Hesperidin 及 hesperidin-3’-O-methylether 抗氣喘的作用

Anti-asthmatic action of hesperidin and hesperidin-3’-O-methylether

王超賢(Chao-Sian Wang)

指導教授 ： 林建煌 ； 柯文昌

臺北醫學大學/醫學院/醫學科學研究所/碩士(2008年)

https://doi.org/10.6831/TMU.2008.00007

摘要

橙皮苷 (hesperidin) 是flavanone glycoside，目前已有文獻指出hesperidin具有抗發炎及止痛的效果，我們曾報告過橙皮素(hesperetin)有抗氣喘效果，而hesperidin結構上比橙皮素hesperetin多一個醣基，富含於柑橘類果皮中，為甜橘及檸檬中主要的flavonoid，其抗氣喘效果值得探討。另外，甲基橙皮苷 (hesperidin-3’-O-methylether) 是橙皮苷甲基化而得，目前僅知有冠狀動脈擴張及舒張多種平滑肌作用，但是否有抗氣喘作用尚不得而知，
將雌性小白鼠 (BALB/c) 腹腔內注射卵蛋白 (ovalbumin, OVA)，使其敏感化，再將卵蛋白以氣化噴霧的方式給予小白鼠，作為卵蛋白第一次激釁 (primary challenge)，而後利用整體體積描述器來分析因methacholine (MCh) 所引起的氣道過度反應 (airway hyperresponsiveness； AHR)。結果顯示，hesperidin (100 μmol/kg, p.o.)及hesperidin-3’-O-methylether (30~100 μmol/kg, p.o.)可減低由MCh所增加的enhanced pause (Penh) 值，以及減少肺泡灌洗液 (BALF) 的總發炎細胞、嗜酸性白血球、嗜中性白血球和淋巴球的產生，也會有意義地降低肺泡灌洗液interleukin (IL)-2, IL-4, IL-5和tumor necrosis factor (TNF)-?悛瘧孺鞢A而interferon (IFN)-?? 的釋放，會降低血清及肺泡灌洗液的total 和OVA-specific IgE的量，但增加血清的IgG2a含量，顯示能加强抗發炎的作用。Hesperidin取代結合在敏感化天竺鼠全腦細胞顆粒high affinity rolipram binding sites (HARBS)之 [3H]-rolipram的EC50值 > 300 μM，hesperidin-3’-O-methylether則為218.3 ± 32.1 μM，因此計算其治療係數(PDE4H/PDE4L)為15.7，並且發現兩者皆無法縮短由xylazine/ketamine所引起的麻醉時間，所以推測如噁心、嘔吐及胃酸分泌過多的副作用很低。
Hesperidin (100 ?嵱) 和hesperidin-3’-O-methylether (100 ?嵱) 兩者均無法抑制累加OVA (10~100 μg/ml) 引起的敏感化離體天竺鼠氣管的收縮，雖然都會有意義地鬆弛其基本張力，顯示無法抑制肥胖細胞的去顆粒化。
結論，hesperidin及hesperidin-3’-O-methylether具抗發炎及抗氣喘的功效，而hesperidin-3’-O-methylether的作用似乎更勝於hesperidin。

關鍵字

氣喘

並列摘要

Hesperidin is a flavanone glycoside. Hesperidin has been reported to possess significant anti-inflammatory and analgesic effects. Our previous study has indicated hesperetin possess antiasthmatic effect. Hesperidin is an abundant and inexpensive by-product of Citrus cultivation and is the major flavonoid in sweet orange and lemon. Hesperidin-3’-O-methylether is a methylation product of hesperidin. We just know hesperidin-3’-O-methylether possess the vasodilation of coronary artery and the relaxation of some smooth muscle now, but these is little study about antiasthmatic effect.
In the sensitized and OVA-primary challenged BALB/c mice, an asthmatic animal model, the airway hyperresponsiveness (AHR) was measured in unrestrained animals by barometric plethysmography using a whole-body plethysmograph after exposure of methacholine (MCh, 6.25~50 mg/ml) and enhanced pause (Penh) values were determined. First, hesperidin (100 μmol/kg, p.o.) and hesperidin-3’-O-methylether (30~100 μmol/kg, p.o.) significantly suppressed the enhancement of MCh -induced Penh values and significantly suppressed the increase of total inflammatory cells, eosinophils, neutrophils, and lymphocytes, and also significantly attenuated the release of interleukin (IL)-2, IL-4, IL-5 and tumor necrosis factor (TNF)-α in bronchoalveolar lavage fluid (BALF) of the mice, but the release of interferon (IFN)-γ is increased. They also significantly reduced total and OVA-specific IgE levels in the serum and in the BALF. In the opposite, it significantly increased IgG2a levels in the serum suggesting that the anti-inflammation was potentiated.
Hesperidin displaced [3H]-rolipram from high affinity rolipram binding sites (HARBS) of particulates of whole brains isolated from sensitized guinea pigs, with an EC50 value beyond 300 ?嵱, and the EC50 value of hesperidin-3’-O-methylether is 218.3 ± 32.1 μM. Therefore, its therapeutic ratio (PDE4H/PDE4L) was calculated to be 15.7. Hesperidin and hesperidin-3’-O-methylether did not shorten the duration of anathesia induced by xylazine/ketamine, suggesting that its adverse effect, such as nausea, vomiting and gastric hypersecretion, may be little.
Hesperidin (100 ?嵱) and hesperidin-3’-O-methylether (100 ?嵱) significantly relaxed the baseline tension, but did not suppress cumulative OVA (10~100 ?慊/ml)-induced contractions in isolated sensitized guinea pig trachealis, suggesting that they can not prevent the degranulation of mast cells.
In conclusion, both of hesperidin and hesperidin-3’-O-methylether possessed anti-inflammatory and anti-asthmatic effects. Hesperidin-3’ -O-methylether had better anti-inflammatory effects than hesperidin.

並列關鍵字

hesperidin ； antiasthmatic

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