老鼠簕生物碱A与乙酰老鼠簕生物碱A抗炎镇痛活性及抗炎机制的研究
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摘要
目的:研究老鼠簕生物碱A ( 4-羟基苯并恶唑-2-酮,4-hydroxy-2-benzoxazolone,简称HBOA),英文名:Ilicifolius alkaloids A(IA)及其衍生物乙酰老鼠簕生物碱A(4-乙酰氧基苯并恶唑-2-酮,4-Acetoxy-2-benzoxazolone,简称ACO-BOA),英文名:Acetyl Ilicifolius alkaloids A(ACO-IA)的抗炎镇痛作用及对小鼠的急性毒性、胃肠刺激作用,并对其抗炎作用机制进行初步研究,致力寻找一种既有良好药效又能最低限度降低毒副作用的新抗炎药。
方法:采用改良寇氏法计算小鼠LD50并观察其毒性作用,采用二甲苯致小鼠耳肿胀法、小鼠热板法、腹腔注射醋酸诱导的小鼠扭体法观察其抗炎镇痛作用,采用毛细管法和剪尾法观察两个化合物对小鼠出血-凝血时间的影响,并观察连续灌胃给药对小鼠胃肠的影响。
在研究抗炎作用机制的试验中,用体外人全血分析方法测定老鼠簕生物碱A及其衍生物乙酰老鼠簕 A对COX-1和COX-2活性的影响。抽取健康志愿者全血标本加入钙离子载体A23187予以刺激,以阿司匹林为对照,通过酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)法检测血栓素B2(thromboxane,TXB2)含量考察不同浓度的老鼠簕生物碱A及其衍生物乙酰老鼠簕 A对COX-1活性的影响;抽取志愿者全血经阿司匹林灭活COX-1后,予脂多糖(lipopolysaccharide,LPS)刺激后,以塞来昔布为对照,通过ELISA检测前列环素I2(postaglandinI2,PGI2)含量考察不同浓度的老鼠簕生物碱A及其衍生物乙酰老鼠簕 A对COX-2活性的影响
结果:IA的对小鼠的半数致死量即LD50值为2198.87mg/kg,其95%可信区间为1690.68mg/kg～2544.46mg/kg;ACO-IA对小鼠的LD50值为2009.43mg/kg,其95%可信区间为1113.49mg/kg～2606.47mg/kg。
NSAIDs的胃肠道的副作用与其对COX-1的抑制有关。本实验研究显示,IA和ACO-IA的100mg/kg、50mg/kg两个剂量组的胃粘膜损伤程度与同等剂量的阿司匹林(100mg/kg)相比,均小于阿司匹林,且差异显著(p<0.05,p<0.01)。
IA和ACO-IA灌胃给药对冰醋酸所引起的小鼠炎性疼痛有显著抑制作用,两个化合物高剂量组400mg/kg的疼痛抑制率分别为69.41%和68.04%与CMC-Na对照组相比有极显著性差异(p<0.01)。
对二甲苯所致的小鼠耳肿胀程度,IA和ACO-IA 4个剂量组均能明显抑制作用,且中剂量组(100mg/kg)抑制作用与阿司匹林相似。但从小鼠热板实验结果看出两个化合物基本上无抑制热板刺激所致的小鼠疼痛反应作用。
毛细管法和剪尾法测定小鼠凝血-出血时间实验显示,IA和ACO-IA均表现出抗凝现象,对小鼠凝血和出血时间起到延长作用。
人全血分析实验结果显示IA和ACO-IA有效抑制全血中PGI2的升高,且成浓度依赖性。而对COX-1的表达或活性抑制实验里,只有高浓度ACO-IA组与空白对照组相比,差异有显著意义(P<0.05),其对COX-1的活性或表达的抑制作用不是很强。
结论:按毒性分级标准两个化合物属于低毒性的药物,且均具有抗炎镇痛作用,能够减轻小鼠胃粘膜的损伤程度。IA和ACO-IA能够通过抑制COX-2的活性,减少PGI2等炎性介质的释放。
[Abstract] Objective: To evaluate the anti-inflammatory , analgesic effects , acute toxicity, the stimulation of gastrointestinal in mice and anti-inflammatory mechanism of Ilicifolius alkaloids A and its derivatives Acetyl Ilicifolius alkaloids A. Methods: The anti-inflammatory effect was observed by mouse auricle swelling test induced by xylene;analgesic effects was observed by mouse the pain threshold caused by hot-Plate test and mouse aceticacid-induced twisting test;The influence of the detervatives upon the mice coagulation-time and bleeding-time were tested with the capillary method and measuring by cutting the tail of mice. The modified Karber method was used to determine LD50 of Ilicifolius alkaloids A and its derivatives Acetyl Ilicifolius alkaloids A;to observe the stimulation of gastrointestinal in mice by continuous intragastric administration.
