橄榄总黄酮的提取及其对大鼠脑缺血再灌注损伤的保护作用的研究
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摘要
目的以橄榄总黄酮(按芦丁折算)提取物为有效成分,筛选出最佳提取条件,用大孔树脂法对橄榄总黄酮进行纯化,确定最佳纯化条件。采用大脑中动脉栓塞(middle cerebral artery occlusion,MCAO)模型,研究TFCO对局灶性脑缺血再灌注损伤(CIRI)的保护作用,并探讨其机制。
方法(1)以橄榄总黄酮(按芦丁折算)提取物为有效成分,采用可见分光光度法,对TFCO的含量进行控制,采用乙醇作为溶剂对不同浓度、不同用量、不同提取时间3个因素按正交实验法设计优选出最佳提取工艺。用大孔树脂法对TFCO进行纯化,筛选了大孔树脂的种类,综合考察了树脂的吸附率,解析率,上样流速,上样液pH,洗脱剂浓度,洗脱体积,流速等各项指标。
(2)线栓法制备大鼠大脑中动脉闭塞2h/再灌注24h模型,于再灌注前4天灌胃给予橄榄总黄酮30、60 mg.kg~(-1)。神经病学评分观察神经功能缺失症状;TTC染色法观察脑梗死体积;AutoCAD图像分析软件计算脑水肿程度;光镜观察脑组织形态学变化;免疫组化法检测脑组织iNOS、TNF-α表达;生化法检测脑组织中MPO、GSH活性及T-AOC含量。
结果(1)超声提取的最佳工艺是:取橄榄适量,加4倍量95%乙醇,超声提取60分钟;(2)纯化的最佳工艺是:使用D101型大孔树脂,配制pH4.5吸附液以2BV/h上柱,至泄漏。用3BV纯水以2BV/h洗柱后,再用3BV 60%乙醇洗脱,流速为1BV/h,将洗脱液减压浓缩,干燥得橄榄总黄酮,纯度为90.1%。
(2)脑缺血2h/再灌注24h后,神经功能缺失,脑组织出现白色梗死灶,脑水肿明显,形态学呈病理改变,脑组织iNOS、TNF-α蛋白表达增强,MPO活性增高,GSH活性降低,T-AOC含量降低;
(3)TFCO 30、60 mg.kg~(-1)均能改善神经功能缺失症状,有效减小脑梗死灶,减轻脑水肿,抑制脑组织iNOS蛋白表达,增高脑组织GSH活性,提高T-AOC含量,还可缓解MPO升高,并能减轻脑组织病理变化,抑制脑组织TNF-α蛋白表达。
结论(1)大孔吸附树脂纯化橄榄总黄酮,使其纯度达到90%以上;(2)再灌注前4天分别给予TFCO30、60mg.kg~(-1),减轻脑损伤;(3)TFCO对CIRI的保护作用,可能与减少iNOS和TNF-α蛋白表达、抗炎、抗脂质过氧化有关。
OBJECTIVE To determine of total flavone ( rutin as standard ) of the extraction is controlled by visible spectrophotometry and to establish the optimal condition for ultrasonic extraction of total flavone from Chinese olive and investigate appropriate macroporous resins ;The optimal technological parameters of the purification process of TFCO are found ; To study the protective effects and possible mechanisms of TFCO on focal cerebral ischemia-reperfusion injury (CIRI) in rats by reversible middle cerebral artery occlusion (MCAO) model.
METHODS The ultrasonic extraction and orthogonal test were used to choose optimum extractive method which was as follows: optimum extractive solvent’s concentration; solvent volume; extractive time .The purification process of total flavone with macroreticular resin was studied and the type of macroporous resin, review the absorption ratio; desorption ration; liquor’s pH; ethanol’s concentration, volume, velocity were established.
MCAO model was produced by intraluminal suture technique, and reperfusion 24h was begun after 2h of occlusion. TFCO was intragastrically administrated at 1d,2d,3d and 4d of the reperfusion. After reperfusion 24h, the extent of neurological deficits was evaluated by Longer’s method; the infarct size of the brain and the degree of cerebral edema were measured by Auto CAD image analysis soft ware; the morphological changes of the brain tissue were observed; the expressions of iNOS and TNF-αproteins were measured;T-AOC、MPO and GSH level in the brain tissue were detected.
RESULTS (1) The optimum extraction procedures was as follows:4times of 95% ethanol ;extractive time :40 minutes .the best technics of purification is as follows: the type of macroporous resin was D101,the sample fluid(pH4.5),the velocity is 2BV/h,the water is 3BV with velocity of 2BV/h,60% ethanol is 3BV with velocity of 1BV/h.
(2)After 2h of occlusion and 24h of reperfusion, the neurological deficits were evidently observed;the brain infarct size and edema degree were increased; the changes of the brain histology were appeared and the expressions of iNOS and TNF-αproteins were increased;the activity of MPO were increased, the activity of GSH was decreased, the contents of T-AOC were increased.
(3)Both 30 and 60 mg.kg~(-1) doses of TFCO can dramatically reduce neurological score, the infarct size and degree of cerebral edema comparing with ischemia reperfusion group. Both 30 and 60 mg.kg~(-1) doses of TFCO can increase the activity of GSH,decrease the activity of MPO and the contents of T-AOC,inhibit the expression of iNOS protein and TNF-αprotein.
