七氟烷对大鼠局灶性脑缺血再灌注损伤的影响及ERK/JNK机制研究
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摘要
目的
缺血再灌注(Ischemia reperfusion injury, IR)损伤是临床上影响脑缺血病人治疗效果的重要因素之一,目前发病机制尚未完全阐明,缺乏特异性治疗手段。凋亡(Cell apoptosis)作为神经元的主要死亡方式之一在脑缺血再灌注损伤中占有重要地位,因此抗凋亡治疗有可能成为临床治疗脑缺血再灌注损伤的重要手段。七氟烷是一种新型吸入麻醉气体,最近有研究发现七氟烷可以通过类似于缺血预处理(Ischemic preconditioning, IPC)或KATP通道激动剂的机制减轻脑缺血再灌注损伤,但对神经元凋亡的保护机制还不甚明了。丝裂原活化蛋白激酶(Mitogen-activated protein kinases, MAPK)是许多信号转导通路的整合点,许多酪氨酸激酶都可以通过刺激信号级联反应(Signaling cascade)激活丝裂原活化蛋白激酶通路。目前己发现至少四种类型的MAPK途径在不同的生物反应中发挥作用,其中,细胞外信号调节激酶(Extracellular signal-regulated kinase, ERK)/应激活化蛋白激酶(c-jun N-terminal kinase/stress-actived protein kinase, JNK/SAPK)主要参与应激条件下细胞的炎症反应、细胞因子分泌和细胞凋亡过程。在中枢神经系统,ERK/JNK的激活与各种病理状态下细胞的死亡和凋亡密切相关。
在这个实验中,我们在建立局灶性脑缺血再灌注模型的基础上,通过观测梗死后大鼠神经功能缺损、并应用氯化-2,3,5-三苯基氮唑(2,3,5-Tripheyltetrazolium chloride, TTC)染色、光镜技术了解细胞存活状况,透射电镜鉴定凋亡发生和免疫组织化学计数磷酸化ERK(p-ERK1,2)和磷酸化JNK(p-JNK)表达,试图解释七氟烷抗凋亡作用和脑保护的可能机制。
方法
第一部分:60只大鼠随机分为缺血再灌注组和对照组(空白对照、假手术、PD98059对照、SP600125对照)。根据Zea Longa等的改良方法建立右大脑中动脉阻闭再灌注模型(Middle cerebral artery occlusion, MCAO)。缺血1h再灌注1d, 3d, 5d后参考Zea Longa等的方法进行神经行为学评分,TTC染色观察各组脑梗死情况。
第二部分:20只大鼠随机分为对照组、缺血再灌注组和七氟烷预处理组。根据改良Zea Longa方法建立大鼠右大脑中动脉阻闭再灌注模型。对照组只分离血管不进行插线,七氟烷预处理组在缺血再灌注前先接受30min的七氟烷预处理(1MAC)。神经功能缺损评分后于再灌注1d, 3d, 5d处死动物,取缺血区脑组织制成石蜡块,HE染色和透射电镜观察海马CA1神经细胞凋亡情况。
第三部分:32只大鼠随机分为对照组、缺血再灌注组、七氟烷预处理组、ERK阻断组和JNK阻断组。根据Zea Longa等的改良方法建立大鼠右大脑中动脉阻闭再灌注模型。对照组只分离血管不进行插线,七氟烷预处理组在缺血再灌注前先接受30min的七氟烷预处理(1MAC),ERK阻断组在七氟烷预处理前给与ERK特异性阻断剂PD98059(1mg·kg~(-1), ip)、JNK阻断组在七氟烷预处理前给与JNK特异性阻断剂SP600125(6mg·kg~(-1), ip)。神经行为学评价后于再灌注后1d, 3d, 5d处死动物,取缺血区脑组织制成石蜡块,HE染色测量存活细胞比例,免疫组织化学法计数各时点p-ERK、p-JNK表达情况。
所有数据均采用均数±标准差(x_±s)表示,多组间比较采用单因素方差分析,多样本中两组均数及多时间点的比较用t检验。取P<0.05作为显著性检验标准。
结果
1.本实验改良了线拴大脑中动脉阻塞模型。在造模的60只大鼠中47只呈现出轻至重度神经功能缺损,造模成功率占78%。统计学证实,Longa评分与神经元存活负相关。(r=-0.561,P<0.01)
2.七氟烷预处理可显著改善大鼠局灶性脑缺血再灌注后的存活神经元数。缺血再灌注组再灌1d, 3d, 5d的存活数分别为46.0±1.4个/μm2; 29.0±2.8个/μm2; 17.0±2.8个/μm2,而七氟烷预处理组的梗死体积百分比为58.0±1.4个/μm2; 47.0±2.8个/μm2; 32.5±2.1个/μm2,P值均小于0.05,差异有统计学意义。
3. HE染色:对照组大脑皮质细胞结构层次清晰,缺血再灌注组可见大脑皮质神经细胞层次欠清晰,可见较多典型凋亡细胞;缺血再灌注组神经元胞体缩小变形,核固缩,胞浆浓缩呈伊红染色,组织疏松,细胞间隙增大;七氟烷预处理组凋亡细胞分布较稀疏。电镜:七氟烷预处理组易观察到正常神经元形态,缺血再灌注组细胞排列紊乱,可见较多凋亡神经元。
4.七氟烷预处理组与缺血再灌注组相比,海马p-ERK(25.5±0.7 vs 19.5±0.7, 1d; 22.5±0.7 vs 16.0±1.4, 3d; 18.0±1.4 vs 9.0±1.4, 5d)和p-JNK(13.5±0.7 vs 19.5±0.7, 1d; 10.5±0.7 vs 14.5±0.7, 3d; 8.5±0.7 vs 11.0±1.4, 5d),差异有统计学意义。
5.使用ERK特异性阻断剂PD98059可以减弱七氟烷的神经保护作用,SP600125—JNK特异性阻断剂也有类似作用。提示两条MAPK传导通路的平衡可能最终决定缺血再灌注神经元是否凋亡的命运。
结论
1.改良大鼠MCAO模型是脑缺血研究中的可靠动物模型。
2.凋亡参与了脑缺血再灌注损伤的病理过程。
3.七氟烷预处理具有减轻大鼠局灶性脑缺血再灌注后神经细胞凋亡的中枢直接保护作用。
4.七氟烷神经保护机制涉及ERK和JNK两条通路。
INTRODUCTION
Cerebral ischemia-reperfusion-induced injury is a major contributor affecting therapy of cerebral ischemia patients. There are no specific treatments in the clinical practice at present. Apoptosis which is one of the main patterns of neuronal death plays an important role in cerebral ischemia-reperfusion induced injury. So anti-apoptosis treatment may become one of the important remedies for cerebral ischemia-reperfusion-induced injury. Sevoflurane is a new volatile anesthetic agent. Recently, it is found that sevoflurane-induced preconditioning