Hesperetin-5,7,3ʹ-O-Trimethylether Dually Inhibits Phosphodiesterase 3/4 and Methacholine-Induced Airway Hyperresponsiveness in Sensitized and Challenged Mice

Abstract

Introduction

Hesperetin-5,7,3ʹ-O-trimethylether (HTME), a synthetic liposoluble hesperetin, has been reported to be a dual phosphodiesterase (PDE)3/4 inhibitor. We investigated its inhibitory effects on methacholine (MCh)-induced airway hyperresponsiveness (AHR) and its potential for treating atypical asthma and COPD.

Methods

FlexiVent system was used to determine AHR in ovalbumin (OVA) sensitized and challenged mice. Determination of cytokines was performed by using mouse T helper (Th)1/Th2 cytokine CBA kits, and of total immunoglobulin (Ig)E and OVA-specific IgE using ELISA kits. The number of inflammatory cells was counted using a hemocytometer. Xylazine/ketamine-induced anesthesia was to assess nausea, vomiting, and gastric hypersecretion in these mice.

Results

HTME dually and competitively inhibited PDE3/4 activities in the Lineweaver–Burk analysis. HTME (30 and 100 μmol/kg) dose-dependently and significantly decreased the airway resistance (R_L) and increased lung dynamic compliance (C_dyn) values induced by MCh. It significantly suppressed numbers of total inflammatory cells and neutrophils, and levels of cytokines in bronchoalveolar lavage fluid (BALF). HTME dose-dependently and significantly inhibited total and OVA-specific IgE levels in the BALF and serum. However, HTME did not influence xylazine/ketamine-induced anesthesia.

Conclusion

HTME exerted anti-inflammatory and bronchodilator effects and may be useful in treating chronic obstructive pulmonary disease and allergic atypical asthma with no gastrointestinal side effects.

Keywords:

• allergic asthma
• chronic obstructive pulmonary disease
• therapeutic PDE4_H/PDE4_L ratio
• ovalbumin
• cytokines
• bronchoalveolar lavage fluid
• inflammation

Acknowledgment

This work was supported by a grant (NSC 96-2320-B-038-020) from the Ministry of Science and Technology, Taipei, Taiwan.

Abbreviations

AHR, airway hyperresponsiveness; BALF, bronchoalveolar lavage fluid; C_dyn, lung dynamic compliance; COPD, chronic obstructive pulmonary disease; ELISA, enzyme-linked immunosorbent assay; GI, gastrointestinal; [³H]cAMP, [³H]adenosine 3ʹ,5ʹ cyclic monophosphate; HTME, hesperetin-5,7,3ʹ-O-trimethylether; IFN-γ, interferon-γ; IL, interleukin; Ig, immunoglobulin; LT, leukotriene; MCh, methacholine; OVA, ovalbumin; PDE, phosphodiesterase; R_L, airway resistance; TNF-α, tumor necrosis factor-α.

Disclosure

The authors report no conflicts of interest in this work.