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Isorhapontigenin, a bioavailable dietary polyphenol, suppresses airway epithelial cell inflammation through a corticosteroid‐independent mechanism
Author(s) -
Yeo Samuel Chao Ming,
Fenwick Peter S,
Barnes Peter J,
Lin Hai Shu,
Donnelly Louise E
Publication year - 2017
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13803
Subject(s) - resveratrol , pharmacology , pharmacokinetics , pi3k/akt/mtor pathway , bioavailability , dexamethasone , protein kinase b , in vivo , chemistry , oral administration , inflammation , interleukin 8 , medicine , signal transduction , biology , biochemistry , microbiology and biotechnology
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 IC 50 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.