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 micro m 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 micro m) 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.
Qing
Hong
H
Neuropsychiatric Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Canada.
Xu
Haiyun
H
Wei
Zelan
Z
Gibson
Kurt
K
Li
Xin-Min
XM
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D006220:Haloperidol / Q000494:pharmacology*; D006540:Herbicides / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016716:PC12 Cells; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D013482:Superoxide Dismutase / Q000187:drug effects
D014150:Antipsychotic Agents; D006540:Herbicides; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D013482:Superoxide Dismutase; D006220:Haloperidol; D015655:1-Methyl-4-phenylpyridinium