MPTP produces differential oxidative stress and antioxidative responses in the nigrostriatal and mesolimbic dopaminergic pathways
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1Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Abstract:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to produce a differential toxicity in the nigrostriatal and mesolimbic dopaminergic pathways with the nigrostriatal pathway being more vulnerable. We, therefore, investigated whether oxidative stress and the antioxidant system play a role in this phenomenon. Balb/c mice were treated with either saline or MPTP (30 mg/kg/d) for 7 d, and were sacrificed on the next day. Results revealed that MPTP increased lipid peroxidation in the striatum (ST) and decreased glutathione concentration in the substantia nigra (SN) without markedly affecting these measures in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Further, MPTP produced approximately twofold increases in both manganese superoxide dismutase (MnSOD) and copper-zinc superoxide dismutase (CuZnSOD) activities in the VTA while it only increased MnSOD activity in the SN. Both catalase and glutathione peroxidase (GPx) activities were not markedly altered by MPTP in both systems. However, the basal levels of catalase and GPx activities were higher in the VTA and NAc than in the SN and ST. These results together suggest that a lesser degree of oxidative damage and a more inducible CuZnSOD activity observed in the mesolimbic dopaminergic pathway may partially explain the differential toxicity MPTP produced in these two dopaminergic systems.
Insights
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes greater damage to the nigrostriatal pathway than the mesolimbic pathway. This difference may be due to less oxidative stress and more antioxidant enzyme activity in the mesolimbic system.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exhibits differential toxicity between the nigrostriatal and mesolimbic dopaminergic pathways.
- The nigrostriatal pathway is more vulnerable to MPTP toxicity compared to the mesolimbic pathway.
Purpose of the Study:
- To investigate the role of oxidative stress and the antioxidant system in the differential neurotoxicity of MPTP.
- To compare the effects of MPTP on oxidative stress markers and antioxidant enzyme activities in the striatum (ST)/substantia nigra (SN) versus the nucleus accumbens (NAc)/ventral tegmental area (VTA).
Main Methods:
- Balb/c mice were administered MPTP (30 mg/kg/d) or saline for 7 days.
- Oxidative stress markers (lipid peroxidation, glutathione) and antioxidant enzyme activities (MnSOD, CuZnSOD, catalase, GPx) were measured in different brain regions.
Main Results:
- MPTP increased lipid peroxidation in the striatum and decreased glutathione in the substantia nigra.
- MPTP significantly increased manganese superoxide dismutase (MnSOD) and copper-zinc superoxide dismutase (CuZnSOD) activities in the ventral tegmental area (VTA), and MnSOD in the substantia nigra (SN).
- Basal levels of catalase and glutathione peroxidase were higher in the ventral tegmental area (VTA) and nucleus accumbens (NAc) than in the substantia nigra (SN) and striatum (ST).
Conclusions:
- The mesolimbic dopaminergic pathway exhibits a lesser degree of oxidative damage compared to the nigrostriatal pathway.
- Enhanced inducible copper-zinc superoxide dismutase (CuZnSOD) activity in the mesolimbic system may contribute to its relative resistance to MPTP toxicity.
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