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Effects of rupatadine on Platelet activating factor (PAF)-induced human mast cell degranulation compared with desloratadine and levocetirizine (The MASPAF study)

Muñoz-Cano R1,2, Ainsua-Enrich E3, Torres-Atencio I4, Martin M3, Sánchez-Lopez J1,2, Bartra J1,2, Picado C1,2,5, Mullol J2,5,6*, Valero A1,2,5 *

1Unitat d’Al·lèrgia. Servei de Pneumologia i Al·lèrgia Respiratòria. Hospital Clínic. Universitat de Barcelona. Barcelona, Catalonia, Spain.
2Immunoal·lèrgia Respiratòria Clínica i Experimental. Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS). Barcelona, Catalonia, Spain.
3Biochemistry Unit, School of Medicine, Universitat de Barcelona. Barcelona, Catalonia, Spain.
4Pharmacology Department, School of Medicine, Universidad de Panamá. Panamá.
5Centro de Investigaciones Biomédicas en Red de Enfermedades Respiratorias (CIBERES). Barcelona, Catalonia, Spain.
6Unitat de Rinologia i Clínica de l’Olfacte, Servei d’Oto-rino-laringologia, Hospital Clínic, Universitat de Barcelona. Barcelona, Catalonia, Spain.

J Investig Allergol Clin Immunol 2016; Vol. 27(3)
doi: 10.18176/jiaci.0117

Rationale: Platelet activating factor (PAF) is a lipid mediator involved in the pathophysiology of several allergic diseases, such as the amplification of mast cell (MC) activation in anaphylaxis. Rupatadine is an antihistamine with demonstrated anti-PAF effect but its capacity to inhibit PAF-induced MC degranulation has not been fully evaluated.
Objective: To investigate the ability of rupatadine to inhibit PAF-induced MC degranulation compared with desloratadine and levocetirizine, to confirm dual rupatadine anti-H1 and anti-PAF activities.
Methods: The human MC line LAD2 and primary MC (human lung tissue (hLMC)) were used. MC mediator release was evaluated by β-hexosaminidase and histamine release assay. Rupatadine (H1 antagonist + PAF receptor antagonist), desloratadine and levocetirizine (H1 antagonists) effects were compared in LAD2 and hLMC. Selective PAF receptor antagonists WEB2086, BN52021, and CV6209 were also tested. PAF receptor protein expression was evaluated in both LAD2 and hLMC.
Results: PAF receptor expression was confirmed in both LAD2 and hLMC. Among anti-PAF inhibitors, CV6209 and rupatadine inhibited PAF-induced MC degranulation in both LAD2 and hLMC. In LAD2, Rupatadine (5 and 10 µM) and levocetirizine (5 µM), but not desloratadine, inhibited PAF-induced β-hexosaminidase release. Rupatadine (1 -10 µM), levocetirizine (1-10 µM), and desloratadine (10 µM) inhibited PAF-induced histamine release. Rupatadine at 10 µM, but neither levocetirizine nor desloratadine, showed an inhibitory effect in hLMC degranulation.
Conclusions: This study shows that rupatadine and, to a lesser extent, levocetirizine, but not desloratadine, inhibit PAF-induced degranulation in both LAD2 and human lungMC. These findings support the dual anti-H1 and anti-PAF effects of rupatadine in allergic disorders.

Key words: CV6209, Desloratadine, LAD2, Levocetirizine, Mast cell, Platelet-activating Factor, Rupatadine