3) MeHg elevated Glu, decreased Gln, and downregulated GLAST and GLT-1 mRNA expression and protein levels; (4) riluzole antagonized MeHg-induced downregulation of GLAST and GLT-1 function and expression, GSH depletion, oxidative stress, pathological injury, and apoptosis obviously. Conclusion. Data indicate that MeHg administration induced oxidative stress in cortex and that riluzole could antagonize this situation through elevation of GSH synthesis by activating of GluTs.

Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective

“…The mechanism of action of Riluzole is not very clear, but some studies point to its antioxidant activity by induction of glutathione synthesis, which can only extend survival by 3 months. Edaravone acts as a free radical scavenger [207]. Overwhelming evidence suggests that mitochondrial dysfunction plays a significant role in proteinopathies of neurodegenerative diseases.…”

Effects of Dietary Supplementation with Glutamate and Aspartate on Diquat-Induced Oxidative Stress in Piglets

“…The present data indicated that glutamate alleviated diquat-induced oxidative stress via enhancing SOD, T-AOC, and NO levels and inhibiting lipid oxidation subsequent with MDA generation. It is widely recognized that glutamate exhibits an antioxidant function as glutamate is a precursor for glutathione (GSH) along with cysteine and glycine [ 33 ]. In our lab, we have found that glutamate is the main limiting substrate compared with cysteine and glycine for liver GSH synthesis in mice (unpublished data).…”

Riluzole increases glutamate uptake by cultured C6 astroglial cells

“…Excitotoxic levels of glutamate induce oxidative stress (Trotti et al, 1998), and this negative self‐regulation could be a relevant mechanism in neurodegenerative diseases. Riluzole has already been shown to exert a beneficial effect on oxidative stress when induced by diverse insults, including streptozotocin, sodium nitrite (Rinwa et al, 2012) and methylmercury (Deng et al, 2012). Here, we show that riluzole had an antioxidant effect and diminished the total reactive oxygen species load.…”