protects against cerebral ischemic neuronal damage by the mechanism like ischemia preconditioning or KATP channel opener, but the mechanism of neuronal apoptosis was not clear up. Mitogen-activated protein kinase (MAPK) is an integration point of different signal transduction pathways. Many tyrosine kinases stimulate signaling cascades that lead to activation of MAPK pathways. In vertebrates, there are at least four different MAPKs that convey distinct biological responses. ERK/JNK play an essential role in regulating inflammatory responses, cytokine secretion and cell apoptosis. In the nervous system, activation of ERK/JNK is closely related to apoptosis and death in response to a variety of pathological conditions.
In this study, We observed the difference of neurological deficits, examined survival neurons through light microscope and transmission electron microscope by HE staining and TTC(triphenyltetrazoliumchloride) staining, explored the expression of p-ERK/p-JNK by immunohistochemistry on the basis of the cerebral ischemic model to study the effects of sevoflurane against focal ischemia-reperfusion-induced injury and the possible mechanism of anti-apoptosis.
METHODS
Part one: Sixty Sprague-Dawlay health rats were randomly divided into ischemia-reperfusion group(IR) and control group (blank control, sham operation, PD98059 control, SP600125 control). First of all, We established right middle cerebral artery occlusion(MCAO) model based on Zea Longa method. Briefly, rats were anesthetized with intraperitoneal injection of pentobarbital sodium(45mg·kg~(-1), ip), the right common carotid artery(CCA), internal carotid artery(ICA) and external carotid artery(ECA) were exposed through amid line incision of the neck. A 4-0 nylon suture was used as an occluder and was inserted via the CCA. The ECA and the CCA were legated. The occluder advanced into the ICA about 17.5-18.5mm beyond the carotid bifurcation(The rats of sham operation group were received the same surgical procedure with only 9mm beyond the carotid bifurcation). At 60min after MCAO, reperfusion began with the suture withdrawn. The neurological scores were determined by the method described by Zea Longa at 1d、3d、5d after operation. Then rats were decapitated, the brains were stained using triphenyltetrazoliumchloride(TTC) to calculate infarct volume.
Part two: Modified middle cerebral artery occlusion models of transient focal cerebral ischemia were established. Twenty SD rats were randomly allocated into three groups: control group (C), ischemia-reperfusion group(IR), sevoflurane preconditioning group(S). In C group, no suture was inserted, while, S group received 30min sevoflurane preconditioning (1MAC) before surgery. The neurological deficit levels were measured at 3 timepionts(1d、3d、5d after reperfusion), then rats were decapitated. Brains were removed, postfixed, embedded, sectioned and processed for HE staining. Hematoxylin and Eosin(HE) staining was used to count survival neutrons in hippocampus CA1. Transmission electron microscope was used to describe neurons apoptosis.
