通脉醒脑滴丸抗脑缺血的药效及机理研究
摘要
目的:通脉醒脑滴丸是防治脑缺血卒中的中药复方制剂,具有活血化瘀,醒脑开窍的作用。本实验研究目的在于考察通脉醒脑滴丸对脑缺血卒中的防治作用,并探讨其可能的作用机理,为其在临床上的应用提供药理学依据。
方法:采用大鼠线栓阻断大脑中动脉法、二血管夹闭加低血压法复制脑缺血再灌注模型,以及小鼠结扎双侧颈总动脉和迷走神经造成脑缺血模型、断头造成脑缺血模型,观察通脉醒脑滴丸对实验性脑缺血模型的保护作用;观察药物对小鼠凝血时间、体内血栓形成和对小鼠软脑膜微循环的影响,考察药物抗血栓和对微循环的作用;选用小鼠常压缺氧、亚硝酸钠致中毒缺氧模型,验证药物抗缺氧损伤的作用;测定模型大鼠脑组织匀浆SOD、MDA、GSH-Px和NO等生化指标,考察药物对自由基过氧化损伤的作用。采用荧光定量PCR方法测定脑组织PI3K、Akt、PTEN的表达,通过免疫组化方法测定脑组织HIF-1α和VEGF的表达,考察药物对PI3K/Akt信号通路的作用;通过免疫组化方法,测定脑组织bcl-2、Bax、CytC和Caspase-3的表达,考察药物对Caspase-3通路的作用。
结果:通脉醒脑滴丸对脑缺血损伤具有明显的防治作用,能够减少脑缺血大鼠脑梗死比率,减轻脑水肿,改善神经系统症状,改善脑组织病理表现;能延长缺血缺氧后小鼠的存活时间;能延长凝血时间,减少体内血栓形成,改善小鼠软脑膜微循环;能提高脑缺血再灌注大鼠SOD和GSH-Px活性,减少了MDA、NO的含量;能上调PI3K、Akt、HIF-1α以及VEGF的表达,下调PTEN的表达,在脑缺血后细胞存活通路的激活和上调中发挥作用;还能下调神经细胞的促凋亡基因Bax、Caspase-3、CytC表达,对脑缺血后细胞凋亡通路有负调作用。
结论:上述研究初步证实通脉醒脑滴丸对脑缺血损伤具有保护作用,其机制可能与参与PI3K/Akt细胞存活通路的激活和上调,以及负调Caspase-3介导的细胞凋亡通路有关。
Objective: Tongmai Xingnao Dripping Pill is a compound preparation of TCM used to treat ischemia cerebral vascular disease (ICVD). It has efficacies of promoting blood circulation to dissipate blood stasis, restoring consciousness and inducing resuscitation. By researching the effects and the mechanisms of the drug, the test is meant to offer pharmacological evidences to the drug for its clinical use.
Methods: We chose the model of middle cerebral artery occlusion(MCAO) by suture embolism in rats, the model of 2-Vasa-occlusion plus hypotension in rats, the model of double CCA and vagus nerve ligated in mice and the model of decollation in mice in order to observe the effects of the drug in opposing ischemia and hypoxia in brain. We determined the clotting time (CT) and observed the internal thrombosis and the microcirculation of piamater to verify the effects of anti-thrombus and microcirculation amelioration of the drug. We chose the two models of hypoxia under ordinary pressure or caused by Sodium Nitrite intoxication to verify the effect of anti-hypoxia of the drug. Through the mensuration of SOD, MDA, GSH-Px and NO in rats' brain we researched the effect of resisting the damages caused by free-radical-peroxidation of the drug. At last, We mensurated the expressions of PI3K, Akt and PTEN in brain by RT-PCR and the expressions of HIF-1αand VEGF in brain by immunohistochemistry to testify if the tested drug can activate the pathway of PI3K/Akt while mensurating the expressions of bcl-2, Bax, CytC and Caspase-3 in brain by immunohistochemistry to testify if the tested drug can activate the pathway of Caspase-3.
Results: Tongmai Xingnao Dripping Pill has obvious effects in preventing and curing ICVD. It can decrease the ratio of cerebral infarction and cerebral edema, meliorate pathologic status, polish up symptoms of nervous system. It can prolong the survival time after ischemia and hypoxia damages. It can also prolong the CT, decrease internal thrombosis and meliorate the microcirculation of piamater in mice. It can enhance the activities of SOD and GSH-Px and decrease the content of MDA and NO in rats. It can up-regulate the expressions of PI3K, Akt, HIF-1αand VEGF and down-regulate the expression of PTEN to activate the pathway of PI3K/Akt while down-regulating the expressions of apoptosis encouraging genes such as Bax, CytC and Caspase-3 in order to lighten the damages of ischemia and hypoxia.