CONCLUSION (1) The total flavones’s purity could reach 90.1%.(2) TFCO 30、60 mg.kg~(-1) can play a protective role in the brain injury. TFCO could protect the focal CIRI by depressing permeability of the blood brain barrier, inhibiting the expressions of iNOS and TNF-αproteins, depressing inflammation reaction, decreasing lipid peroxidation.
方法(1)以橄榄总黄酮(按芦丁折算)提取物为有效成分,采用可见分光光度法,对TFCO的含量进行控制,采用乙醇作为溶剂对不同浓度、不同用量、不同提取时间3个因素按正交实验法设计优选出最佳提取工艺。用大孔树脂法对TFCO进行纯化,筛选了大孔树脂的种类,综合考察了树脂的吸附率,解析率,上样流速,上样液pH,洗脱剂浓度,洗脱体积,流速等各项指标。
(2)线栓法制备大鼠大脑中动脉闭塞2h/再灌注24h模型,于再灌注前4天灌胃给予橄榄总黄酮30、60 mg.kg~(-1)。神经病学评分观察神经功能缺失症状;TTC染色法观察脑梗死体积;AutoCAD图像分析软件计算脑水肿程度;光镜观察脑组织形态学变化;免疫组化法检测脑组织iNOS、TNF-α表达;生化法检测脑组织中MPO、GSH活性及T-AOC含量。
结果(1)超声提取的最佳工艺是:取橄榄适量,加4倍量95%乙醇,超声提取60分钟;(2)纯化的最佳工艺是:使用D101型大孔树脂,配制pH4.5吸附液以2BV/h上柱,至泄漏。用3BV纯水以2BV/h洗柱后,再用3BV 60%乙醇洗脱,流速为1BV/h,将洗脱液减压浓缩,干燥得橄榄总黄酮,纯度为90.1%。
(2)脑缺血2h/再灌注24h后,神经功能缺失,脑组织出现白色梗死灶,脑水肿明显,形态学呈病理改变,脑组织iNOS、TNF-α蛋白表达增强,MPO活性增高,GSH活性降低,T-AOC含量降低;
(3)TFCO 30、60 mg.kg~(-1)均能改善神经功能缺失症状,有效减小脑梗死灶,减轻脑水肿,抑制脑组织iNOS蛋白表达,增高脑组织GSH活性,提高T-AOC含量,还可缓解MPO升高,并能减轻脑组织病理变化,抑制脑组织TNF-α蛋白表达。
结论(1)大孔吸附树脂纯化橄榄总黄酮,使其纯度达到90%以上;(2)再灌注前4天分别给予TFCO30、60mg.kg~(-1),减轻脑损伤;(3)TFCO对CIRI的保护作用,可能与减少iNOS和TNF-α蛋白表达、抗炎、抗脂质过氧化有关。
OBJECTIVE To determine of total flavone ( rutin as standard ) of the extraction is controlled by visible spectrophotometry and to establish the optimal condition for ultrasonic extraction of total flavone from Chinese olive and investigate appropriate macroporous resins ;The optimal technological parameters of the purification process of TFCO are found ; To study the protective effects and possible mechanisms of TFCO on focal cerebral ischemia-reperfusion injury (CIRI) in rats by reversible middle cerebral artery occlusion (MCAO) model.
METHODS The ultrasonic extraction and orthogonal test were used to choose optimum extractive method which was as follows: optimum extractive solvent’s concentration; solvent volume; extractive time .The purification process of total flavone with macroreticular resin was studied and the type of macroporous resin, review the absorption ratio; desorption ration; liquor’s pH; ethanol’s concentration, volume, velocity were established.
MCAO model was produced by intraluminal suture technique, and reperfusion 24h was begun after 2h of occlusion. TFCO was intragastrically administrated at 1d,2d,3d and 4d of the reperfusion. After reperfusion 24h, the extent of neurological deficits was evaluated by Longer’s method; the infarct size of the brain and the degree of cerebral edema were measured by Auto CAD image analysis soft ware; the morphological changes of the brain tissue were observed; the expressions of iNOS and TNF-αproteins were measured;T-AOC、MPO and GSH level in the brain tissue were detected.
RESULTS (1) The optimum extraction procedures was as follows:4times of 95% ethanol ;extractive time :40 minutes .the best technics of purification is as follows: the type of macroporous resin was D101,the sample fluid(pH4.5),the velocity is 2BV/h,the water is 3BV with velocity of 2BV/h,60% ethanol is 3BV with velocity of 1BV/h.
(2)After 2h of occlusion and 24h of reperfusion, the neurological deficits were evidently observed;the brain infarct size and edema degree were increased; the changes of the brain histology were appeared and the expressions of iNOS and TNF-αproteins were increased;the activity of MPO were increased, the activity of GSH was decreased, the contents of T-AOC were increased.
(3)Both 30 and 60 mg.kg~(-1) doses of TFCO can dramatically reduce neurological score, the infarct size and degree of cerebral edema comparing with ischemia reperfusion group. Both 30 and 60 mg.kg~(-1) doses of TFCO can increase the activity of GSH,decrease the activity of MPO and the contents of T-AOC,inhibit the expression of iNOS protein and TNF-αprotein.
CONCLUSION (1) The total flavones’s purity could reach 90.1%.(2) TFCO 30、60 mg.kg~(-1) can play a protective role in the brain injury. TFCO could protect the focal CIRI by depressing permeability of the blood brain barrier, inhibiting the expressions of iNOS and TNF-αproteins, depressing inflammation reaction, decreasing lipid peroxidation.
引文
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