title: Sulforaphane Prevents Methylmercury-Induced Oxidative Damage and Excitotoxicity Through Activation of the Nrf2-ARE Pathway.
abstract: Methylmercury (MeHg) is a prominent environmental neurotoxicant, which induces oxidative damage and an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. However, the interaction between oxidative damage and excitotoxicity in MeHg-exposed rats has not been fully recognized. Here, we explored the interaction between oxidative damage and excitotoxicity and evaluated the preventive effects of sulforaphane (SFN) on MeHg-induced neurotoxicity in rat cerebral cortex. Seventy-two rats were randomly assigned to four groups: control group, MeHg-treated groups (4 and 12 μmol/kg), and SFN pretreatment group. After treatment (28 days), the rats were killed and the cerebral cortex was analyzed. Then, Hg, glutathione (GSH), malondialdehyde (MDA), protein sulfhydryl, protein carbonyl, 8-hydroxy-2-deoxyguanosine (8-OHdG), and the levels of reactive oxygen species (ROS) and apoptosis were examined. Glu and glutamine (Gln) levels, glutamine synthetase (GS), phosphate-activated glutaminase (PAG), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), Na+-K+-ATPase and Ca2+-ATPase activities, intracellular Ca2+levels, and the mRNA and protein expressions of Nrf2, Nrf2-regulated gene products, and N-methyl-D-aspartate receptors (NMDARs) were investigated in rat cerebral cortex. In our study, MeHg exposure not only induced Hg accumulation, apoptosis, ROS formation, GSH depletion, inhibition of antioxidant enzyme activities, and activation of Nrf2-ARE pathway signaling but also caused lipid, protein, and DNA peroxidative damage in a dose-dependent manner in rat cerebral cortex. Moreover, MeHg treatment significantly altered Gln/Glu cycling and NMDAR expression and resulted in calcium overloading. Furthermore, the present study also indicated that SFN pretreatment significantly reinforced the activation of the Nrf2-ARE pathway, which could prevent the toxic effects of MeHg exposure. Collectively, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to oxidative damage and excitotoxicity in rat cerebral cortex; pretreatment with SFN might prevent the MeHg-induced neurotoxicity by reinforcing the activation of the Nrf2-ARE pathway and then downregulating the interaction between oxidative damage and excitotoxicity pathways.
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, Liaoning Province, People's Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Feng
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, Liaoning Province, People's Republic of China. zfxu@mail.cmu.edu.cn.
authors.forename: Zhaofa
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, Liaoning Province, People's Republic of China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, Liaoning Province, People's Republic of China.
authors.forename: Tianyao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, Liaoning Province, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, Liaoning Province, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, Liaoning Province, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D008767:Methylmercury Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013454:Sulfoxides
chemical_list: D017879:Isothiocyanates; D008767:Methylmercury Compounds; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D013454:Sulfoxides; D002265:Carboxylic Ester Hydrolases; C019734:arylesterase; C016766:sulforaphane
keywords: Excitotoxicity; Methylmercury; Nrf2-ARE pathway; Oxidative damage; Sulforaphane