Conclusion: All the results showed above can elementarily attest to that Tongmai Xingnao Dripping Pill can lighten the damages of ICVD and it is probably related to the up-regulation of PI3K/Akt pathway and the down-regulation of Caspase-3 pathway.
方法:采用大鼠线栓阻断大脑中动脉法、二血管夹闭加低血压法复制脑缺血再灌注模型,以及小鼠结扎双侧颈总动脉和迷走神经造成脑缺血模型、断头造成脑缺血模型,观察通脉醒脑滴丸对实验性脑缺血模型的保护作用;观察药物对小鼠凝血时间、体内血栓形成和对小鼠软脑膜微循环的影响,考察药物抗血栓和对微循环的作用;选用小鼠常压缺氧、亚硝酸钠致中毒缺氧模型,验证药物抗缺氧损伤的作用;测定模型大鼠脑组织匀浆SOD、MDA、GSH-Px和NO等生化指标,考察药物对自由基过氧化损伤的作用。采用荧光定量PCR方法测定脑组织PI3K、Akt、PTEN的表达,通过免疫组化方法测定脑组织HIF-1α和VEGF的表达,考察药物对PI3K/Akt信号通路的作用;通过免疫组化方法,测定脑组织bcl-2、Bax、CytC和Caspase-3的表达,考察药物对Caspase-3通路的作用。
结果:通脉醒脑滴丸对脑缺血损伤具有明显的防治作用,能够减少脑缺血大鼠脑梗死比率,减轻脑水肿,改善神经系统症状,改善脑组织病理表现;能延长缺血缺氧后小鼠的存活时间;能延长凝血时间,减少体内血栓形成,改善小鼠软脑膜微循环;能提高脑缺血再灌注大鼠SOD和GSH-Px活性,减少了MDA、NO的含量;能上调PI3K、Akt、HIF-1α以及VEGF的表达,下调PTEN的表达,在脑缺血后细胞存活通路的激活和上调中发挥作用;还能下调神经细胞的促凋亡基因Bax、Caspase-3、CytC表达,对脑缺血后细胞凋亡通路有负调作用。
结论:上述研究初步证实通脉醒脑滴丸对脑缺血损伤具有保护作用,其机制可能与参与PI3K/Akt细胞存活通路的激活和上调,以及负调Caspase-3介导的细胞凋亡通路有关。
Objective: Tongmai Xingnao Dripping Pill is a compound preparation of TCM used to treat ischemia cerebral vascular disease (ICVD). It has efficacies of promoting blood circulation to dissipate blood stasis, restoring consciousness and inducing resuscitation. By researching the effects and the mechanisms of the drug, the test is meant to offer pharmacological evidences to the drug for its clinical use.
Methods: We chose the model of middle cerebral artery occlusion(MCAO) by suture embolism in rats, the model of 2-Vasa-occlusion plus hypotension in rats, the model of double CCA and vagus nerve ligated in mice and the model of decollation in mice in order to observe the effects of the drug in opposing ischemia and hypoxia in brain. We determined the clotting time (CT) and observed the internal thrombosis and the microcirculation of piamater to verify the effects of anti-thrombus and microcirculation amelioration of the drug. We chose the two models of hypoxia under ordinary pressure or caused by Sodium Nitrite intoxication to verify the effect of anti-hypoxia of the drug. Through the mensuration of SOD, MDA, GSH-Px and NO in rats' brain we researched the effect of resisting the damages caused by free-radical-peroxidation of the drug. At last, We mensurated the expressions of PI3K, Akt and PTEN in brain by RT-PCR and the expressions of HIF-1αand VEGF in brain by immunohistochemistry to testify if the tested drug can activate the pathway of PI3K/Akt while mensurating the expressions of bcl-2, Bax, CytC and Caspase-3 in brain by immunohistochemistry to testify if the tested drug can activate the pathway of Caspase-3.
Results: Tongmai Xingnao Dripping Pill has obvious effects in preventing and curing ICVD. It can decrease the ratio of cerebral infarction and cerebral edema, meliorate pathologic status, polish up symptoms of nervous system. It can prolong the survival time after ischemia and hypoxia damages. It can also prolong the CT, decrease internal thrombosis and meliorate the microcirculation of piamater in mice. It can enhance the activities of SOD and GSH-Px and decrease the content of MDA and NO in rats. It can up-regulate the expressions of PI3K, Akt, HIF-1αand VEGF and down-regulate the expression of PTEN to activate the pathway of PI3K/Akt while down-regulating the expressions of apoptosis encouraging genes such as Bax, CytC and Caspase-3 in order to lighten the damages of ischemia and hypoxia.
Conclusion: All the results showed above can elementarily attest to that Tongmai Xingnao Dripping Pill can lighten the damages of ICVD and it is probably related to the up-regulation of PI3K/Akt pathway and the down-regulation of Caspase-3 pathway.
引文
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