Abstract
ScopeFirst- and second-generation antipsychotics (FGAs and SGAs, respectively), both inhibit cholesterol biosynthesis and impair the intracellular cholesterol trafficking, leading to lipid accumulation in the late endosome/lysosome compartment. In this study we examined if curcumin, a plant polyphenol that stimulates exosome release, can alleviate antipsychotic-induced intracellular lipid accumulation.MethodsHepG2 hepatocarcinoma cells were treated with antipsychotics or placebo and DiI-labelled LDL for 18 h and then exposed to curcumin for the last 2 h. Cells and media were collected separately and used for biochemical analyses, electron microscopy and immunocytochemistry. Exosomes were isolated from the incubation medium by ultracentrifugation.ResultsCurcumin treatment reduced the number of heterolysosomes and shifted their subcellular localization to the periphery, as revealed by electron microscopy, and stimulated the release of lysosomal β-hexosaminidase and exosome markers flotillin-2 and CD63 into the media. The presence of DiI in exosomes released by cells preloaded with DiI-LDL demonstrated the endolysosomal origin of the microvesicles. Furthermore, curcumin increased the secretion of cholesterol as well as LDL-derived DiI and [3H]-cholesterol, in association with a decrease of intracellular lipids. Thus, the disruption of lipid trafficking induced by FGAs or SGAs can be relieved by curcumin treatment. This polyphenol, however, did not mitigate the reduction of cholesterol esterification induced by antipsychotics.ConclusionCurcumin stimulates exosome release to remove cholesterol (and presumably other lipids) accumulated within the endolysosomal compartment, thereby normalizing intracellular lipid homeostasis. This action may help minimize the adverse metabolic effects of antipsychotic treatment, which should now be evaluated in clinical trials.
Highlights
Antipsychotic drugs are widely used to alleviate a number of psychiatric disorders
Curcumin increased the secretion of cholesterol as well as low-density lipoprotein (LDL)-derived DiI and [3H]-cholesterol, in association with a decrease of intracellular lipids
The disruption of lipid trafficking induced by typical or first-generation antipsychotic (FGA) or atypical or second generation antipsychotic (SGA) can be relieved by curcumin treatment
Summary
Antipsychotic drugs are widely used to alleviate a number of psychiatric disorders. There are two classes of antipsychotic drugs, typical or first-generation antipsychotics (FGAs) and atypical or second generation antipsychotics (SGAs). The therapeutic efficacy of both classes is strongly associated with antagonism of D2 dopamine receptors [1], SGAs exhibiting lower affinity for D2 receptors and greater affinity to serotonergic, histaminergic, muscarinic, and adrenergic receptors than FGAs [1]. Both classes of antipsychotics are associated with serious side effects. A higher risk of stroke in antipsychotic users has been reported, especially in older patients with vascular illness, the pathophysiology of such association is still unclear [4]
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