Background and Purpose

Chronic obstructive pulmonary disease (COPD) is a corticosteroid-resistant airway inflammatory condition. Resveratrol has exhibited anti-inflammatory activities in COPD but has weak potency and poor pharmacokinetics. This study aims to evaluate the potential of isorhapontigenin, another dietary polyphenol, as a novel anti-inflammatory agent for COPD by examining its effects in vitro and its 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. Their effects on the release of IL-6 and chemokine (C-X-C motif) ligand 8 (CXCL8) were determined and the activation of NF-κB, AP-1, MAPKs and PI3K/Akt/FoxO3A pathways compared to dexamethasone were evaluated. The pharmacokinetic profiles of isorhapontigenin were assessed in Sprague-Dawley rats after respective intravenous and oral administration.
Key Results

Isorhapontigenin exhibited concentration-dependent inhibition of IL-6 and CXCL8 release, with IC50 values at least two-fold lower than resveratrol. These were associated with suppressed NF-κB and AP-1 activation and notably, the PI3K/Akt/FoxO3A pathway that was relatively insensitive to dexamethasone. In vivo, isorhapontigenin was rapidly absorbed with abundant plasma exposure 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 to 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.