Effect of H4R Antagonist N-(2-Aminoethyl)-5-Chloro-1H-Indole-2-Carboxamide (Compound A) in a Mouse Model of Allergic Asthma

Abstract

ABSTRACT Context: Allergic asthma is a multifactorial airway disease characterised by chronic lung inflammation and airway remodelling. The histamine H4 receptor involved in the chemotaxis of leukocytes and mast cells to the site of inflammation is suggested to be a potential drug target for allergy and asthma. In this study we examined the effect of Compound A, N-(2-Aminoethyl)-5-chloro-1H-indol-2-carboxamide a H4 receptor antagonist in allergic asthma mice model. Objective: To investigate the anti-asthmatic effect of compound A in in vivo, airway inflammation in ovalbumin (OVA) induced allergic asthma mouse model was used. Methodology: Allergic asthma was induced in Balb/c mice using ovalbumin. BAL fluid was examined for the level of IgE, IL-4, IL-5, IL-13 and IL-17 using ELISA. Furthermore, infiltration of leucocytes by histopathology and effect of compound A on signalling molecules were examined in lung tissue. Results: In mice pre-treatment with compound A (10 mg/kg, 20 mg/kg, 30 mg/kg) at different concentrations markedly reduced the levels of IgE, Th2 cytokine IL-4, IL-5, IL-13 and Th17 cytokine IL-17 in BAL fluid. Histopathological examination of lung tissue showed that compound A was able to reduce the level of inflammatory infiltrates. Furthermore, lung tissue from Compound A treated group shown to down-regulate the levels of signalling molecules such as ERK1/2, Akt, SAPK/JNK and NF-κB compared to OVA treated group. Discussion and conclusion: Taken together our data demonstrates that compound A has shown to block the H4R-mediated allergic inflammation in this allergic asthma mice model and may be used as a molecule to study the function of H4R. Abbreviations: Compound A, N-(2-Aminoethyl)-5-chloro-1H-indol-2-carboxamide; JNJ7777120, 1-[(5-chloro-1H-indol-2-yl)carbonyl]-4-methylpiperazine; H4R: Histamine 4 Receptor; AHR: Airway hyper responsiveness