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

Abstract

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.

The impact of omega-3 fatty acids on lung histopathology in mice model of chronic asthma

“…Preliminary studies demonstrated almost always an increase in the numbers of neutrophils, eosinophils, macrophages and lymphocytes in the respiratory system of animals sensitized via OVA (Nabe et al, 2005;Nabe et al, 2011;Yang et al, 2011;Brandenberger et al, 2013;Kim et al, 2013). In this study, there was no difference between the two groups for eosinophilia and macrophage, with a slight difference in the number of lymphocytes (p=0.085).…”

Effects of the Flavanone combination Hesperetin‐Naringenin, and Orange and Grapefruit Juices, on Airway inflammation and Remodeling in a murine asthma model

“…or 3–30 µmol/kg o.p.) reduced all types of inflammatory cells and cytokines, including IL‐5 and tumor necrosis factor‐α (TNF‐α) levels in BAL fluid of methacholine‐sensitized mice (Yang et al ., ; Shih et al ., ). Our study revealed that hesperetin–naringenin, orange, and grapefruit juices each could significantly reduce infiltration of inflammatory cells to airway and mucus plug formation.…”

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

“…In accordance with the previous method and schedule, 13 the AHR of female BABL/c mice was assessed by measuring changes in the airway resistance (R L, cmH 2 O/mL/sec) and lung dynamic compliance (C dyn , mL/cmH 2 O) after challenge with aerosolized methacholine (MCh, 0.78~25 mg/mL) using the FlexiVent system (SCIREQ, Montreal, Quebec, Canada). Anesthetized (urethane 600 mg/kg and chloralose 120 mg/kg, i.p.…”