After stimulating the lood sample of healthy volunteer with calcium ionophore A23187, concentration of thromboxane B2(TXB2) in the health volunteer,s blood was detected by enzyme-linked immunosorbent assay (ELISA) to observe the effects of IA and ACO-IA at low-and high-dose on the activity of COX-1, with aspirin as control drug.The concentration of prostaglandin I2 (PGI2) in the healthy volunteer,s blood sample, in which aspirin was added to destroy activity of COX-1 beforehand with lipopolysaccharide, was detected by ELISA mentod to observe effects of IA and ACO-IA at low-and high-dose on the activity of COX-2 with celecoxib as control drug. Results: The LD50 of IA in mice was 2198.87mg/kg , 95% confidence interval (CI) was 1690.68mg/kg～2544.46mg/kg and LD50 of ACO-IA in mice was 2009.43mg/kg, 95% confidence interval (CI) was 1113.49mg/kg～2606.47mg/kg.
NSAIDs' side effect on gastrointestinal was related to the inhibition of COX-1.The study of test about IA and ACO-IA showed that 2 doses (100mg/kg,50mg/kg) of gastric mucosal injury degree were less than the equal dose of aspirin(100mg/kg).Moreover,the differences were significant(p<0.05,p<0.01).
IA and ACO-IA can significantly inhibit inflammatory pain in mice that caused by the acetic acid, and the inhibition of IA and ACO-IA were 69.41% and 68.04%, which is significant difference bettween control group and treatment group (p<0.01).
The four-dose of IA and ACO-IA evidently suppressing the mouse ear edema induced by dimethylbenzene,and the effect of middle-dose was similar to that of aspirin,but none of two derivative exhibited significant analgesic activities in hot-plate test.
It was showed that IA and ACO-IA can prolong blood coagulation time in mice through capillary and tail-cutting methods. The human whole belood analysis test show that IA and ACO-IA can reduce elevated levels of PGI2, which demonstrated selective inhibition of COX-2 activity.
Conclusion: By the grading standard of toxicity, the two compounds belong to the low toxicity of drugs. They have analgesic and anti-inflammatory effect, and are able to reduce mouse gastric mucosal damage. IA and ACO-IA can reduce the releasing of inflammatory mediators ,such as PGI2,by inhibiting the activities of COX-2.
方法:采用改良寇氏法计算小鼠LD50并观察其毒性作用,采用二甲苯致小鼠耳肿胀法、小鼠热板法、腹腔注射醋酸诱导的小鼠扭体法观察其抗炎镇痛作用,采用毛细管法和剪尾法观察两个化合物对小鼠出血-凝血时间的影响,并观察连续灌胃给药对小鼠胃肠的影响。
在研究抗炎作用机制的试验中,用体外人全血分析方法测定老鼠簕生物碱A及其衍生物乙酰老鼠簕 A对COX-1和COX-2活性的影响。抽取健康志愿者全血标本加入钙离子载体A23187予以刺激,以阿司匹林为对照,通过酶联免疫吸附测定(enzyme-linked immunosorbent assay,ELISA)法检测血栓素B2(thromboxane,TXB2)含量考察不同浓度的老鼠簕生物碱A及其衍生物乙酰老鼠簕 A对COX-1活性的影响;抽取志愿者全血经阿司匹林灭活COX-1后,予脂多糖(lipopolysaccharide,LPS)刺激后,以塞来昔布为对照,通过ELISA检测前列环素I2(postaglandinI2,PGI2)含量考察不同浓度的老鼠簕生物碱A及其衍生物乙酰老鼠簕 A对COX-2活性的影响
结果:IA的对小鼠的半数致死量即LD50值为2198.87mg/kg,其95%可信区间为1690.68mg/kg～2544.46mg/kg;ACO-IA对小鼠的LD50值为2009.43mg/kg,其95%可信区间为1113.49mg/kg～2606.47mg/kg。
NSAIDs的胃肠道的副作用与其对COX-1的抑制有关。本实验研究显示,IA和ACO-IA的100mg/kg、50mg/kg两个剂量组的胃粘膜损伤程度与同等剂量的阿司匹林(100mg/kg)相比,均小于阿司匹林,且差异显著(p<0.05,p<0.01)。
IA和ACO-IA灌胃给药对冰醋酸所引起的小鼠炎性疼痛有显著抑制作用,两个化合物高剂量组400mg/kg的疼痛抑制率分别为69.41%和68.04%与CMC-Na对照组相比有极显著性差异(p<0.01)。
对二甲苯所致的小鼠耳肿胀程度,IA和ACO-IA 4个剂量组均能明显抑制作用,且中剂量组(100mg/kg)抑制作用与阿司匹林相似。但从小鼠热板实验结果看出两个化合物基本上无抑制热板刺激所致的小鼠疼痛反应作用。
毛细管法和剪尾法测定小鼠凝血-出血时间实验显示,IA和ACO-IA均表现出抗凝现象,对小鼠凝血和出血时间起到延长作用。
人全血分析实验结果显示IA和ACO-IA有效抑制全血中PGI2的升高,且成浓度依赖性。而对COX-1的表达或活性抑制实验里,只有高浓度ACO-IA组与空白对照组相比,差异有显著意义(P<0.05),其对COX-1的活性或表达的抑制作用不是很强。
