Protective effects of MK-801 on methylmercury-induced neuronal injury in rat cerebral cortex: involvement of oxidative stress and glutamate metabolism dysfunction.
Methylmercury (MeHg) is one of the ubiquitous environmental toxicants, which can induce oxidative stress and an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. However, little is known of the interaction between oxidative stress and Glu metabolism play in MeHg poisoning rats. We have investigated the neuroprotective role of MK-801, a non-competitive N-methyl-d-aspartate receptors (NMDAR) antagonist, against MeHg-induced neurotoxicity. Fifty rats were randomly divided into five groups of 10 animals in each group: control group, MK-801 control group, MeHg-treated group (4 and 12 μmol/kg) and MK-801 pre-treated group. Administration of MeHg at a dose of 12 μmol/kg for four weeks significantly increased in ROS and total Hg levels and that caused lipid, protein and DNA peroxidative damage in cerebral cortex. In addition, MeHg also reduced nonenzymic (reduced glutathione, GSH) and enzymic (glutathione peroxidase, GPx and superoxide dismutase, SOD) antioxidants and enhanced neurocyte apoptosis rate in cerebral cortex. MeHg-induced ROS production appears to inhibit the activity of the glutamine synthetase (GS), leading to Glu metabolism dysfunction. Pretreatment with MK-801 at a dose of 0.3 μmol/kg prevented the alterations of the activities of PAG and GS and oxidative stress. In addition, pretreatment with MK-801 significantly alleviated the neurocyte apoptosis rate and histopathological damage. In conclusion, the results suggested ROS formation resulting from MeHg- and Glu-induced oxidative stress contributed to neuronal injury. MK-801 possesses the ability to attenuate MeHg-induced neurotoxicity in the cerebral cortex through mechanisms involving its NMDA receptor binding properties and antioxidation.
Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning 110001, People's Republic of China.
Bin
B
Xu
Zhao-Fa
ZF
Xu
Yu
Y
Deng
Wei
W
Liu
Hai-Bo
HB
Yang
Yan-Gang
YG
Wei
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D020262:Mercury Poisoning, Nervous System / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008767:Methylmercury Compounds / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D004785:Environmental Pollutants; D008767:Methylmercury Compounds; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; C004925:methylmercuric chloride