脑缺血再灌注损伤后COX-2、5-LO通路的激活及棓丙酯的保护作用研究
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摘要
目的研究局灶性脑缺血再灌注损伤(CIRI)后花生四烯酸(AA)代谢改变及其相关因素的影响,观察环氧酶-2/5-脂氧酶(COX-2/5-LO)双向抑制剂棓丙酯(PrG)的神经保护作用,并探讨其保护机制。
方法线栓法制作大鼠大脑中动脉闭塞/再灌注(MCAO/R)模型,缺血2h,再灌注24h。动物分为假手术组、溶媒组、PrG5、7.5mg?kg-1组(PrG5、PrG7.5),于再灌注0、2h ip给药。神经功能评分法观察神经功能缺损症状;TTC染色观察脑梗死体积;HE染色观察脑组织形态学变化;AutoCAD图像分析软件计算脑水肿程度;伊文氏蓝示踪剂检测血脑屏障(BBB)通透性;免疫组化法检测脑组织COX-2、5-LO、核因子-κB(NF-κB)、肿瘤坏死因子-α(TNF-α)和诱导型一氧化氮合酶(iNOS)蛋白表达;放免法检测血浆TXA2、PGI2含量;酶联免疫吸附法(ELISA)检测血清白三烯B4(LTB4)浓度;生化法检测脑组织髓过氧化物酶(MPO)、还原型谷胱甘肽(GSH)及总抗氧化能力(T-AOC)。
结果(1)MCAO 2h /R 24h后,脑组织缺血半暗带(IP)、海马、杏仁核区COX-2、5-LO、NF-κB蛋白表达均升高,尤以IP明显;(2)CIRI后,大鼠神经组织损伤严重,BBB破坏,脑水肿明显,神经功能缺失严重;外周血TXA2浓度上升,PGI2含量下降,TXA2/PGI2比值失调,LTB4的浓度上升;脑组织GSH和T-AOC活性下降,MPO活性升高,TNF-α与iNOS蛋白表达增加。(3)PrG5、7.5mg?kg-1均能有效缩小脑梗死灶,抑制脑水肿,改善脑组织病理改变,减轻BBB破坏,降低血浆TXA2/PGI2比值和血清LTB4浓度;下调神经细胞TNF-α、iNOS蛋白表达;增加脑组织GSH和T-AOC活性、缓解MPO升高。
结论CIRI后,AA代谢途径的COX-2/5-LO通路酶激活,活性产物增加,脑组织出现严重病理改变、炎症反应、脂质过氧化等。PrG5、7.5mg?kg-1对此有明显保护作用,且大剂量效果更佳,其机制与抑制COX-2和5-LO通路活化,减轻血脑屏障破坏,抗炎,抗脂质过氧化,抑制脑组织TNF-α与iNOS表达均有关。
OBJECTIVE: To investigate the changes of AA metabolism and the effects of related factors, the neuronal protective effects and mechanism of cyclooxygenase-2 and 5-lipoxygenase inhibitor propyl gallate(PrG)on focal cerebral ischemia reperfusion injury in rats.
METHODS: The right middle cerebral artery of the rat was occluded by inserting a thread through internal carotid artery for 2h, and then reperfused for 24h. The rats were divided into sham, vehicle, PrG5 mg?kg-1 and 7.5 mg?kg-1group (PrG5 and PrG7.5). PrG was interaperitoneally administered 0 and 2h after reperfusion. The neurofunctional score was given. The infarction size of brain tissue was measured by TTC staining technique. Morphological changes of brain were observed by HE staining technique. The degree of brain edema was measured by AutoCAD image analysis software. EB was used as labelled compound to detect the permeability of blood-brain barrier(BBB). The expressions of COX-2, 5-LO, NF-κB, iNOS and TNF-αwere measured by immunohistochemcial technique. The activities of reduced glutathione hormone(GSH), myeloperoxidase(MPO)and total-antioxidation capability(T-AOC) were measured by biochemical technique. The contents of thromboxane A2 (TXA2) and prostaglandin I2 (PGI2) in plasma were measured by radioimmune technique.The concentration of leukotriene B4 (LTB4) in serum was measured by enzyme linked immunosorbent assay (ELISA) technique.
