丹参酮ⅡA对小鼠永久性局灶脑缺血的保护作用
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摘要
脑缺血是危害人类健康的严重疾病,已经成为继心脏疾病之后世界第二大致死因素。虽然目前关于脑缺血的研究已经越来越受到重视,但是脑缺血的治疗药物仍然非常缺乏。丹参是常用的活血化瘀中药,被广泛地应用于心脑血管疾病的治疗。丹参酮ⅡA(TSA)是丹参主要的脂溶性活性成分之一,近年来已有报道证明TSA对一过性脑缺血有很好的治疗效果,但其对于永久性脑缺血的作用及保护机制仍然未知。本实验目的在于研究TSA是否对小鼠永久性局灶性脑缺血损伤具有保护作用,并探讨其可能的作用机制。
本实验共分为两个部分,第一部分通过整体模型评价TSA对小鼠永久性局灶性脑缺血的治疗效果。第二部分从体内和体外两方面入手,探讨TSA可能的作用机制。方法:动物主要分5个组:假手术组、模型组、TSA高剂量组(20mg/kg),TSA中剂量组(10mg/kg),TSA低剂量组(5mg/kg)。另外第一部分药效实验还添加了尼莫地平阳性对照组。实验采用永久性中动脉栓塞法造模(pMCAO),造模后24小时取材,通过行为学指标以及梗死面积评价脑损伤程度;生化检测用于测定血清中SOD活性、MDA含量以及脑组织匀浆中iNOS活性、NO含量;免疫组化用于检测脑冰冻切片中iNOS的表达情况。体外实验分5组:正常对照组、模型组、TSA高剂量组(8μM)、TSA中剂量组(4μM)、TSA低剂量组(2μM),采用过氧化氢损伤模型对星形胶质细胞进行研究。通过细胞存活率、细胞上清中的NO含量以及NF-κB的转录来进一步探讨TSA可能的作用机制。结果:TSA高、中剂量组均可显著减少梗死面积(P＜0.01);在行为学方面,20mg/kgTSA给药组自缺血后8h起可显著缓解行为学症状(P＜0.05),其余剂量组行为学指标相对于模型组均有不同程度的改善。TSA高、中剂量组小鼠血清中的MDA含量显著下降,SOD含量显著提高,脑组织匀浆中NO含量明显下降(P＜0.01,0.05);三个药物剂量组均能显著降低脑组织匀浆中iNOS活性(P＜0.01),免疫组化结果同时显示,缺血半球iNOS表达被抑制。体外实验中,三个TSA干预组(2,4and 8μM)均能显著减轻H_2O_2造成的星形胶质细胞损伤,并减少由此诱导产生的NO(P＜0.01);免疫印记实验证明NF-κB的转录也被抑制。结论:TSA对小鼠永久性脑缺血损伤有一定的保护作用。这一保护作用可能由于TSA可以减少受损组织的ROS含量,减轻氧化应激损伤;进而抑制ROS下游炎症因子iNOS的表达来减少NO的产生,从而缓解脑缺血后的炎症损伤。
Stroke is one of the most frequent causes of disability and death worldwide, but the treatment of it was short of. Danshen is a commonly used traditional Chinese medicine for the treatment of cardiovascular and Cerebrovascular diseases. Tanshinone IIA (TSA), as a key compound of Danshen, has been proved to protect the brain from transient ischemia injury. But there was no report of its effects on brain injury after permanent focal cerebral ischemia and little is known about its mechanism. The objective of this study was to evaluate whether Tanshinone IIA (TSA) was neuroprotective in permanent focal cerebral ischemia and to determine the possible mechanisms of its neuroprotection.
This experiment contains two parts. The first part was to measure the neuroprotection of TSA and the second part was to find the possible mechanisms of its function. Method: Animals were randomly divided into 5 groups: sham, vehicle, TSA 20mg/kg, TSA 10mg/kg and TSA 5mg/kg. In addition, there was a positive control group in the first part of the experiment. Mice were subjected to permanent middle cerebral artery occlusion for 24h. The neuroprotection of TSA was investigated with respect to neurological deficit scores and infarct volume. Biochemical analysis for malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in serum, and nitric oxide (NO) content and the inducible nitric oxide synthase (iNOS) activity in brain tissue were performed at 24h after ischemia. Immunohistochemistry was used to measure the expression of iNOS. In vitro, 5 groups were used: control, model, TSA 8μM, TSA 4μM and TSA 2μM. The effects of TSA were tested in the cultured astrocytes exposed to hydrogen dioxide (H_2O_2). Result: TSA (10 and 20 mg/kg, i.p.) significantly reduced the infarct volume and TSA 20mg/kg improve neurological deficit 8h after ischemia remarkably. TSA (10 and 20 mg/kg, i.p.) significantly increased the activity of SOD after 24h of ischemia and decreased the MDA level in serum, and suppressed the NO content in brain tissue. All of the three treatment groups remarkably reduced the activity of iNOS in brain, and the expression of iNOS was also inhibited. In vitro, the translocation of NF-κB was inhibited by TSA and the survival rate of astrocytes was markedly increased as well as the NO production was decreased.
