Haloperidol induces apoptosis via the sigma2 receptor system and Bcl-XS.
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 (sigma2) receptor system and does not involve the expected antagonism of the dopamine D(2) 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 beta-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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Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Mousseau
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Dai
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Cao
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Li
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D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000633:toxicity; D000818:Animals; D014150:Antipsychotic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002227:Carbazoles / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006220:Haloperidol / Q000633:toxicity*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D016716:PC12 Cells; D010446:Peptide Fragments / Q000187:drug effects / Q000633:toxicity; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017480:Receptors, sigma / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D014150:Antipsychotic Agents; C494813:Bcl2l1 protein, rat; D002227:Carbazoles; D010446:Peptide Fragments; D012333:RNA, Messenger; D017480:Receptors, sigma; D016159:Tumor Suppressor Protein p53; C078592:amyloid beta-protein (1-40); D051020:bcl-X Protein; C106107:sigma-2 receptor; C034931:rimcazole; D006220:Haloperidol