结论:按毒性分级标准两个化合物属于低毒性的药物,且均具有抗炎镇痛作用,能够减轻小鼠胃粘膜的损伤程度。IA和ACO-IA能够通过抑制COX-2的活性,减少PGI2等炎性介质的释放。
[Abstract] Objective: To evaluate the anti-inflammatory , analgesic effects , acute toxicity, the stimulation of gastrointestinal in mice and anti-inflammatory mechanism of Ilicifolius alkaloids A and its derivatives Acetyl Ilicifolius alkaloids A. Methods: The anti-inflammatory effect was observed by mouse auricle swelling test induced by xylene;analgesic effects was observed by mouse the pain threshold caused by hot-Plate test and mouse aceticacid-induced twisting test;The influence of the detervatives upon the mice coagulation-time and bleeding-time were tested with the capillary method and measuring by cutting the tail of mice. The modified Karber method was used to determine LD50 of Ilicifolius alkaloids A and its derivatives Acetyl Ilicifolius alkaloids A;to observe the stimulation of gastrointestinal in mice by continuous intragastric administration.
After stimulating the lood sample of healthy volunteer with calcium ionophore A23187, concentration of thromboxane B2(TXB2) in the health volunteer,s blood was detected by enzyme-linked immunosorbent assay (ELISA) to observe the effects of IA and ACO-IA at low-and high-dose on the activity of COX-1, with aspirin as control drug.The concentration of prostaglandin I2 (PGI2) in the healthy volunteer,s blood sample, in which aspirin was added to destroy activity of COX-1 beforehand with lipopolysaccharide, was detected by ELISA mentod to observe effects of IA and ACO-IA at low-and high-dose on the activity of COX-2 with celecoxib as control drug. Results: The LD50 of IA in mice was 2198.87mg/kg , 95% confidence interval (CI) was 1690.68mg/kg～2544.46mg/kg and LD50 of ACO-IA in mice was 2009.43mg/kg, 95% confidence interval (CI) was 1113.49mg/kg～2606.47mg/kg.
NSAIDs' side effect on gastrointestinal was related to the inhibition of COX-1.The study of test about IA and ACO-IA showed that 2 doses (100mg/kg,50mg/kg) of gastric mucosal injury degree were less than the equal dose of aspirin(100mg/kg).Moreover,the differences were significant(p<0.05,p<0.01).
IA and ACO-IA can significantly inhibit inflammatory pain in mice that caused by the acetic acid, and the inhibition of IA and ACO-IA were 69.41% and 68.04%, which is significant difference bettween control group and treatment group (p<0.01).
The four-dose of IA and ACO-IA evidently suppressing the mouse ear edema induced by dimethylbenzene,and the effect of middle-dose was similar to that of aspirin,but none of two derivative exhibited significant analgesic activities in hot-plate test.
It was showed that IA and ACO-IA can prolong blood coagulation time in mice through capillary and tail-cutting methods. The human whole belood analysis test show that IA and ACO-IA can reduce elevated levels of PGI2, which demonstrated selective inhibition of COX-2 activity.
Conclusion: By the grading standard of toxicity, the two compounds belong to the low toxicity of drugs. They have analgesic and anti-inflammatory effect, and are able to reduce mouse gastric mucosal damage. IA and ACO-IA can reduce the releasing of inflammatory mediators ,such as PGI2,by inhibiting the activities of COX-2.
引文
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