Part three: Thirty-two SD rats were divided randomly as follows: control group (C),ischemia-reperfusion group(IR), sevoflurane preconditioning group(S), PD98059 group(PD), SP600125 group(SP). We established right middle cerebral artery occlusion(MCAO) model based on Zea Longa method. In C group, no suture was inserted, while, S group received 30min sevoflurane preconditioning (1MAC) before MCAO. In PD group, an ERK pathway inhibitor PD98059 was administered before sevoflurane preconditioning(1mg·kg~(-1), ip).In SP group, SP60015—JNK pathway inhibitor is used(6mg·kg~(-1), ip). The neurological behavior were measured by Longa Scores at 3 timepionts(1d、3d、5d after reperfusion), then rats were decapitated. Apoptosis neurons in hippocampus were observed by TEM and HE staining. ERK/JNK phosphorylation was detected by immunohistochemistry.
All the data were expressed by x_±s and analyzed statistically by One-Way ANOVA of variance among groups, t-test between two groups. The significant testing standard was P<0.05.
RESULTS
1. The study presents a modified model for the pathophysiological investigation of ischemia stroke, which is produced by nylon suture occlude the right middle cerebral artery. In all model groups, 47 of 60 rats(78%) showed mild to severe neurological deficits, and no neurological deficits were found in control group. Statistically, the Longa score(neurological deficit grading) is negative correlation with survival neurons.(r=-0.561,P<0.01)
2. The neurological scores of sevoflurane preconditioning group were significantly lower than those of ischemia-reperfusion group. The survival neurons of IR group and S group was 46.0±1.4 and 58.0±1.4 perμm2, 1d(P<0.05); 29.0±2.8 and 47.0±2.8, perμm2, 3d(P<0.05); 17.0±2.8 and 32.5±2.1 perμm2, 5d(P<0.05). Sevoflurane preconditioning can improve neurological outcome induced by ischemia-reperfusion.
3. It was observed clearly by HE staining and light microscope and transmission electron microscope that there were many apoptosis neurons in the hippocampus CA1 zone in ischemia-reperfusion group. Brain tissue section HE staining show that there was no infarction in control group, the shape and structure of the neurons were normal, there was no edema interstitial, and there was obvious infarction in ischemia-reperfusion group, the neurons were found deformed and shrunken, nucleus and cytoplasm were concentrated, edema was obvious. Apoptosis neurons in sevoflurane preconditioning group distribute sparsely.
4. Compared the ischemia-reperfusion group with sevoflurane preconditioning group, the levels of p-ERK in hippocampus ischemia zone are 25.5±0.7 vs 19.5±0.7, 1d; 22.5±0.7 vs 16.0±1.4, 3d; 18.0±1.4 vs 9.0±1.4, 5d, the differences have significant(P<0.05); on the contrary, the levels of p-JNK in hippocampus ischemia zone are 13.5±0.7 vs 19.5±0.7, 1d; 10.5±0.7 vs 14.5±0.7, 3d; 8.5±0.7 vs 11.0±1.4, 5d, the differences have significant(P<0.05). Cerebral ischemia-reperfusion may be result in the activity of ERK up-regulation and JNK down-regulation, which maybe associated with the process of neurons apoptosis.
5. Administered ERK pathway inhibitor—PD98059, the sevoflurane neuroprotective effect was blocked; furthermore, SP600125—JNK pathway inhibitor probably involved. The final results of the neuronal apoptosis were balanced between the two pathways.
CONCLUSION
1. The modified focal cerebral ischemia-reperfusion model (MCAO) in the rat was reliable and reproducible for cerebral vascular disease study.
2. Neuronal apoptosis plays an important role in cerebral ischemia-reperfusion induced injury.
3. Sevoflurane preconditioning can provides neuroprotection by inhibiting neuron apoptosis induced by ischemia-reperfusion.
4. The sevoflurane neuroprotection against ischemia-reperfusion is possibly related to the ERK/JNK signal transduction pathways.
