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Open AccessArticle

First-Generation Antipsychotic Haloperidol Alters the Functionality of the Late Endosomal/Lysosomal Compartment in Vitro

1
Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain
2
Unidad de Neurología Experimental, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain
3
Servicio de Bioquímica-Clínica, Hospital Universitario Ramón y Cajal, IRyCIS, 28034 Madrid, Spain
4
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Domenico De Berardis and Michele Fornaro
Int. J. Mol. Sci. 2016, 17(3), 404; https://doi.org/10.3390/ijms17030404
Received: 26 January 2016 / Revised: 7 March 2016 / Accepted: 14 March 2016 / Published: 18 March 2016
(This article belongs to the Special Issue Antipsychotics)
First- and second-generation antipsychotics (FGAs and SGAs, respectively), have the ability to inhibit cholesterol biosynthesis and also to interrupt the intracellular cholesterol trafficking, interfering with low-density lipoprotein (LDL)-derived cholesterol egress from late endosomes/lysosomes. In the present work, we examined the effects of FGA haloperidol on the functionality of late endosomes/lysosomes in vitro. In HepG2 hepatocarcinoma cells incubated in the presence of 1,1′-dioctadecyl-3,3,3,3′-tetramethylindocarbocyanineperchlorate (DiI)-LDL, treatment with haloperidol caused the enlargement of organelles positive for late endosome markers lysosome-associated membrane protein 2 (LAMP-2) and LBPA (lysobisphosphatidic acid), which also showed increased content of both free-cholesterol and DiI derived from LDL. This indicates the accumulation of LDL-lipids in the late endosomal/lysosomal compartment caused by haloperidol. In contrast, LDL traffic through early endosomes and the Golgi apparatus appeared to be unaffected by the antipsychotic as the distribution of both early endosome antigen 1 (EEA1) and coatomer subunit β (β-COP) were not perturbed. Notably, treatment with haloperidol significantly increased the lysosomal pH and decreased the activities of lysosomal protease and β-d-galactosidase in a dose-dependent manner. We conclude that the alkalinization of the lysosomes’ internal milieu induced by haloperidol affects lysosomal functionality. View Full-Text
Keywords: antipsychotic; haloperidol; cholesterol; intracellular lipid traffic; late endosome/lysosome; pH antipsychotic; haloperidol; cholesterol; intracellular lipid traffic; late endosome/lysosome; pH
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MDPI and ACS Style

Canfrán-Duque, A.; Barrio, L.C.; Lerma, M.; De la Peña, G.; Serna, J.; Pastor, O.; Lasunción, M.A.; Busto, R. First-Generation Antipsychotic Haloperidol Alters the Functionality of the Late Endosomal/Lysosomal Compartment in Vitro. Int. J. Mol. Sci. 2016, 17, 404.

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