title: Preventive effects of dextromethorphan on methylmercury-induced glutamate dyshomeostasis and oxidative damage in rat cerebral cortex.
abstract: Methylmercury (MeHg) is a well-known environmental pollutant leading to neurotoxicant associated with aberrant central nervous system (CNS) functions, but its toxic mechanisms have not yet been fully recognized. In the present study, we tested the hypothesis that MeHg induces neuronal injury via glutamate (Glu) dyshomeostasis and oxidative damage mechanisms and that these effects are attenuated by dextromethorphan (DM), a low-affinity and noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist. Seventy-two rats were randomly divided into four groups of 18 animals in each group: control group, MeHg-treated group (4 and 12 μmol/kg), and DM-pretreated group. After the 4-week treatment, we observed that the administration of MeHg at a dose of 12 μmol/kg significantly increased in total mercury (Hg) levels, disrupted Glu metabolism, overexcited NMDARs, and led to intracellular calcium overload in the cerebral cortex. We also found that MeHg reduced nonenzymatic and enzymatic antioxidants, enhanced neurocyte apoptosis, induced reactive oxygen species (ROS), and caused lipid, protein, and DNA peroxidative damage in the cerebral cortex. Moreover, glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) appeared to be inhibited by MeHg exposure. These alterations were significantly prevented by the pretreatment with DM at a dose of 13.5 μmol/kg. In conclusion, these findings strongly implicate that DM has potential to protect the brain from Glu dyshomeostasis and oxidative damage resulting from MeHg-induced neurotoxicity in rat.
authors.affiliation: Department of Environmental Health, School of Public Health, China Medical University, Shenyang, People's Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Feng
authors.forename: Zhaofa
authors.initials: Z
authors.lastname: Xu
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Yuehui
authors.initials: Y
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D003915:Dextromethorphan / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D008767:Methylmercury Compounds; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D003915:Dextromethorphan; C004925:methylmercuric chloride