Jiang Jiunn-Song, Chien Hui-Chi, Chen Chien-Ming, Lin Chun-Nan, Ko Wun-Chang
Department of Internal Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, and Graduate Institute of Pharmacology, Department of Medical Technology, College of Medicine, Taipei Medical University, Taiwan.
Planta Med. 2007 Sep;73(11):1156-62. doi: 10.1055/s-2007-981587. Epub 2007 Sep 7.
We investigated the suppressive effects of 3-O-methylquercetin 5,7,3',4'- O-tetraacetate (QMTA), a more-potent phosphodiesterase (PDE)3/4 inhibitor than quercetin 3-O-methyl ether (3-MQ), which has been reported to have the potential for treating asthma, against ovalbumin (OVA)-induced airway hyperresponsiveness (AHR). The IC50 value of QMTA for PDE3 was significantly less than that for PDE4. According to the Lineweaver-Burk analysis, QMTA (1-10 microM) competitively inhibited PDE3 and PDE4 activities. The Ki values were 0.9+/-0.3 (n=5) and 3.9+/-0.5 (n=5) microM, respectively, which significantly differed from each other, suggesting that QMTA has higher affinity for PDE3 than for PDE4. QMTA (3-10 microM) concentration-dependently relaxed the baseline level, and significantly inhibited cumulative OVA (10-100 microg/mL)-induced contractions in isolated sensitized guinea pig trachealis suggesting that QMTA has bronchodilator and inhibiting effects on mast cell degranulation. After the secondary challenge, the AHR was measured in unrestrained OVA-sensitized mice, with nebulized methacholine (MCh, 6.25-50 mg/mL), by barometric plethysmography using a whole-body plethysmograph. In the present results, QMTA (3-10 micromol/kg, I. P.) dose-dependently attenuated the enhanced pause (Penh) value induced by MCh (25-50 mg/mL). QMTA (3-10 micromol/kg, I. P.) also significantly inhibited total inflammatory cells, macrophages, neutrophils, lymphocytes, and eosinophils in BALF after determination of Penh values. It also significantly suppressed the release of interleukin (IL)-2, IL-4, IL-5, IFN-gamma, and TNF-alpha, with the exception that 3 micromol/kg QMTA did not suppress the releases of IL-5. QMTA even at 1 micromol/kg significantly inhibited eosinophils, IL-2, and TNF-alpha. In conclusion, our results strongly suggest that QMTA has greater potential than 3-MQ for the treatment of asthma.
我们研究了3-O-甲基槲皮素5,7,3',4'-O-四乙酸酯（QMTA）对卵清蛋白（OVA）诱导的气道高反应性（AHR）的抑制作用。QMTA是一种比槲皮素3-O-甲基醚（3-MQ）更强效的磷酸二酯酶（PDE）3/4抑制剂，据报道3-MQ具有治疗哮喘的潜力。QMTA对PDE3的IC50值显著低于对PDE4的IC50值。根据Lineweaver-Burk分析，QMTA（1-10 microM）竞争性抑制PDE3和PDE4的活性。Ki值分别为0.9±0.3（n=5）和3.9±0.5（n=5） microM，两者有显著差异，表明QMTA对PDE3的亲和力高于对PDE4的亲和力。QMTA（3-10 microM）浓度依赖性地使基线水平舒张，并显著抑制在离体致敏豚鼠气管中累积OVA（10-100 microg/mL）诱导的收缩，提示QMTA具有支气管扩张作用并能抑制肥大细胞脱颗粒。二次激发后，通过使用全身体积描记器的气压体积描记法，在无束缚的OVA致敏小鼠中用雾化的乙酰甲胆碱（MCh，6.25-50 mg/mL）测量AHR。在本研究结果中，QMTA（3-10 micromol/kg，腹腔注射）剂量依赖性地减弱MCh（25-50 mg/mL）诱导的增强暂停（Penh）值。在测定Penh值后，QMTA（3-10 micromol/kg，腹腔注射）还显著抑制支气管肺泡灌洗液（BALF）中的总炎性细胞、巨噬细胞、中性粒细胞、淋巴细胞和嗜酸性粒细胞。它还显著抑制白细胞介素（IL）-2、IL-4、IL-5、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）的释放，例外的是3 micromol/kg QMTA不抑制IL-5的释放。即使在1 micromol/kg时，QMTA也显著抑制嗜酸性粒细胞、IL-2和TNF-α。总之，我们的结果强烈表明，与3-MQ相比，QMTA在治疗哮喘方面具有更大的潜力。