缺血再灌注(Ischemia reperfusion injury, IR)损伤是临床上影响脑缺血病人治疗效果的重要因素之一,目前发病机制尚未完全阐明,缺乏特异性治疗手段。凋亡(Cell apoptosis)作为神经元的主要死亡方式之一在脑缺血再灌注损伤中占有重要地位,因此抗凋亡治疗有可能成为临床治疗脑缺血再灌注损伤的重要手段。七氟烷是一种新型吸入麻醉气体,最近有研究发现七氟烷可以通过类似于缺血预处理(Ischemic preconditioning, IPC)或KATP通道激动剂的机制减轻脑缺血再灌注损伤,但对神经元凋亡的保护机制还不甚明了。丝裂原活化蛋白激酶(Mitogen-activated protein kinases, MAPK)是许多信号转导通路的整合点,许多酪氨酸激酶都可以通过刺激信号级联反应(Signaling cascade)激活丝裂原活化蛋白激酶通路。目前己发现至少四种类型的MAPK途径在不同的生物反应中发挥作用,其中,细胞外信号调节激酶(Extracellular signal-regulated kinase, ERK)/应激活化蛋白激酶(c-jun N-terminal kinase/stress-actived protein kinase, JNK/SAPK)主要参与应激条件下细胞的炎症反应、细胞因子分泌和细胞凋亡过程。在中枢神经系统,ERK/JNK的激活与各种病理状态下细胞的死亡和凋亡密切相关。
在这个实验中,我们在建立局灶性脑缺血再灌注模型的基础上,通过观测梗死后大鼠神经功能缺损、并应用氯化-2,3,5-三苯基氮唑(2,3,5-Tripheyltetrazolium chloride, TTC)染色、光镜技术了解细胞存活状况,透射电镜鉴定凋亡发生和免疫组织化学计数磷酸化ERK(p-ERK1,2)和磷酸化JNK(p-JNK)表达,试图解释七氟烷抗凋亡作用和脑保护的可能机制。
方法
第一部分:60只大鼠随机分为缺血再灌注组和对照组(空白对照、假手术、PD98059对照、SP600125对照)。根据Zea Longa等的改良方法建立右大脑中动脉阻闭再灌注模型(Middle cerebral artery occlusion, MCAO)。缺血1h再灌注1d, 3d, 5d后参考Zea Longa等的方法进行神经行为学评分,TTC染色观察各组脑梗死情况。
第二部分:20只大鼠随机分为对照组、缺血再灌注组和七氟烷预处理组。根据改良Zea Longa方法建立大鼠右大脑中动脉阻闭再灌注模型。对照组只分离血管不进行插线,七氟烷预处理组在缺血再灌注前先接受30min的七氟烷预处理(1MAC)。神经功能缺损评分后于再灌注1d, 3d, 5d处死动物,取缺血区脑组织制成石蜡块,HE染色和透射电镜观察海马CA1神经细胞凋亡情况。
第三部分:32只大鼠随机分为对照组、缺血再灌注组、七氟烷预处理组、ERK阻断组和JNK阻断组。根据Zea Longa等的改良方法建立大鼠右大脑中动脉阻闭再灌注模型。对照组只分离血管不进行插线,七氟烷预处理组在缺血再灌注前先接受30min的七氟烷预处理(1MAC),ERK阻断组在七氟烷预处理前给与ERK特异性阻断剂PD98059(1mg·kg~(-1), ip)、JNK阻断组在七氟烷预处理前给与JNK特异性阻断剂SP600125(6mg·kg~(-1), ip)。神经行为学评价后于再灌注后1d, 3d, 5d处死动物,取缺血区脑组织制成石蜡块,HE染色测量存活细胞比例,免疫组织化学法计数各时点p-ERK、p-JNK表达情况。
所有数据均采用均数±标准差(x_±s)表示,多组间比较采用单因素方差分析,多样本中两组均数及多时间点的比较用t检验。取P<0.05作为显著性检验标准。
结果
1.本实验改良了线拴大脑中动脉阻塞模型。在造模的60只大鼠中47只呈现出轻至重度神经功能缺损,造模成功率占78%。统计学证实,Longa评分与神经元存活负相关。(r=-0.561,P<0.01)
2.七氟烷预处理可显著改善大鼠局灶性脑缺血再灌注后的存活神经元数。缺血再灌注组再灌1d, 3d, 5d的存活数分别为46.0±1.4个/μm2; 29.0±2.8个/μm2; 17.0±2.8个/μm2,而七氟烷预处理组的梗死体积百分比为58.0±1.4个/μm2; 47.0±2.8个/μm2; 32.5±2.1个/μm2,P值均小于0.05,差异有统计学意义。
3. HE染色:对照组大脑皮质细胞结构层次清晰,缺血再灌注组可见大脑皮质神经细胞层次欠清晰,可见较多典型凋亡细胞;缺血再灌注组神经元胞体缩小变形,核固缩,胞浆浓缩呈伊红染色,组织疏松,细胞间隙增大;七氟烷预处理组凋亡细胞分布较稀疏。电镜:七氟烷预处理组易观察到正常神经元形态,缺血再灌注组细胞排列紊乱,可见较多凋亡神经元。
4.七氟烷预处理组与缺血再灌注组相比,海马p-ERK(25.5±0.7 vs 19.5±0.7, 1d; 22.5±0.7 vs 16.0±1.4, 3d; 18.0±1.4 vs 9.0±1.4, 5d)和p-JNK(13.5±0.7 vs 19.5±0.7, 1d; 10.5±0.7 vs 14.5±0.7, 3d; 8.5±0.7 vs 11.0±1.4, 5d),差异有统计学意义。
5.使用ERK特异性阻断剂PD98059可以减弱七氟烷的神经保护作用,SP600125—JNK特异性阻断剂也有类似作用。提示两条MAPK传导通路的平衡可能最终决定缺血再灌注神经元是否凋亡的命运。
结论
1.改良大鼠MCAO模型是脑缺血研究中的可靠动物模型。
2.凋亡参与了脑缺血再灌注损伤的病理过程。
3.七氟烷预处理具有减轻大鼠局灶性脑缺血再灌注后神经细胞凋亡的中枢直接保护作用。
4.七氟烷神经保护机制涉及ERK和JNK两条通路。
INTRODUCTION
Cerebral ischemia-reperfusion-induced injury is a major contributor affecting therapy of cerebral ischemia patients. There are no specific treatments in the clinical practice at present. Apoptosis which is one of the main patterns of neuronal death plays an important role in cerebral ischemia-reperfusion induced injury. So anti-apoptosis treatment may become one of the important remedies for cerebral ischemia-reperfusion-induced injury. Sevoflurane is a new volatile anesthetic agent. Recently, it is found that sevoflurane-induced preconditioning protects against cerebral ischemic neuronal