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Even though both N-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine have been widely used to establish the experimental model for dopaminergic neuronal cell death. mechanisms underlying this phenomenon have not been firmly explored. To investigate how these dopaminergic neurotoxins induce neuronal cell death, murine dopaminergic neuronal cell line, MN9D cells were treated with various concentration of either 6-hydroxydopamine or active form of MPTP, N methyl-4-phenylpyridinium (MPP+). Treatment of cells with 5-100uM 6-hydroxydopamine resulted in apoptotic cell death whereas cell death induced by 5~50uM MPP+ was not demonstrated typical apoptotic characteristics such as cell shrinkage, apoptotic body and nuclear condensation. Cell death induced by 6-hydroxydopamine was partially blocked in the presence of antioxidants including soluble form of vitamin E or desferrioxamine suggesting that generation of oxidative stress may be associated with 6-hydroxydopamine-induced cell death in MN9D cells. In contrast, MPP+-induced cell death was not blocked by treatment with any of antioxidants tested. As previously demonstrated that MPP+ caused metabolic alterations such as glucose metabolism, removal of glucose from the medium partially inhibited MPP+-induced cell death suggesting excessive cycles of glycolysis may be associated with MPP+-induced cell death. Taken together, these studies demonstrate that two types of dopaminergic neurotoxins recruit distinct neuronal cell death pathways.
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