Limonene Reduces Airway Hyperreactivity and Inflammation through Activation of A 2A Adenosine Receptors

Animal models of asthma have shown that limonene, a naturally occurring terpene in citrus fruits, may have beneficial effects by reducing inflammation and airway reactivity. However, the mechanism of these effects is unknown. We hypothesized that limonene activates A 2A adenosine receptors (A 2A AR) to produce its effects in asthma. Computational analysis comparing Glide scores for Limonene (‐5.19) and A 2A AR agonist CGS 21680 (‐8.43) suggests that Limonene binds to the A 2A AR as an agonist. We then investigated the pharmacological effects of limonene on lung inflammation and airway responsiveness to methacholine (MCh), and the effect of A 2A AR antagonist SCH 58261 on NECA (nonselective adenosine agonist) response in a mouse model of allergic asthma. Mice were divided into control (CON) and allergen sensitized‐challenged (SEN) groups, and were sensitized i.p. on days 1, 6 with 20μg ovalbumin (OVA) followed by 5% OVA aerosol challenges on days 11–13. Limonene (1mg/kg) was administered as an aerosol before the OVA challenges on days 11–13 (SEN+LIM). Whole body plethysmography (measuring airway responsiveness as enhanced pause, Penh) and bronchoalveolar lavage (BAL) studies were performed. Airway responsiveness to MCh (48mg/ml) was highest in SEN group (420±92.57 vs. 50.39±24.72% in CON, p<0.05) and was significantly lower with limonene treatment (56.23±25% in SEN+LIM). SCH 58261 (10 −5 M) increased the NECA‐mediated airway response in SEN+LIM, suggesting that effects of limonene were blocked by SCH 58261. Differential BAL cell analysis showed that limonene reduced levels of eosinophils (70.66±2.6% in SEN vs. 28.66±1.45% in SEN+LIM, p<0.05). These data suggest that limonene reduces airway inflammation and airway reactivity, possibly by activating the A 2A AR. Support or Funding Information LIU Start‐up fund (DSP)Computational model showing limonene bound to A 2A adenosine receptor