Atypical antipsychotics attenuate neurotoxicity of beta-amyloid(25-35) by modulating Bax and Bcl-X(l/s) expression and localization.
We have demonstrated recently that atypical antipsychotics possess neuroprotective actions in H2O2-mediated and serum-withdrawal models of cell death. In the present study, we compared the ability of atypical and typical antipsychotics to protect against an insult mediated by Abeta(25-35), an apoptogenic fragment of the Alzheimer's disease-related beta-amyloid (Abeta) peptide. Treatment of PC12 cell cultures with Abeta(25-35) did not significantly alter total cellular expression levels of Bax, a proapoptotic Bcl-2 family member, or levels of Bcl-XL, an antiapoptotic analogue. Treatment with Abeta(25-35), however, did result in mitochondrial translocation of Bax, which effectively increased the mitochondrial ratio of Bax to Bcl-X(L). This relative increase in proapoptotic molecules was reduced by pretreatment with atypical (quetiapine and olanzapine) and typical (haloperidol) antipsychotics. We also observed a selective increase in proapoptotic Bcl-XS immunodetection in haloperidol-treated cells, which was evident particularly in the mitochondrial compartment. This increase in proapoptotic molecules may account for the lower neuroprotective potential of haloperidol, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) reduction assay. The disparate neuroprotective effects of atypical and typical antipsychotics/neuroleptics may be due to their respective abilities to regulate pro- and anti-apoptotic protein translocation and expression.
Wei
Zelan
Z
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada.
Mousseau
Darrell D
DD
Richardson
J Steven
JS
Dyck
Lillian E
LE
Li
Xin-Min
XM
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; C494828:Bax protein, rat; C494813:Bcl2l1 protein, rat; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C074636:amyloid beta-protein (25-35); D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein