The 5-hydroxytryptamine receptor type 4 regulates blood-brain-barrier permeability

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 10 μM in absence or presence of the 5-HT4R antagonist GR113808 1 μM. 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   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.