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

Abstract

Background: The human histamine H₁ receptor is constitutively active and exhibits basal activation of nuclear factor-ĸB (NF-ĸB), an important modulator of allergic inflammation. Certain H₁ antihistamines have recently been shown to inhibit basal NF-ĸB activity by stabilizing the H₁ receptor in an inactive state, a phenomenon called ‘inverse agonism’. Methods: We evaluated the effect of the new H₁ antihistamine, desloratadine, on basal and histamine-stimulated NF-ĸB activity and compared it with the activities of other H₁ antihistamines. Results: Transiently transfected COS-7 cells co-expressing NF-ĸB-luciferase and the H₁ receptor exhibited constitutive NF-ĸB activity. H₁ 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 H₁ 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 H₁ receptor. Conclusions: Desloratadine, acting through the histamine H₁ 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.

Constitutively Active Mutants of the Histamine H1 Receptor Suggest a Conserved Hydrophobic Asparagine-Cage That Constrains the Activation of Class A G Protein-Coupled Receptors

“…Loratadine was not taken as a reference full inverse agonist with an intrinsic activity (␣) of Ϫ1 because of its previously reported inhibition of non-H 1 R mediated NF-B activation in this assay (Bakker et al, 2001 (Yu et al, 2006), and the activities of a variety of reporter genes (Bakker et al, 2001;Weiner et al, 2001;Smit et al, 2002;Wu et al, 2004). Because we aimed at the generation and characterization of a large number of mutant receptors, we selected R-SAT functional assays for the initial characterization because the R-SAT assay is extremely robust, allows high throughput, and yields a similar H 1 R pharmacological profile for a wide variety of inverse H 1 R agonists compared with the more standard NF-B reportergene assay (see Bakker et al, 2007).…”

Resveratrol and Loratadine Effects on Oxidative Stress Induced by Experimental Inflammation

“…Loratadine (selective inverse-agonist of peripheral receptor H 1 ) is used in allergy treatment. Desloratadine, the active metabolite of loratadine, also inhibits the basal and histamine-increased activity of NF-kB [5]. Our study used resveratrol and loratadine to test their efficiency in neutralization of the oxidative stress generated by inflammation, induced by carrageenan injections.…”

Modern approaches to therapy of allergic rhinosinusitis

“…Следовательно, препарат можно принимать как после еды, так и натощак. Метаболизм и выведение пре-парата не зависят от возраста и пола больного [13][14][15].…”

“…В физиологической концентрации эффективно угнетает продукцию гистаминзависимых провоспалительных цито-кинов -ИЛ-6 и ИЛ-8, отрицательно влияет на синтез и продолжительность жизни эозинофилов. Также за счет обратного агонизма препарат снижает экспрессию ядер-ного фактора NF-κB, известного в качестве индуктора RANTES, главного аттрактанта для эозинофилов, моно цитов и Т-лимфоцитов, способствующего активации эозино филов и секрецией гистамина базофилами [15,16].…”