The ability of atypical antipsychotic drugs vs. haloperidol to protect PC12 cells against MPP+‐induced apoptosis

The present study examined the effects of the atypical antipsychotic drugs clozapine, olanzapine, quetiapine and risperidone, on N‐methyl‐4‐phenylpyridinium ion‐induced apoptosis and DNA damage in PC12 cells, and explored the molecular mechanisms underlying these effects. Haloperidol, a typical antipsychotic drug, was used for comparison. Exposure of PC12 cells to 50 µm N‐methyl‐4‐phenylpyridinium ion for 24 h resulted in a 35–45% loss of cells in culture. Pretreatment with the aforementioned atypical antipsychotic drugs significantly reduced the N‐methyl‐4‐phenylpyridinium ion‐induced cell loss, whereas haloperidol (10–100 µm) did not have this protective effect. Hoechst 33258 staining revealed the apoptotic nuclear features of the N‐methyl‐4‐phenylpyridinium ion‐induced cell death, and showed that the atypical antipsychotic drugs, but not haloperidol, effectively prevented PC12 cells from this N‐methyl‐4‐phenylpyridinium ion‐induced apoptosis. DNA fragmentation assays further confirmed the N‐methyl‐4‐phenylpyridinium ion‐induced nuclear fragmentation. Pretreatment with the atypical antipsychotic drugs completely prevented this nuclear fragmentation, whereas haloperidol only partially prevented it. In vitro oligonucleotide assays indicated an activation of a specific glycosylase that recognizes and cleaves bases (at the 8‐hydroxyl‐2‐deoxyguanine site) that were damaged by N‐methyl‐4‐phenylpyridinium ion. Pretreatment with the atypical antipsychotic drugs more effectively attenuated this N‐methyl‐4‐phenylpyridinium ion‐induced activation than did haloperidol. Northern blot analyses showed that the atypical antipsychotic drugs, but not haloperidol, blocked the N‐methyl‐4‐phenylpyridinium ion‐induced substantial increase of copper/zinc superoxide dismutase mRNA in PC12 cells. Atypical antipsychotic drugs slightly up‐regulated the expression of copper/zinc superoxide dismutase mRNA, whereas haloperidol strongly increased the expression of copper/zinc superoxide dismutase mRNA. These data may account for the different therapeutic effects and side‐effect profiles of typical and atypical antipsychotic drugs in schizophrenia.

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