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Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS

The Pharmacogenomics Journal volume 6, pages 279–288 (2006)Cite this article

Abstract

Toxicity of the typical antipsychotic haloperidol (HAL) comprises an apoptotic component that we link to pro-apoptotic Bcl-XS in PC12 preneuronal and N2a neuroblastoma cells. The mitochondrial translocation of Bcl-XS and its interaction with the pore-forming voltage-dependent anion channel (VDAC) correlates with the redistribution of cytochrome c and the cleavage of Poly(ADP-ribose) polymerase. Haloperidol-induced apoptosis is mediated by the sigma2 (σ2) receptor system and does not involve the expected antagonism of the dopamine D2 receptor, nor is it influenced by Vitamin E- or p53/Bax-mediated events. Pathological relevance is demonstrated by the cytotoxic synergism between HAL and the Alzheimer disease-related peptide β-amyloid(1–40), which correlates with Bcl-XS expression and its interaction with VDAC, and with cytosolic cytochrome c translocation. These data provide for a unique apoptotic mechanism that could underscore the clinical risks associated with HAL, particularly following chronic regimens or in the elderly.

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Abbreviations

HAL:

haloperidol

DTG:

1,3-di-o-tolylguanidine

SKF:

SKF 10,047 [(+)N-allyl-normetazocine]

PARP:

poly(ADP-ribose) polymerase

VDAC:

voltage-dependent anion channel

Aβ40:

β-amyloid(1–40)

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium

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Acknowledgements

We thank Dr Rémi Quirion, Douglas Hospital Research Center, Montréal (Québec), and Dr Deborah Anderson, Saskatchewan Cancer Agency, for comments on the manuscript. This work was supported by the Saskatchewan Health Research Foundation (to DDM), by the Canadian Institutes of Health Research (CIHR; to XML) and by a post-doctoral Fellowship (to ZW) from the CIHR/Rx&D Research Program (200104DFE-91579-112515) and AstraZeneca/Alzheimer Society of Canada.

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  1. Department of Psychiatry, Neuropsychiatry Research Unit, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

    Z Wei, D D Mousseau, Y Dai, X Cao & X-M Li

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Correspondence to D D Mousseau.

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Wei, Z., Mousseau, D., Dai, Y. et al. Haloperidol induces apoptosis via the σ2 receptor system and Bcl-XS. Pharmacogenomics J 6, 279–288 (2006). https://doi.org/10.1038/sj.tpj.6500373

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