- 作者: You-Lan Yang, Hsin-Te Hsu, Kuo-Hsien Wang, Cheng-Ying Han, Chien-Ming Chen, Chi-Ming Chen and Wun-Chang Ko
- 作者服務機構: School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
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 of these mice. In addition, HDME (3~30 μmol/kg, p.o.)
dose-dependently and significantly suppressed total and OVA-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. - 中文關鍵字: --
- 英文關鍵字: Airway hyperresponsiveness; allergic asthma; chronic obstructive pulmonary disease; cytokine; hesperetin-7,3’-O-dimethylether; phosphodiesterase-4 inhibitor