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Limonene-induced activation of A2A adenosine receptors reduces airway inflammation and reactivity in a mouse model of asthma

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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.

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Acknowledgments

This work was supported by LIU startup funds (DSP) and National Institutes of Health grant HL027339 (SJM).

Funding

Long Island University start-up funds (DSP), HL027339 (SJM).

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Authors and Affiliations

  1. Division of Pharmaceutical Sciences Arnold & Marie Schwartz College of Pharmacy & Health Sciences, Long Island University, Brooklyn, NY, USA

    Mehaben Patel, Deven Narke, Mangesh Kurade, Sahith Rajalingam, Armaan Siddiquee & Dovenia S. Ponnoth

  2. Fairleigh Dickinson University School of Pharmacy and Health Sciences, Teaneck, NJ, USA

    Kathleen M. Frey

  3. Department of Physiology and Pharmacology, West Virginia University, Morgantown, WV, USA

    S Jamal Mustafa

  4. Université Libre de Bruxelles, Brussels, Belgium

    Catherine Ledent

  5. Department of Biomedical Sciences, West Virginia School of Osteopathic Medicine, WV, Lewisburg, USA

    Dovenia S. Ponnoth

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  1. Mehaben Patel
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  2. Deven Narke
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  9. Dovenia S. Ponnoth
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Correspondence to Dovenia S. Ponnoth.

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All applicable institutional guidelines for the care and use of animals were followed. All procedures performed were in accordance with the ethical standards of Long Island University under an approved IACUC protocol DP-AA-2018.

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Patel, M., Narke, D., Kurade, M. et al. Limonene-induced activation of A2A adenosine receptors reduces airway inflammation and reactivity in a mouse model of asthma. Purinergic Signalling 16, 415–426 (2020). https://doi.org/10.1007/s11302-020-09697-z

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