MPTP와 대사물인 $MPP^+$의 도파민 신경세포에 대한 독성효과에 관한 연구

Studies on the Dopaminergic Neuronal Toxicity of MPTP and its Pyridium Metabolite, $MPP^+$

Dissociated cell cultures from rat embryonic ventral mesencephalon were used to evaluate the mechanisms of $MPP^+$ neurotoxicity. The cells were treated with MPTP or $MPP^+$ 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 $MPP^+$, 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 $MPP^+$. 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 $MPP^+$ exposed cells. These results indicate that cytotoxicity of $MPP^+$ 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, $MPP^+$ to exert the toxicity on the dopaminergic neurons.