Blood–Brain Barrier Permeability: Is 5-Hydroxytryptamine Receptor Type 4 a Game Changer?
Guillaume Becker,
Sylvia Da Silva,
Amelia-Naomi Sabo,
Maria Cristina Antal,
Véronique Kemmel,
Laurent Monassier
Affiliations
Guillaume Becker
Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire UR7296, Département Universitaire de Pharmacologie, Addictologie, Toxicologie et Thérapeutique, Centre de Recherche en Biomédecine de Strasbourg (CRBS), Université de Strasbourg, 1 Rue Eugène Boeckel, CEDEX, 67085 Strasbourg, France
Sylvia Da Silva
Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire UR7296, Département Universitaire de Pharmacologie, Addictologie, Toxicologie et Thérapeutique, Centre de Recherche en Biomédecine de Strasbourg (CRBS), Université de Strasbourg, 1 Rue Eugène Boeckel, CEDEX, 67085 Strasbourg, France
Amelia-Naomi Sabo
Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire UR7296, Département Universitaire de Pharmacologie, Addictologie, Toxicologie et Thérapeutique, Centre de Recherche en Biomédecine de Strasbourg (CRBS), Université de Strasbourg, 1 Rue Eugène Boeckel, CEDEX, 67085 Strasbourg, France
Maria Cristina Antal
Faculté de Médecine, Institut d’Histologie—Service Central de Microscopie Électronique, Équipe IMIS—ICube UMR7357, Université de Strasbourg, 4 Rue Kirschleger, CEDEX, 67085 Strasbourg, France
Véronique Kemmel
Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire UR7296, Département Universitaire de Pharmacologie, Addictologie, Toxicologie et Thérapeutique, Centre de Recherche en Biomédecine de Strasbourg (CRBS), Université de Strasbourg, 1 Rue Eugène Boeckel, CEDEX, 67085 Strasbourg, France
Laurent Monassier
Laboratoire de Pharmacologie et Toxicologie NeuroCardiovasculaire UR7296, Département Universitaire de Pharmacologie, Addictologie, Toxicologie et Thérapeutique, Centre de Recherche en Biomédecine de Strasbourg (CRBS), Université de Strasbourg, 1 Rue Eugène Boeckel, CEDEX, 67085 Strasbourg, France
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-HT4 in the hCMEC/D3 cell line, in the rat and the human BBB. We also examined the effect of prucalopride, a 5-HT4 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-HT4 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-HT4 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-HT4 receptor contributes to the regulation of BBB permeability.