Desloratadine Inhibits Constitutive and Histamine-Stimulated Nuclear Factor-κB Activity Consistent with Inverse Agonism at the Histamine H1 Receptor

Background: The human histamine H 1 receptor is constitutively active and exhibits basal activation of nuclear factor-ĸB (NF-ĸB), an important modulator of allergic inflammation. Certain H 1 antihistamines have recently been shown to inhibit basal NF-ĸB activity by stabilizing the H 1 receptor in an inactive state, a phenomenon called ‘inverse agonism’. Methods: We evaluated the effect of the new H 1 antihistamine, desloratadine, on basal and histamine-stimulated NF-ĸB activity and compared it with the activities of other H 1 antihistamines. Results: Transiently transfected COS-7 cells co-expressing NF-ĸB-luciferase and the H 1 receptor exhibited constitutive NF-ĸB activity. H 1 antihistamines reduced basal NF-ĸB activity (rank order of potency: desloratadine > pyrilamine > cetirizine > loratadine > fexofenadine). Histamine stimulated basal NF-ĸB activity 8-fold, which was blocked by H 1 antihistamines (rank order of potency: desloratadine > cetirizine > pyrilamine > loratadine > fexofenadine). Neither histamine nor antihistamines had any effect on NF-ĸB activity in the absence of the H 1 receptor. Conclusions: Desloratadine, acting through the histamine H 1 receptor, inhibited basal NF-ĸB activity and can thus be classified as an inverse agonist. Inhibition of basal and histamine-stimulated NF-ĸB activity may help to explain previously reported inhibitory effects of desloratadine on allergic inflammatory mediators.