damage by the mechanism like ischemia preconditioning or KATP channel opener, but the mechanism of neuronal apoptosis was not clear up. Mitogen-activated protein kinase (MAPK) is an integration point of different signal transduction pathways. Many tyrosine kinases stimulate signaling cascades that lead to activation of MAPK pathways. In vertebrates, there are at least four different MAPKs that convey distinct biological responses. ERK/JNK play an essential role in regulating inflammatory responses, cytokine secretion and cell apoptosis. In the nervous system, activation of ERK/JNK is closely related to apoptosis and death in response to a variety of pathological conditions.
In this study, We observed the difference of neurological deficits, examined survival neurons through light microscope and transmission electron microscope by HE staining and TTC(triphenyltetrazoliumchloride) staining, explored the expression of p-ERK/p-JNK by immunohistochemistry on the basis of the cerebral ischemic model to study the effects of sevoflurane against focal ischemia-reperfusion-induced injury and the possible mechanism of anti-apoptosis.
METHODS
Part one: Sixty Sprague-Dawlay health rats were randomly divided into ischemia-reperfusion group(IR) and control group (blank control, sham operation, PD98059 control, SP600125 control). First of all, We established right middle cerebral artery occlusion(MCAO) model based on Zea Longa method. Briefly, rats were anesthetized with intraperitoneal injection of pentobarbital sodium(45mg·kg~(-1), ip), the right common carotid artery(CCA), internal carotid artery(ICA) and external carotid artery(ECA) were exposed through amid line incision of the neck. A 4-0 nylon suture was used as an occluder and was inserted via the CCA. The ECA and the CCA were legated. The occluder advanced into the ICA about 17.5-18.5mm beyond the carotid bifurcation(The rats of sham operation group were received the same surgical procedure with only 9mm beyond the carotid bifurcation). At 60min after MCAO, reperfusion began with the suture withdrawn. The neurological scores were determined by the method described by Zea Longa at 1d、3d、5d after operation. Then rats were decapitated, the brains were stained using triphenyltetrazoliumchloride(TTC) to calculate infarct volume.
Part two: Modified middle cerebral artery occlusion models of transient focal cerebral ischemia were established. Twenty SD rats were randomly allocated into three groups: control group (C), ischemia-reperfusion group(IR), sevoflurane preconditioning group(S). In C group, no suture was inserted, while, S group received 30min sevoflurane preconditioning (1MAC) before surgery. The neurological deficit levels were measured at 3 timepionts(1d、3d、5d after reperfusion), then rats were decapitated. Brains were removed, postfixed, embedded, sectioned and processed for HE staining. Hematoxylin and Eosin(HE) staining was used to count survival neutrons in hippocampus CA1. Transmission electron microscope was used to describe neurons apoptosis.
