Article date: July 2017
By: Samuel Chao Ming Yeo, Peter S Fenwick, Peter J Barnes, Hai Shu Lin, Louise E Donnelly in Volume 174, Issue 13, pages 2043-2059
Background and Purpose
Chronic obstructive pulmonary disease (COPD) is a corticosteroid‐resistant airway inflammatory condition. Resveratrol exhibits anti‐inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aimed to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti‐inflammatory agent for COPD by examining its effects in vitro and pharmacokinetics in vivo.
Experimental Approach
Primary human airway epithelial cells derived from healthy and COPD subjects, and A549 epithelial cells were incubated with isorhapontigenin or resveratrol and stimulated with IL‐1β in the presence or absence of cigarette smoke extract. Effects of isorhapontigenin and resveratrol on the release of IL‐6 and chemokine (C‐X‐C motif) ligand 8 (CXCL8), and the activation of NF‐κB, activator protein‐1 (AP‐1), MAPKs and PI3K/Akt/FoxO3A pathways were determined and compared with those of dexamethasone. The pharmacokinetic profiles of isorhapontigenin, after i.v. or oral administration, were assessed in Sprague–Dawley rats.
Key Results
Isorhapontigenin concentration‐dependently inhibited IL‐6 and CXCL8 release, with IC50 values at least twofold lower than those of resveratrol. These were associated with reduced activation of NF‐κB and AP‐1 and, notably, the PI3K/Akt/FoxO3A pathway, that was relatively insensitive to dexamethasone. In vivo, isorhapontigenin was rapidly absorbed with abundant plasma levels after oral dosing. Its oral bioavailability was approximately 50% higher than resveratrol.
Conclusions and Implications
Isorhapontigenin, an orally bioavailable dietary polyphenol, displayed superior anti‐inflammatory effects compared with resveratrol. Furthermore, it suppressed the PI3K/Akt pathway that is insensitive to corticosteroids. These favourable efficacy and pharmacokinetic properties support its further development as a novel anti‐inflammatory agent for COPD.
DOI: 10.1111/bph.13803
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