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.[1]References
- Haloperidol induces apoptosis via the sigma2 receptor system and Bcl-XS. Wei, Z., Mousseau, D.D., Dai, Y., Cao, X., Li, X.M. Pharmacogenomics J. (2006) [Pubmed]
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