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Published on: July 14, 2010
Atypical antipsychotics attenuate neurotoxicity of beta-amyloid(25-35) by modulating Bax and Bcl-X(l/s) expression
Zelan Wei1, Darrell D Mousseau, J Steven Richardson
1Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, SK, Canada.
Abstract:
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.
Insights
Atypical antipsychotics offer neuroprotection against Alzheimer's peptide damage by regulating apoptotic proteins. Typical antipsychotics like haloperidol show less protection, potentially due to increased pro-apoptotic molecules.
Area of Science:
- Neuroscience
- Pharmacology
- Cell Biology
Background:
- Atypical antipsychotics demonstrate neuroprotective effects in various cell death models.
- Alzheimer's disease is characterized by beta-amyloid (Abeta) peptide toxicity.
- Understanding the mechanisms of antipsychotic neuroprotection is crucial.
Purpose of the Study:
- To compare the neuroprotective abilities of atypical and typical antipsychotics against Abeta(25-35) induced cell damage.
- To investigate the effects of these antipsychotics on apoptotic protein expression and translocation.
- To elucidate the molecular mechanisms underlying differential neuroprotection.
Main Methods:
- PC12 cell cultures were treated with Abeta(25-35) peptide.
- Western blotting and immunofluorescence were used to assess Bax, Bcl-XL, and Bcl-XS protein levels and localization.
- Cell viability was measured using the MTT reduction assay.
Main Results:
- Abeta(25-35) induced mitochondrial translocation of Bax, increasing the Bax to Bcl-XL ratio.
- Atypical antipsychotics (quetiapine, olanzapine) and typical haloperidol reduced this Bax translocation.
- Haloperidol treatment selectively increased proapoptotic Bcl-XS, correlating with reduced neuroprotection.
Conclusions:
- Atypical and typical antipsychotics exhibit differential neuroprotective effects against Abeta(25-35) toxicity.
- Regulation of pro- and anti-apoptotic protein translocation is a key mechanism.
- These findings suggest distinct therapeutic potentials for antipsychotics in neurodegenerative diseases.
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