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Protective effects of MK-801 on manganese-induced glutamate metabolism disorder in rat striatum
1Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning, People's Republic of China.
Abstract:
Manganese (Mn) is one of the ubiquitous environmental pollutants that can induce an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. The present study has been carried out to investigate the mechanisms of Glu metabolism disorder and the neuroprotective role of MK-801, a non-competitive N-methyl-D-aspartate receptor antagonist, against Mn-induced excitotoxicity in rat striatum. Fifty rats were randomly divided into five groups with 10 animals in each group: control group, Mn-treated group (8, 40, and 200micromol/kg), and MK-801-pre-treated group. Administration of MnCl(2) x 6H(2)O at dose of 200micromol/kg body weight for 4 weeks significantly increased the concentrations of Glu and Mn in the striatum (P<0.01). In addition, Mn also increased the activity of phosphate-activated glutaminase (PAG) (54.38%, P<0.01), enhanced striatum cell apoptosis rate (65.04%, P<0.01) and decreased the activity of glutamine synthetase (GS) (28.88%, P<0.01). Pre-treatment with MK-801 at a dose of 0.3micromol/kg body weight for 4 weeks prior to 200micromol/kg Mn administration prevents the alterations of the activities of PAG and GS and concentrations of glutamine (Gln). In addition, pre-treatment with MK-801 significantly reduced the striatum cell apoptosis rate. In conclusion, the results suggest that MK-801 possesses the ability to attenuate Mn-induced Glu metabolism disorder in the striatum through mechanisms involving disruption enzyme activities of GS and PAG.
Insights
Manganese exposure disrupts glutamate metabolism and increases excitotoxicity in rat striatum. MK-801, an NMDA receptor antagonist, effectively protected against these manganese-induced neurotoxic effects.
Area of Science:
- Neuroscience
- Environmental Toxicology
- Biochemistry
Background:
- Manganese (Mn) is a common environmental pollutant.
- Mn exposure can lead to excitotoxicity via altered glutamate (Glu) metabolism.
- Understanding Mn's neurotoxic mechanisms is crucial for developing interventions.
Purpose of the Study:
- Investigate mechanisms of Glu metabolism disorder induced by Mn.
- Evaluate the neuroprotective role of MK-801 against Mn-induced excitotoxicity.
- Examine Mn's effects on enzyme activities and cell apoptosis in rat striatum.
Main Methods:
- Fifty rats were divided into control, Mn-treated (8, 40, 200 µmol/kg), and MK-801 pre-treated groups.
- MnCl2 administration for 4 weeks.
- Assessed Mn and Glu concentrations, phosphate-activated glutaminase (PAG) and glutamine synthetase (GS) activities, and striatal cell apoptosis.
Main Results:
- High-dose Mn (200 µmol/kg) significantly increased striatal Glu and Mn levels (P<0.01).
- Mn exposure elevated PAG activity (54.38%, P<0.01), decreased GS activity (28.88%, P<0.01), and enhanced striatal cell apoptosis (65.04%, P<0.01).
- MK-801 pre-treatment normalized PAG and GS activities and reduced apoptosis.
Conclusions:
- Mn exposure disrupts glutamate metabolism in the striatum by altering PAG and GS enzyme activities.
- MK-801 demonstrates neuroprotective effects against Mn-induced excitotoxicity.
- These findings highlight potential therapeutic strategies for Mn-related neurotoxicity.
