The 5-hydroxytryptamine receptor type 4 regulates blood-brain-barrier permeability - 18/05/21
Résumé |
Introduction |
Serotonin (5-HT) plays a major role in cardiovascular regulations. The 5-HT4 Receptor (5-HT4R) elicits positive cardiac inotropic responses and contributes to atrial arrhythmias and ventricular hypertrophy. Nevertheless, headache is a common side effect of prucalopride, a non-arrhythmogenic 5-HT4R agonist. 5-HT released by platelets has been suggested to modulate Blood-Brain-Barrier (BBB) permeability. We hypothesized that 5-HT, through the stimulation of 5-HT4Rs, could affect BBB permeability.
Objective |
This work aims to characterize the functional role of 5-HT4R at the BBB interface.
Method |
Studies have been performed on human cerebral microvascular endothelial cells hCMEC/D3. The BBB permeability was assessed by TransEndothelial Electrical Resistance (TEER). The hCMEC/D3 were stimulated with prucalopride 10μM in absence or presence of the 5-HT4R antagonist GR113808 1μM. Additionally, protein expression of occludin was evaluated. Finally, the intracellular pathway involved in this regulation was investigated.
Results |
A 96-hour treatment with prucalopride decreased the TEER (47.0%, n=6, P<1.10−4) attesting the BBB opening. When GR113808 alone did not change the TEER (92.2%, P=0.51), it significantly prevented the effect of prucalopride (70.1%, P<1.10−4). Occludin protein expression was reduced after prucalopride stimulation (77.83%, n=6, P<0.05) leading to the opening of the BBB. Conversely, GR113808 increased occludin expression (129.83%, n=6, P<0.05). This effect seems to be driven by ERK1/2 phosphorylation (n=3; prucalopride: 210,3%, P<0.05; GR113808: 103,7%, P>0.05; GR113808+prucalopride: 130%, P>0.05), a pathway described to affect occludin expression.
Conclusion |
Our findings support the hypothesis that 5-HT4R plays a role in the regulation of BBB permeability. Studies are ongoing to determine the entire signalling pathway. The contribution of platelets and 5-HT4R in the pathological change in BBB permeability is suggested.
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Vol 13 - N° 2
P. 184 - mai 2021 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.