Part three: Thirty-two SD rats were divided randomly as follows: control group (C),ischemia-reperfusion group(IR), sevoflurane preconditioning group(S), PD98059 group(PD), SP600125 group(SP). We established right middle cerebral artery occlusion(MCAO) model based on Zea Longa method. In C group, no suture was inserted, while, S group received 30min sevoflurane preconditioning (1MAC) before MCAO. In PD group, an ERK pathway inhibitor PD98059 was administered before sevoflurane preconditioning(1mg·kg~(-1), ip).In SP group, SP60015—JNK pathway inhibitor is used(6mg·kg~(-1), ip). The neurological behavior were measured by Longa Scores at 3 timepionts(1d、3d、5d after reperfusion), then rats were decapitated. Apoptosis neurons in hippocampus were observed by TEM and HE staining. ERK/JNK phosphorylation was detected by immunohistochemistry.
All the data were expressed by x_±s and analyzed statistically by One-Way ANOVA of variance among groups, t-test between two groups. The significant testing standard was P<0.05.
RESULTS
1. The study presents a modified model for the pathophysiological investigation of ischemia stroke, which is produced by nylon suture occlude the right middle cerebral artery. In all model groups, 47 of 60 rats(78%) showed mild to severe neurological deficits, and no neurological deficits were found in control group. Statistically, the Longa score(neurological deficit grading) is negative correlation with survival neurons.(r=-0.561,P<0.01)
2. The neurological scores of sevoflurane preconditioning group were significantly lower than those of ischemia-reperfusion group. The survival neurons of IR group and S group was 46.0±1.4 and 58.0±1.4 perμm2, 1d(P<0.05); 29.0±2.8 and 47.0±2.8, perμm2, 3d(P<0.05); 17.0±2.8 and 32.5±2.1 perμm2, 5d(P<0.05). Sevoflurane preconditioning can improve neurological outcome induced by ischemia-reperfusion.
3. It was observed clearly by HE staining and light microscope and transmission electron microscope that there were many apoptosis neurons in the hippocampus CA1 zone in ischemia-reperfusion group. Brain tissue section HE staining show that there was no infarction in control group, the shape and structure of the neurons were normal, there was no edema interstitial, and there was obvious infarction in ischemia-reperfusion group, the neurons were found deformed and shrunken, nucleus and cytoplasm were concentrated, edema was obvious. Apoptosis neurons in sevoflurane preconditioning group distribute sparsely.
4. Compared the ischemia-reperfusion group with sevoflurane preconditioning group, the levels of p-ERK in hippocampus ischemia zone are 25.5±0.7 vs 19.5±0.7, 1d; 22.5±0.7 vs 16.0±1.4, 3d; 18.0±1.4 vs 9.0±1.4, 5d, the differences have significant(P<0.05); on the contrary, the levels of p-JNK in hippocampus ischemia zone are 13.5±0.7 vs 19.5±0.7, 1d; 10.5±0.7 vs 14.5±0.7, 3d; 8.5±0.7 vs 11.0±1.4, 5d, the differences have significant(P<0.05). Cerebral ischemia-reperfusion may be result in the activity of ERK up-regulation and JNK down-regulation, which maybe associated with the process of neurons apoptosis.
5. Administered ERK pathway inhibitor—PD98059, the sevoflurane neuroprotective effect was blocked; furthermore, SP600125—JNK pathway inhibitor probably involved. The final results of the neuronal apoptosis were balanced between the two pathways.
CONCLUSION
1. The modified focal cerebral ischemia-reperfusion model (MCAO) in the rat was reliable and reproducible for cerebral vascular disease study.
2. Neuronal apoptosis plays an important role in cerebral ischemia-reperfusion induced injury.
3. Sevoflurane preconditioning can provides neuroprotection by inhibiting neuron apoptosis induced by ischemia-reperfusion.
4. The sevoflurane neuroprotection against ischemia-reperfusion is possibly related to the ERK/JNK signal transduction pathways.
引文
[1] Nitatori T., Sato N., Waguri S.et al. Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis[J]. J Neurosci, 1995, 15(2): 1001-1011.
[2] Mehmet H., Edwards A. D. Hypoxia, ischaemia, and apoptosis[J]. Archives of disease in childhood, 1996, 75(2): F73-75.
[3] Wise-Faberowski L., Raizada M. K., Sumners C. Oxygen and glucose deprivation-induced neuronal apoptosis is attenuated by halothane and isoflurane[J]. Anesthesia and analgesia, 2001, 93(5): 1281-1287.
[4] Kapinya K. J., Prass K., Dirnagl U. Isoflurane induced prolonged protection against cerebral ischemia in mice: a redox sensitive mechanism?[J]. Neuroreport, 2002, 13(11): 1431-1435.
[5] Kehl F., Payne R. S., Roewer N.et al. Sevoflurane-induced preconditioning of rat brain in vitro and the role of KATP channels[J]. Brain research, 2004, 1021(1): 76-81.
[6] Payne R. S., Akca O., Roewer N.et al. Sevoflurane-induced preconditioning protects against cerebral ischemic neuronal damage in rats[J]. Brain research, 2005, 1034(1-2): 147-152.
