The antipsychotic actions of classic neuroleptics (typical or fi rst-generation antipsychotics, FGA) revolutionized the therapy of schizophrenia, but their extensive use has been impeded by side effects, such as extrapyramidal symptoms, and a high incidence of nonresponders. FGAs, such as haloperidol, act predominantly by blocking dopamine D 2 receptors ( 1 ). Atypical or second-generation antipsychotics (SGA) display relatively weaker antagonism of dopamine D 2 receptors but potent antagonism to serotonin 5-HT 2A receptors ( 1 ). The therapeutic use of SGAs has reduced concern on neurological side effects, but they are not free of metabolically adverse effects. An increase in body weight is fairly rapid after initiating treatment with these drugs. At long term, this may result in overt obesity, along with dyslipidemia, insulin resistance, abnormal glucose tolerance, and diabetes ( 2-4 ). Dyslipidemia is commonly manifested as an increase in total triglyceride and a decrease of high-density lipoprotein (HDL)-cholesterol plasma

These findings indicate that curcumin ameliorates the U18666A-induced endolysosomal cholesterol accumulation by shuttling cholesterol and presumably other lipids out of the cell via exosomes/microvesicles secretion. This action may contribute to the potential of curcumin in the treatment of lysosomal storage diseases.

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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.