Hesperetin-7,3'-O-dimethylether selectively inhibits phosphodiesterase 4 and effectively suppresses ovalbumin-induced airway hyperresponsiveness with a high therapeutic ratio

Journal of Biomedical Science

Research

Kuo-Hsien Wang¹  Chien-Ming Chen²  Chi-Ming Chen³  Hsin-Te Hsu⁴  Wun-Chang Ko⁵  Cheng-Ying Han⁶  You-Lan Yang⁷ 

[1] Department of Dermatology, Taipei Medical University Hospital, 252 Wu-Hsing St, Taipei 110, Taiwan;Department of Medical Technology, College of Medicine, Taipei Medical University, 250 Wu-Hsing St, Taipei 110, Taiwan;Department of Medicinal Chemistry, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing St, Taipei 110, Taiwan;Department of Otolaryngology, Taipei Medical University Hospital, 252 Wu-Hsing St, Taipei 110, Taiwan;Department of Otolaryngology, Taipei Medical University Hospital, 252 Wu-Hsing St, Taipei 110, Taiwan;Department of Pharmacology, College of Medicine, Taipei Medical University, 250 Wu-Hsing St, Taipei 110, Taiwan;Department of Pharmacology, College of Medicine, Taipei Medical University, 250 Wu-Hsing St, Taipei 110, Taiwan;School of Respiratory Therapy, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei 110, Taiwan;

关键词: Airway hyperresponsiveness;    allergic asthma;    chronic obstructive pulmonary disease;    cytokine;    O;    phosphodiesterase-4 inhibitor;   

DOI  :  10.1186/1423-0127-18-84

 received in 2011-09-29, accepted in 2011-11-11,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundHesperetin was reported to selectively inhibit phosphodiesterase 4 (PDE4). While hesperetin-7,3'-O-dimethylether (HDME) is a synthetic liposoluble hesperetin. Therefore, we were interested in investigating its selectivity on PDE4 and binding ability on high-affinity rolipram-binding sites (HARBs) in vitro, and its effects on ovalbumin-induced airway hyperresponsiveness in vivo, and clarifying its potential for treating asthma and chronic obstructive pulmonary disease (COPD).MethodsPDE1~5 activities were measured using a two-step procedure. The binding of HDME on high-affinity rolipram-binding sites was determined by replacing 2 nM [3H]-rolipram. AHR was assessed using the FlexiVent system and barometric plethysmography. Inflammatory cells were counted using a hemocytometer. Cytokines were determined using mouse T helper (Th)1/Th2 cytokine CBA kits, and total immunoglobulin (Ig)E or IgG2a levels were done using ELISA method. Xylazine (10 mg/kg)/ketamine (70 mg/kg)-induced anesthesia was performed.ResultsHDME revealed selective phosphodiesterase 4 (PDE4) inhibition with a therapeutic (PDE4H/PDE4L) ratio of 35.5 in vitro. In vivo, HDME (3~30 μmol/kg, orally (p.o.)) dose-dependently and significantly attenuated the airway resistance (RL) and increased lung dynamic compliance (Cdyn), and decreased enhanced pause (Penh) values induced by methacholine in sensitized and challenged mice. It also significantly suppressed the increases in the numbers of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF) of these mice. In addition, HDME (3~30 μmol/kg, p.o.) dose-dependently and significantly suppressed total and ovalbumin-specific immunoglobulin (Ig)E levels in the BALF and serum, and enhanced IgG2a level in the serum of these mice.ConclusionsHDME exerted anti-inflammatory effects, including suppression of AHR, and reduced expressions of inflammatory cells and cytokines in this murine model, which appears to be suitable for studying the effects of drugs on atypical asthma and COPD, and for screening those on typical asthma. However, HDME did not influnce xylazine/ketamine-induced anesthesia. Thus HDME may have the potential for use in treating typical and atypical asthma, and COPD.

【 授权许可】

Unknown   
© Yang et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.