title: Hesperetin-7,3'-O-dimethylether selectively inhibits phosphodiesterase 4 and effectively suppresses ovalbumin-induced airway hyperresponsiveness with a high therapeutic ratio.
abstract: BACKGROUND
  Hesperetin 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).
  
  
  METHODS
  PDE1~5 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.
  
  
  RESULTS
  HDME 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.
  
  
  CONCLUSIONS
  HDME 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.
authors.forename: You-Lan
authors.initials: YL
authors.lastname: Yang
authors.forename: Hsin-Te
authors.initials: HT
authors.lastname: Hsu
authors.forename: Kuo-Hsien
authors.initials: KH
authors.lastname: Wang
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Han
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Chen
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Chen
authors.forename: Wun-Chang
authors.initials: WC
authors.lastname: Ko
mesh_terms: D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D001665:Binding Sites; D001772:Blood Cell Count; D016535:Bronchial Hyperreactivity / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D006168:Guinea Pigs; D006569:Hesperidin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D007136:Immunoglobulins / Q000032:analysis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D020889:Rolipram / Q000494:pharmacology
chemical_list: D016207:Cytokines; D007136:Immunoglobulins; D058988:Phosphodiesterase 4 Inhibitors; C570235:hesperetin-7,3'-O-dimethylether; D010047:Ovalbumin; D006569:Hesperidin; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517293:Pde3b protein, mouse; D020889:Rolipram
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