Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?

Serotonin affects many functions in the body, both in the central nervous system (CNS) and the periphery. However, its effect on the blood–brain barrier (BBB) in separating these two worlds has been scarcely investigated. The aim of this work was to characterize the serotonin receptor 5-HT<sub>...

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Autores principales:	Guillaume Becker, Sylvia Da Silva, Amelia-Naomi Sabo, Maria Cristina Antal, Véronique Kemmel, Laurent Monassier
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	serotonin 5-HT<sub>4</sub> receptor prucalopride blood–brain barrier permeability hCMEC/D3 microvascular endothelial cells Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/3a6789f2a2a94bc0992d59504cf71e65
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spelling	oai:doaj.org-article:3a6789f2a2a94bc0992d59504cf71e652021-11-25T18:41:12ZBlood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?10.3390/pharmaceutics131118561999-4923https://doaj.org/article/3a6789f2a2a94bc0992d59504cf71e652021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1856https://doaj.org/toc/1999-4923Serotonin affects many functions in the body, both in the central nervous system (CNS) and the periphery. However, its effect on the blood–brain barrier (BBB) in separating these two worlds has been scarcely investigated. The aim of this work was to characterize the serotonin receptor 5-HT<sub>4</sub> in the hCMEC/D3 cell line, in the rat and the human BBB. We also examined the effect of prucalopride, a 5-HT<sub>4</sub> receptor agonist, on the permeability of the hCMEC/D3 in an in vitro model of BBB. We then confirmed our observations by in vivo experiments. In this work, we show that the 5-HT<sub>4</sub> receptor is expressed by hCMEC/D3 cells and in the capillaries of rat and human brains. Prucalopride increases the BBB permeability by downregulating the expression of the tight junction protein, occludin. This effect is prevented by GR113808, a 5-HT<sub>4</sub> receptor antagonist, and is mediated by the Src/ERK1/2 signaling pathway. The canonical G-protein-dependent pathway does not appear to be involved in this phenomenon. Finally, the administration of prucalopride increases the diffusion of Evans blue in the rat brain parenchyma, which is synonymous with BBB permeabilization. All these data indicate that the 5-HT<sub>4</sub> receptor contributes to the regulation of BBB permeability.Guillaume BeckerSylvia Da SilvaAmelia-Naomi SaboMaria Cristina AntalVéronique KemmelLaurent MonassierMDPI AGarticleserotonin5-HT<sub>4</sub> receptorprucaloprideblood–brain barrier permeabilityhCMEC/D3microvascular endothelial cellsPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1856, p 1856 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	serotonin 5-HT<sub>4</sub> receptor prucalopride blood–brain barrier permeability hCMEC/D3 microvascular endothelial cells Pharmacy and materia medica RS1-441
spellingShingle	serotonin 5-HT<sub>4</sub> receptor prucalopride blood–brain barrier permeability hCMEC/D3 microvascular endothelial cells Pharmacy and materia medica RS1-441 Guillaume Becker Sylvia Da Silva Amelia-Naomi Sabo Maria Cristina Antal Véronique Kemmel Laurent Monassier Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?
description	Serotonin affects many functions in the body, both in the central nervous system (CNS) and the periphery. However, its effect on the blood–brain barrier (BBB) in separating these two worlds has been scarcely investigated. The aim of this work was to characterize the serotonin receptor 5-HT<sub>4</sub> in the hCMEC/D3 cell line, in the rat and the human BBB. We also examined the effect of prucalopride, a 5-HT<sub>4</sub> receptor agonist, on the permeability of the hCMEC/D3 in an in vitro model of BBB. We then confirmed our observations by in vivo experiments. In this work, we show that the 5-HT<sub>4</sub> receptor is expressed by hCMEC/D3 cells and in the capillaries of rat and human brains. Prucalopride increases the BBB permeability by downregulating the expression of the tight junction protein, occludin. This effect is prevented by GR113808, a 5-HT<sub>4</sub> receptor antagonist, and is mediated by the Src/ERK1/2 signaling pathway. The canonical G-protein-dependent pathway does not appear to be involved in this phenomenon. Finally, the administration of prucalopride increases the diffusion of Evans blue in the rat brain parenchyma, which is synonymous with BBB permeabilization. All these data indicate that the 5-HT<sub>4</sub> receptor contributes to the regulation of BBB permeability.
format	article
author	Guillaume Becker Sylvia Da Silva Amelia-Naomi Sabo Maria Cristina Antal Véronique Kemmel Laurent Monassier
author_facet	Guillaume Becker Sylvia Da Silva Amelia-Naomi Sabo Maria Cristina Antal Véronique Kemmel Laurent Monassier
author_sort	Guillaume Becker
title	Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?
title_short	Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?
title_full	Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?
title_fullStr	Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?
title_full_unstemmed	Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?
title_sort	blood–brain barrier permeability: is 5-hydroxytryptamine receptor type 4 a game changer?
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3a6789f2a2a94bc0992d59504cf71e65
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Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?

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