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Atypical antipsychotics attenuate neurotoxicity of β‐amyloid(25–35) by modulating Bax and Bcl‐X l/s expression and localization
Author(s) -
Wei Zelan,
Mousseau Darrell D.,
Richardson J. Steven,
Dyck Lillian E.,
Li XinMin
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10832
Subject(s) - neuroprotection , haloperidol , neurotoxicity , pharmacology , apoptosis , programmed cell death , mitochondrion , chemistry , amyloid beta , microbiology and biotechnology , peptide , biology , medicine , biochemistry , neuroscience , toxicity , dopamine
We have demonstrated recently that atypical antipsychotics possess neuroprotective actions in H 2 O 2 ‐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 Aβ(25–35), an apoptogenic fragment of the Alzheimer's disease‐related β‐amyloid (Aβ) peptide. Treatment of PC12 cell cultures with Aβ(25–35) did not significantly alter total cellular expression levels of Bax, a proapoptotic Bcl‐2 family member, or levels of Bcl‐X L , an antiapoptotic analogue. Treatment with Aβ(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‐X S 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. © 2003 Wiley‐Liss, Inc.