RESULTS: (1) The expressions of COX-2, 5-LO and NF-κB proteins of vehicle group were significantly increased compared with sham group after 2h ischemia and 24h reperfusion. The changes happened mainly in IP area, amygdala and hippocampus, especially in IP area. (2) Several changes were observed after CIRI, such as the nerve tissue damage and the brain edema, the concentrations of TXA2 and LTB4 were significantly increased and PGI2 was significantly reduced in peripheral blood, and then the ratio of TXA2 to PGI2 was disturb. The activity of GSH, T-AOC and MPO was dramatically reduced in the brain tissue. The expressions of TNF-αand iNOS proteins were remarkably induced in the brain tissue. (3) Compared with vehicle group, PrG5 and PrG7.5 groups can improve the morphological changes of the brain,minimize the infarct size,inhibit the degree of the brain edema. Meanwhile, it can relieve the destroy of the BBB, reduce the content of TXA2 and induce the activity of PGI2 in plasma and so regulate the ratio of TXA2 to PGI2 disturbance, decrease LTB4 concentration in serum, reduce the expressions of TNF-αand iNOS proteins in the brain tissue. Also it can induce the activity T-AOC, GSH and inhibit MPO activation in the brain tissue.
CONCLUSIONS: The enzymes of the COX-2 and 5-LO pathways of AA mechanism were activated, then the active products were increased in the brain tissue of the rats after CIRI. Since the brain tissue will suffer from neuronal damage, inflammatory reaction and lipid peroxidation. PrG5, 7.5mg?kg-1 can protect the neuronal cells injury after CIRI and it would be better by using a large dose. The mechanisms may be as followings: PrG can inhibit the activation of COX-2 and 5-LO pathways, relieve the damage of BBB,inhibit the inflammatory reaction and lipid peroxidation, reduce the expressions of iNOS and TNF-αproteins in the brain tissue.
方法线栓法制作大鼠大脑中动脉闭塞/再灌注(MCAO/R)模型,缺血2h,再灌注24h。动物分为假手术组、溶媒组、PrG5、7.5mg?kg-1组(PrG5、PrG7.5),于再灌注0、2h ip给药。神经功能评分法观察神经功能缺损症状;TTC染色观察脑梗死体积;HE染色观察脑组织形态学变化;AutoCAD图像分析软件计算脑水肿程度;伊文氏蓝示踪剂检测血脑屏障(BBB)通透性;免疫组化法检测脑组织COX-2、5-LO、核因子-κB(NF-κB)、肿瘤坏死因子-α(TNF-α)和诱导型一氧化氮合酶(iNOS)蛋白表达;放免法检测血浆TXA2、PGI2含量;酶联免疫吸附法(ELISA)检测血清白三烯B4(LTB4)浓度;生化法检测脑组织髓过氧化物酶(MPO)、还原型谷胱甘肽(GSH)及总抗氧化能力(T-AOC)。
结果(1)MCAO 2h /R 24h后,脑组织缺血半暗带(IP)、海马、杏仁核区COX-2、5-LO、NF-κB蛋白表达均升高,尤以IP明显;(2)CIRI后,大鼠神经组织损伤严重,BBB破坏,脑水肿明显,神经功能缺失严重;外周血TXA2浓度上升,PGI2含量下降,TXA2/PGI2比值失调,LTB4的浓度上升;脑组织GSH和T-AOC活性下降,MPO活性升高,TNF-α与iNOS蛋白表达增加。(3)PrG5、7.5mg?kg-1均能有效缩小脑梗死灶,抑制脑水肿,改善脑组织病理改变,减轻BBB破坏,降低血浆TXA2/PGI2比值和血清LTB4浓度;下调神经细胞TNF-α、iNOS蛋白表达;增加脑组织GSH和T-AOC活性、缓解MPO升高。
结论CIRI后,AA代谢途径的COX-2/5-LO通路酶激活,活性产物增加,脑组织出现严重病理改变、炎症反应、脂质过氧化等。PrG5、7.5mg?kg-1对此有明显保护作用,且大剂量效果更佳,其机制与抑制COX-2和5-LO通路活化,减轻血脑屏障破坏,抗炎,抗脂质过氧化,抑制脑组织TNF-α与iNOS表达均有关。
OBJECTIVE: To investigate the changes of AA metabolism and the effects of related factors, the neuronal protective effects and mechanism of cyclooxygenase-2 and 5-lipoxygenase inhibitor propyl gallate(PrG)on focal cerebral ischemia reperfusion injury in rats.
