| Summary: | 碩士 === 臺北醫學大學 === 藥理學研究所 === 92 === Part I
Quercetin effectively inhibits PDE1~4. Especially it potently inhibits PDE3 and PDE4. Whether it possesses anti-asthmatic effect is the aim of this investigation. Female BALB/c mice were sensitized by an intraperitoneal injection of ovalbumin (OVA), then challenged via the airway by ultrasonic nebulization of 1% OVA two times.
The airway hyperresponsiveness was measured in unrestrained animals by barometric plethysmography using a whole-body plethysmography, and nebulized methacholin (MCh, 5~50 mg/ml). Quercetin (30~100 μmol/kg, i.p.) revealed it dose-dependently attenuated the enhanced pause (Penh) vale induced by MCh (25~50 mg/ml). Futhermore, quercetin (100 μmol/kg, i.p.) also significantly inhibited MCh (12.5 mg/ml)-induced Penh value. The Penh values of mice adminstered quercetin (10~100 μmol/kg, i.p.) did not significantly differ from those of sensitized mice without challenge by OVA (non-treatment). ? Quercetin (10~100 μmol/kg, i.p.) also significantly inhibited total inflammatory cells, neutrophils, eosinophils, lymphocytes and macrophages, from precipitate of BALF. It also significantly attenuated the release of IL-2, IL-4, IFN-γ and TNF-α. It at doses of 30~100 μmol/kg furthermore significantly inhibited the release of IL-5. Quercetin (10~100 μM) significantly inhibited cumulative OVA (10~100μg/ml) induced contractions of isolated sensitized guinea pig trachea.
Quercetin (30~100 μM) further significantly inhibited OVA (1μg/ml)-induced contractions of these trchealis. Quercetin (3~30 μM) competitively inhibited PDE3 and PDE4 activities by Lineweaver-Burk analysis. In conclusion, quercetin selectively and competitively inhibited PDE3 and PDE4 activities. At doses of 10~100 μmol/kg (i.p.), it possessed anti-inflammatory and bronchodilating effects. Therefore it may have potential in the treatment of asthma.
Part II
New selective phosphodiesterase inhibitors have anti-inflammatory and bronchodilating effects, but have less side effects. Therefore, these drugs will be helpful in the treatment of asthma. Aim of this study was investigation for the relationships between the structures and inhibitory effects of quercetin and its derivaties on phosphodiesterase isozymes activities. In the furture, we hope can synthesize more useful drugs to ameliorate the treatment of asthma.
In our labolatory, we homogenized the lungs and hearts of guinea pigs, and then centrifugated. The supernatant was chromatographed over Q-sepharose, an anion exchange resin. The bound proteins (phosphodiesterases, PDEs) were eluted with various concentrations of NaCl, and separated into PDE1, PDE5, PDE2 and PDE4 in the order, whereas PDE3 was separated from hearts. Cyclic nucleotide phosphodiesterase activitices were measured by a two-step procedure according the method of Thompson and Appleman, using cAMP with [3H]-cAMP or cGMP with [3H]-cGMP as substrate.
Quercetin potently inhibited PDE3 and PDE4, while moderately inhibited PDE1 and PDE2, but had no effect on PDE5 activity. Ayanin potently inhibited PDE1 and PDE3, whereas moderately inhibited PDE2 and PDE4, but had no effect on PDE5 avtivity. QPME potently inhibited PDE1, PDE2, PDE3 and PDE4, but moderately inhibited PDE5 activity. QPA potently inhibited PDE3, while moderately inhibited PDE1 and PDE4, but had no effect on PDE5 activity. QMPA very potently inhibited PDE3, while potently inhibited PDE1,PDE2 and PDE4, but moderatly inhibited PDE5 activity. Overall, QTME moderatly but selectively inhibited PDE3, because it had no effect on other isozymes activity. It is possible to synthesize highly selective PDE4 and/or PDE3 inhibitors, which may be useful in the treatment of asthma.
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