Conclusion: These results illustrated that TSA protected brain from ischemic injury by suppressing the oxidative stress and the radical-mediated inflammatory insult.
本实验共分为两个部分,第一部分通过整体模型评价TSA对小鼠永久性局灶性脑缺血的治疗效果。第二部分从体内和体外两方面入手,探讨TSA可能的作用机制。方法:动物主要分5个组:假手术组、模型组、TSA高剂量组(20mg/kg),TSA中剂量组(10mg/kg),TSA低剂量组(5mg/kg)。另外第一部分药效实验还添加了尼莫地平阳性对照组。实验采用永久性中动脉栓塞法造模(pMCAO),造模后24小时取材,通过行为学指标以及梗死面积评价脑损伤程度;生化检测用于测定血清中SOD活性、MDA含量以及脑组织匀浆中iNOS活性、NO含量;免疫组化用于检测脑冰冻切片中iNOS的表达情况。体外实验分5组:正常对照组、模型组、TSA高剂量组(8μM)、TSA中剂量组(4μM)、TSA低剂量组(2μM),采用过氧化氢损伤模型对星形胶质细胞进行研究。通过细胞存活率、细胞上清中的NO含量以及NF-κB的转录来进一步探讨TSA可能的作用机制。结果:TSA高、中剂量组均可显著减少梗死面积(P＜0.01);在行为学方面,20mg/kgTSA给药组自缺血后8h起可显著缓解行为学症状(P＜0.05),其余剂量组行为学指标相对于模型组均有不同程度的改善。TSA高、中剂量组小鼠血清中的MDA含量显著下降,SOD含量显著提高,脑组织匀浆中NO含量明显下降(P＜0.01,0.05);三个药物剂量组均能显著降低脑组织匀浆中iNOS活性(P＜0.01),免疫组化结果同时显示,缺血半球iNOS表达被抑制。体外实验中,三个TSA干预组(2,4and 8μM)均能显著减轻H_2O_2造成的星形胶质细胞损伤,并减少由此诱导产生的NO(P＜0.01);免疫印记实验证明NF-κB的转录也被抑制。结论:TSA对小鼠永久性脑缺血损伤有一定的保护作用。这一保护作用可能由于TSA可以减少受损组织的ROS含量,减轻氧化应激损伤;进而抑制ROS下游炎症因子iNOS的表达来减少NO的产生,从而缓解脑缺血后的炎症损伤。
Stroke is one of the most frequent causes of disability and death worldwide, but the treatment of it was short of. Danshen is a commonly used traditional Chinese medicine for the treatment of cardiovascular and Cerebrovascular diseases. Tanshinone IIA (TSA), as a key compound of Danshen, has been proved to protect the brain from transient ischemia injury. But there was no report of its effects on brain injury after permanent focal cerebral ischemia and little is known about its mechanism. The objective of this study was to evaluate whether Tanshinone IIA (TSA) was neuroprotective in permanent focal cerebral ischemia and to determine the possible mechanisms of its neuroprotection.
This experiment contains two parts. The first part was to measure the neuroprotection of TSA and the second part was to find the possible mechanisms of its function. Method: Animals were randomly divided into 5 groups: sham, vehicle, TSA 20mg/kg, TSA 10mg/kg and TSA 5mg/kg. In addition, there was a positive control group in the first part of the experiment. Mice were subjected to permanent middle cerebral artery occlusion for 24h. The neuroprotection of TSA was investigated with respect to neurological deficit scores and infarct volume. Biochemical analysis for malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in serum, and nitric oxide (NO) content and the inducible nitric oxide synthase (iNOS) activity in brain tissue were performed at 24h after ischemia. Immunohistochemistry was used to measure the expression of iNOS. In vitro, 5 groups were used: control, model, TSA 8μM, TSA 4μM and TSA 2μM. The effects of TSA were tested in the cultured astrocytes exposed to hydrogen dioxide (H_2O_2). Result: TSA (10 and 20 mg/kg, i.p.) significantly reduced the infarct volume and TSA 20mg/kg improve neurological deficit 8h after ischemia remarkably. TSA (10 and 20 mg/kg, i.p.) significantly increased the activity of SOD after 24h of ischemia and decreased the MDA level in serum, and suppressed the NO content in brain tissue. All of the three treatment groups remarkably reduced the activity of iNOS in brain, and the expression of iNOS was also inhibited. In vitro, the translocation of NF-κB was inhibited by TSA and the survival rate of astrocytes was markedly increased as well as the NO production was decreased.
Conclusion: These results illustrated that TSA protected brain from ischemic injury by suppressing the oxidative stress and the radical-mediated inflammatory insult.
引文
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