Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability

Wenjia Du; Huanhuan Chen; Ilona Gróf; Lucien Lemaitre; Alexandra Bocsik; Adrian Perdyan; Jakub Mieczkowski; Mária A. Deli; Tibor Hortobágyi; Qi Wan; Oleg O. Glebov

doi:10.1038/s41380-024-02626-1

Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability

Wenjia Du, Huanhuan Chen, Ilona Gróf, Lucien Lemaitre, Alexandra Bocsik, Adrian Perdyan, Jakub Mieczkowski, Mária A. Deli, Tibor Hortobágyi, Qi Wan, Oleg O. Glebov^*

^*Corresponding author for this work

Psychological Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below. We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression. Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo. These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain.

Original language	English
Pages (from-to)	3590-3598
Number of pages	9
Journal	Molecular Psychiatry
Volume	29
Issue number	11
DOIs	https://doi.org/10.1038/s41380-024-02626-1
Publication status	Published - 30 May 2024

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title = "Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability",

abstract = "As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below. We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression. Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo. These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain.",

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AU - Du, Wenjia

AU - Chen, Huanhuan

AU - Gróf, Ilona

AU - Lemaitre, Lucien

AU - Bocsik, Alexandra

AU - Perdyan, Adrian

AU - Mieczkowski, Jakub

AU - Deli, Mária A.

AU - Hortobágyi, Tibor

AU - Wan, Qi

AU - Glebov, Oleg O.

PY - 2024/5/30

Y1 - 2024/5/30

N2 - As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below. We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression. Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo. These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain.

AB - As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below. We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression. Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo. These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain.

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JO - Molecular Psychiatry

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Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability

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