[7] Toner C. C., Connelly K., Whelpton R.et al. Effects of sevoflurane on dopamine, glutamate and aspartate release in an in vitro model of cerebral ischaemia[J]. British journal of anaesthesia, 2001, 86(4): 550-554.
[8] Zablocka B., Dluzniewska J., Zajac H.et al. Opposite reaction of ERK and JNK in ischemia vulnerable and resistant regions of hippocampus: involvement of mitochondria[J]. Brain Res Mol Brain Res, 2003, 110(2): 245-252.
[9] Zhou L., Del Villar K., Dong Z.et al. Neurogenesis response to hypoxia-induced cell death: map kinase signal transduction mechanisms[J]. Brain research, 2004, 1021(1): 8-19.
[10] Longa E. Z., Weinstein P. R., Carlson S.et al. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke; a journal of cerebral circulation, 1989, 20(1): 84-91.
[11] Tsuchidate R., He Q. P., Smith M. L.et al. Regional cerebral blood flow during and after 2 hours of middle cerebral artery occlusion in the rat[J]. J Cereb Blood Flow Metab, 1997, 17(10): 1066-1073.
[12] van Lookeren Campagne M., Thomas G. R., Thibodeaux H.et al. Secondary reduction in the apparent diffusion coefficient of water, increase in cerebral blood volume, and delayed neuronal death after middle cerebral artery occlusion and early reperfusion in the rat[J]. J Cereb Blood Flow Metab, 1999, 19(12): 1354-1364.
[13] Kitagawa K., Matsumoto M., Tagaya M.et al. 'Ischemic tolerance' phenomenon found in the brain[J]. Brain research, 1990, 528(1): 21-24.
[14] Kersten J. R., Schmeling T. J., Pagel P. S.et al. Isoflurane mimics ischemic preconditioning via activation of K(ATP) channels: reduction of myocardial infarct size with an acute memory phase[J]. Anesthesiology, 1997, 87(2): 361-370.
[15] Hengartner M. O. Apoptosis: corralling the corpses[J]. Cell, 2001, 104(3): 325-328.
[16] Li Y., Chopp M., Jiang N.et al. In situ detection of DNA fragmentation after focal cerebral ischemia in mice[J]. Brain Res Mol Brain Res, 1995, 28(1): 164-168.
[17] MacManus J. P., Buchan A. M., Hill I. E.et al. Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain[J]. Neuroscience letters, 1993, 164(1-2): 89-92.
[18] Hashiguchi H., Morooka H., Miyoshi H.et al. Isoflurane protects renal function against ischemia and reperfusion through inhibition of protein kinases, JNK and ERK[J]. Anesthesia and analgesia, 2005, 101(6): 1584-1589.
[19] Fukunaga K., Miyamoto E. Role of MAP kinase in neurons[J]. Molecular neurobiology, 1998, 16(1): 79-95.
[20] Impey S., Obrietan K., Storm D. R. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity[J]. Neuron, 1999, 23(1): 11-14.
[21] Keyse S. M. An emerging family of dual specificity MAP kinase phosphatases[J]. Biochimica et biophysica acta, 1995, 1265(2-3): 152-160.
[22] Seger R., Krebs E. G. The MAPK signaling cascade[J]. Faseb J, 1995, 9(9): 726-735.
[23] Kyriakis J. M., Banerjee P., Nikolakaki E.et al. The stress-activated protein kinase subfamily of c-Jun kinases[J]. Nature, 1994, 369(6476): 156-160.
[24] Gao Y., Signore A. P., Yin W.et al. Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway[J]. J Cereb Blood Flow Metab, 2005, 25(6): 694-712.
[25] Lei K., Nimnual A., Zong W. X.et al. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase[J]. Molecular and cellular biology, 2002, 22(13): 4929-4942.
[26] Tournier C., Hess P., Yang D. D.et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway[J]. Science (New York, NY, 2000, 288(5467): 870-874.
[27] Sgambato V., Vanhoutte P., Pages C.et al. In vivo expression and regulation of Elk-1, a target of the extracellular-regulated kinase signaling pathway, in the adult rat brain[J]. J Neurosci, 1998, 18(1): 214-226.
[28] Shimizu N., Yoshiyama M., Omura T.et al. Activation of mitogen-activated protein kinases and activator protein-1 in myocardial infarction in rats[J]. Cardiovascular research, 1998, 38(1): 116-124.
[29] Kindy M. S. Inhibition of tyrosine phosphorylation prevents delayed neuronal death following cerebral ischemia[J]. J Cereb Blood Flow Metab, 1993, 13(3): 372-377.
[30] Hu B. R., Wieloch T. Tyrosine phosphorylation and activation of mitogen-activated protein kinase in the rat brain following transient cerebral ischemia[J]. Journal of neurochemistry, 1994, 62(4): 1357-1367.