METHODS: The right middle cerebral artery of the rat was occluded by inserting a thread through internal carotid artery for 2h, and then reperfused for 24h. The rats were divided into sham, vehicle, PrG5 mg?kg-1 and 7.5 mg?kg-1group (PrG5 and PrG7.5). PrG was interaperitoneally administered 0 and 2h after reperfusion. The neurofunctional score was given. The infarction size of brain tissue was measured by TTC staining technique. Morphological changes of brain were observed by HE staining technique. The degree of brain edema was measured by AutoCAD image analysis software. EB was used as labelled compound to detect the permeability of blood-brain barrier(BBB). The expressions of COX-2, 5-LO, NF-κB, iNOS and TNF-αwere measured by immunohistochemcial technique. The activities of reduced glutathione hormone(GSH), myeloperoxidase(MPO)and total-antioxidation capability(T-AOC) were measured by biochemical technique. The contents of thromboxane A2 (TXA2) and prostaglandin I2 (PGI2) in plasma were measured by radioimmune technique.The concentration of leukotriene B4 (LTB4) in serum was measured by enzyme linked immunosorbent assay (ELISA) technique.
RESULTS: (1) The expressions of COX-2, 5-LO and NF-κB proteins of vehicle group were significantly increased compared with sham group after 2h ischemia and 24h reperfusion. The changes happened mainly in IP area, amygdala and hippocampus, especially in IP area. (2) Several changes were observed after CIRI, such as the nerve tissue damage and the brain edema, the concentrations of TXA2 and LTB4 were significantly increased and PGI2 was significantly reduced in peripheral blood, and then the ratio of TXA2 to PGI2 was disturb. The activity of GSH, T-AOC and MPO was dramatically reduced in the brain tissue. The expressions of TNF-αand iNOS proteins were remarkably induced in the brain tissue. (3) Compared with vehicle group, PrG5 and PrG7.5 groups can improve the morphological changes of the brain,minimize the infarct size,inhibit the degree of the brain edema. Meanwhile, it can relieve the destroy of the BBB, reduce the content of TXA2 and induce the activity of PGI2 in plasma and so regulate the ratio of TXA2 to PGI2 disturbance, decrease LTB4 concentration in serum, reduce the expressions of TNF-αand iNOS proteins in the brain tissue. Also it can induce the activity T-AOC, GSH and inhibit MPO activation in the brain tissue.
CONCLUSIONS: The enzymes of the COX-2 and 5-LO pathways of AA mechanism were activated, then the active products were increased in the brain tissue of the rats after CIRI. Since the brain tissue will suffer from neuronal damage, inflammatory reaction and lipid peroxidation. PrG5, 7.5mg?kg-1 can protect the neuronal cells injury after CIRI and it would be better by using a large dose. The mechanisms may be as followings: PrG can inhibit the activation of COX-2 and 5-LO pathways, relieve the damage of BBB,inhibit the inflammatory reaction and lipid peroxidation, reduce the expressions of iNOS and TNF-αproteins in the brain tissue.
引文
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