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

Abstract

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.

Bromodomains in Human-Immunodeficiency Virus-Associated Neurocognitive Disorders: A Model of Ferroptosis-Induced Neurodegeneration

“…In addition, as GSH possesses antiviral properties, psychotropic drugs may enhance autophagy, facilitating the clearance of cancerous and pathogen-infected cells ( Fraternale et al, 2006 ). Indeed, as some psychotropics enter cells via ELS, they may eliminate the viruses they encounter throughout this pathway ( Benton et al, 2010 ; Canfrán-Duque et al, 2016 ; Schneider et al, 2016 ; Vela, 2020 ; Fred et al, 2022 ). Moreover, as several psychotropic drugs display anticancer properties, they likely inhibit CatB, lowering the cytotoxicity of this protein ( Varalda et al, 2020 ).…”

The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans

“…In contrast to D1-like receptors (D1 and D5), members of the D2 receptor family (D2, D3, and D4) are quickly internalized after agonist stimulation and eventually degraded through the intracellular lysosomal pathway [6,7]. Intracellular trafficking processes might be altered in schizophrenia [8][9][10] and are implicated in antipsychotic drug modes of action [11][12][13][14][15].…”

On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2

“…Siramesine, a σ2 receptor ligand similarly is a lysosomotropic and LMP-inducing agent 31 , although it may also target mitochondria 32 . Haloperidol, yet another σ2 receptor ligand, can cause lysosomal alkalinisation 33 and inhibit autophagy 34 . Chlorpromazine, an antipsychotic, is yet another drug with a well-established lysosomotropism that modulates autophagy 35 , 36 and inhibits clathrin-mediated endocytosis 37 .…”