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It has been reported that the treatment of the PC12 cells with MPP+, a Parkinsonian neurotoxin, results in their death through apoptosis. In the present study, we compared the cytotoxic effects of MPP+, 1-methyl-4-phenylpyridinium (MPP+), 2-methyl-6-phenyl-1,2,3,6-tetrahydropyridine (MSITC), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using PC12 cells, and the cytotoxic mechanisms were examined. MPP+ caused the rapid cell shrinkage of PC12 cells, whereas MSITC and MPTP induced the morphological changes characteristic of apoptosis. In fact, the morphological observation revealed that PC12 cells treated with MPP+, MSITC and MPTP showed chromatin condensation, membrane blebbing and nuclei fragmentation. In addition, flow cytometric analysis using the acridine orange/ethidium bromide stain demonstrated that the nuclei of the cells treated with these compounds appeared to be of both hypo-diploid and polyploid size. However, in the experiment to assess mitochondrial function, MPTP and MSITC suppressed the mitochondrial membrane potential (DeltaPsim), whereas this was not observed with MPP+. These results indicate that MSITC induces apoptosis of PC12 cells through the activation of the cell death machinery, although its activity is much weaker than that of MPTP. Furthermore, the results suggest that
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