Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Becker G

PROVIDER: S-EPMC8619119 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Becker Guillaume G Da Silva Sylvia S Sabo Amelia-Naomi AN Antal Maria Cristina MC Kemmel Véronique V Monassier Laurent L

Pharmaceutics 20211103 11

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 o ...[more]

PMID: 34834271

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Project description:BackgroundThe blood-brain barrier (BBB) is a semipermeable interface that prevents the non-selective transport into the central nervous system. It controls the delivery of macromolecules fueling the brain metabolism and the immunological surveillance. The BBB permeability is locally regulated depending on the physiological requirements, maintaining the tissue homeostasis and influencing pathological conditions. Given its relevance in vertebrate CNS, it is surprising that little is known about the BBB in Amphibians, some of which are capable of adult CNS regeneration.ResultsThe BBB size threshold of the anuran Xenopus laevis (African clawed toad), as well as two urodele species, Ambystoma mexicanum (axolotl) and Pleurodeles waltl (Iberian ribbed newt), was evaluated under physiological conditions through the use of synthetic tracers. We detected important differences between the analyzed species. Xenopus exhibited a BBB with characteristics more similar to those observed in mammals, whereas the BBB of axolotl was found to be permeable to the 1 kDa tracer. The permeability of the 1 kDa tracer measured in Pleurodeles showed values in between axolotl and Xenopus vesseks. We confirmed that these differences are species-specific and not related to metamorphosis. In line with these results, the tight junction protein Claudin-5 was absent in axolotl, intermediate in Pleurodeles and showed full-coverage in Xenopus vessels. Interestingly, electron microscopy analysis and the retention pattern of the larger tracers (3 and 70 kDa) demonstrated that axolotl endothelial cells exhibit higher rates of macropinocytosis, a non-regulated type of transcellular transport.ConclusionsOur study demonstrated that, under physiological conditions, the blood-brain barrier exhibited species-specific variations, including permeability threshold, blood vessel coverage, and macropinocytosis rate. Future studies are needed to test whether the higher permeability observed in salamanders could have metabolic and immunological consequences contributing to their remarkable regenerative capacity.

Dataset Information

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

Publications

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

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