Limonene-induced activation of A 2A adenosine receptors reduces airway inflammation and reactivity in a mouse model of a
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ORIGINAL ARTICLE
Limonene-induced activation of A2A adenosine receptors reduces airway inflammation and reactivity in a mouse model of asthma Mehaben Patel 1 & Deven Narke 1 & Mangesh Kurade 1 & Kathleen M. Frey 2 & Sahith Rajalingam 1 & Armaan Siddiquee 1 & S Jamal Mustafa 3 & Catherine Ledent 4 & Dovenia S. Ponnoth 1,5 Received: 20 August 2019 / Accepted: 19 March 2020 # Springer Nature B.V. 2020
Abstract Animal models of asthma have shown that limonene, a naturally occurring terpene in citrus fruits, can reduce inflammation and airway reactivity. However, the mechanism of these effects is unknown. We first performed computational and molecular docking analyses that showed limonene could bind to both A2A and A2B receptors. The pharmacological studies were carried out with A2A adenosine receptor knock-out (A2AKO) and wild-type (WT) mice using ovalbumin (OVA) to generate the asthma phenotype. We investigated the effects of limonene on lung inflammation and airway responsiveness to methacholine (MCh) and NECA (nonselective adenosine analog) by administering limonene as an inhalation prior to OVA aerosol challenges in one group of allergic mice for both WT and KO. In whole-body plethysmography studies, we observed that airway responsiveness to MCh in WT SEN group was significantly lowered upon limonene treatment but no effect was observed in A2AKO. Limonene also attenuated NECA-induced airway responsiveness in WT allergic mice with no effect being observed in A2AKO groups. Differential BAL analysis showed that limonene reduced levels of eosinophils in allergic WT mice but not in A2AKO. However, limonene reduced neutrophils in sensitized A2AKO mice, suggesting that it may activate A2B receptors as well. These data indicate that limonene-induced reduction in airway inflammation and airway reactivity occurs mainly via activation of A2AAR but A2B receptors may also play a supporting role. Keywords A2A adenosine receptors . Asthma . Airway inflammation . Airway responsiveness . Limonene
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11302-020-09697-z) contains supplementary material, which is available to authorized users. * Dovenia S. Ponnoth [email protected]
S Jamal Mustafa [email protected]
Mehaben Patel [email protected] Deven Narke [email protected]
Catherine Ledent [email protected] 1
Mangesh Kurade [email protected]
Division of Pharmaceutical Sciences Arnold & Marie Schwartz College of Pharmacy & Health Sciences, Long Island University, Brooklyn, NY, USA
2
Kathleen M. Frey [email protected]
Fairleigh Dickinson University School of Pharmacy and Health Sciences, Teaneck, NJ, USA
3
Sahith Rajalingam [email protected]
Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, USA
4
Université Libre de Bruxelles, Brussels, Belgium
5
Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, WV Lewisburg, USA
Armaan Siddiquee [email protected]
Puri
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