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MPTP와 대사물인 MPP<sup>+</sup>의 도파민 신경세포에 대한 독성효과에 관한 연구

Studies on the Dopaminergic Neuronal Toxicity of MPTP and its Pyridium Metabolite, MPP<sup>+</sup>

Dissociated cell cultures from rat embryonic ventral mesencephalon were used to evaluate the mechanisms of MPP<sup>+</sup> neurotoxicity. The cells were treated with MPTP or MPP<sup>+</sup> and the viability of the cells was assessed biochemically; tyrosine hydroxylase (TH) immunoreactivity, protein, intracellular ATP and lactate content and lipid peroxidation. Also the generation of the intracellular oxidants was measured after loading 2 , 7‘-dichlorofluorescin diacetate to the cells. When cultures were exposed to 0.1 mM MPP<sup>+</sup>, at 2 hour incubation lactate was significantly accumulated in the cells and then the intracellular ATP content and TH immunoreactivity were decreased dose- and time-dependently. But, malondialdehyde as an index for lipid peroxidation was not changed even though the generation of the intracellular oxidants was stimulated by the addition of MPP<sup>+</sup>. On the other hand, 1 mM MPTP significantly reduced the TH immunoreactivity at 24 hour exposure without any change in the intracellular A TP, lactate and MDA content until 6 hour exposure. And also MPTP inhibited the generation of the intracellular oxidants from control cells and MPP<sup>+</sup> exposed cells. These results indicate that cytotoxicity of MPP<sup>+</sup> is mediated by inhibiting the mitochondrial energy metabolism rather than generating the intracellular oxidants. And MPTP would have direct action in addition to conveting to the toxic metabolite, MPP<sup>+</sup> to exert the toxicity on the dopaminergic neurons.