[31] Alessandrini A., Namura S., Moskowitz M. A.et al. MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia[J]. Proceedings of the National Academy of Sciences of the United States of America, 1999, 96(22): 12866-12869.
[32] Kerr J. F., Wyllie A. H., Currie A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics[J]. British journal of cancer, 1972, 26(4): 239-257.
[33] Mehmet H., Yue X., Squier M. V.et al. Increased apoptosis in the cingulate sulcus of newborn piglets following transient hypoxia-ischaemia is related to the degree of high energy phosphate depletion during the insult[J]. Neuroscience letters, 1994, 181(1-2): 121-125.
[34] Guglielmo M. A., Chan P. T., Cortez S.et al. The temporal profile and morphologic features of neuronal death in human stroke resemble those observed in experimental forebrain ischemia: the potential role of apoptosis[J]. Neurological research, 1998, 20(4): 283-296.
[35] Martin L. J., Al-Abdulla N. A., Brambrink A. M.et al. Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis[J]. Brain research bulletin, 1998, 46(4): 281-309.
[36] Petito C. K., Torres-Munoz J., Roberts B.et al. DNA fragmentation follows delayed neuronal death in CA1 neurons exposed to transient global ischemia in the rat[J]. J Cereb Blood Flow Metab, 1997, 17(9): 967-976.
[37] Soriano S. G., Wang Y. F., Lipton S. A.et al. ICAM-1 dependent pathway is not involved in the development of neuronal apoptosis after transient focal cerebral ischemia[J]. Brain research, 1998, 780(2): 337-341.
[38] Lee S. H., Kim M., Kim Y. J.et al. Ischemic intensity influences the distribution of delayed infarction and apoptotic cell death following transient focal cerebral ischemia in rats[J]. Brain research, 2002, 956(1): 14-23.
[39] Gupta S., Barrett T., Whitmarsh A. J.et al. Selective interaction of JNK protein kinase isoforms with transcription factors[J]. The EMBO journal, 1996, 15(11): 2760-2770.
[40] Clarke N., Arenzana N., Hai T.et al. Epidermal growth factor induction of the c-jun promoter by a Rac pathway[J]. Molecular and cellular biology, 1998, 18(2): 1065-1073.
[41] Widmann C., Gibson S., Jarpe M. B.et al. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human[J]. Physiological reviews,1999, 79(1): 143-180.
[42] Takagi Y., Nozaki K., Sugino T.et al. Phosphorylation of c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase after transient forebrain ischemia in mice[J]. Neuroscience letters, 2000, 294(2): 117-120.
[43] Davis R. J. Signal transduction by the JNK group of MAP kinases[J]. Cell, 2000, 103(2): 239-252.
[44] Dong C., Davis R. J., Flavell R. A. Signaling by the JNK group of MAP kinases. c-jun N-terminal Kinase[J]. Journal of clinical immunology, 2001, 21(4): 253-257.
[45] Lennmyr F., Karlsson S., Gerwins P.et al. Activation of mitogen-activated protein kinases in experimental cerebral ischemia[J]. Acta neurologica Scandinavica, 2002, 106(6): 333-340.
[46] Hayashi T., Sakai K., Sasaki C.et al. c-Jun N-terminal kinase (JNK) and JNK interacting protein response in rat brain after transient middle cerebral artery occlusion[J]. Neuroscience letters, 2000, 284(3): 195-199.
[47] Okuno S., Saito A., Hayashi T.et al. The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia[J]. J Neurosci, 2004, 24(36): 7879-7887.
[48] Asanuma T., Inanami O., Tabu K.et al. Protection against malonate-induced ischemic brain injury in rat by a cell-permeable peptidic c-Jun N-terminal kinase inhibitor, (L)-HIV-TAT48-57-PP-JBD20, observed by the apparent diffusion coefficient mapping magnetic resonance imaging method[J]. Neuroscience letters, 2004, 359(1-2): 57-60.
[49] Hirt L., Badaut J., Thevenet J.et al. D-JNKI1, a cell-penetrating c-Jun-N-terminal kinase inhibitor, protects against cell death in severe cerebral ischemia[J]. Stroke; a journal of cerebral circulation, 2004, 35(7): 1738-1743.
[1] Koizumi J,Yoshida Y,Nakazawa T. Experimental studies of ischemic brain edema,1:a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemia area. Stroke,1986,8:1-8.
[2] 李毅平,张雅洁,罗毅男,等. 应用改良的血管内栓线技术制造大鼠局灶脑缺血模型. 中国神经精神疾病杂志,1995,21(2):107-108.
[3] Ginsberg MD,Busto R. Rodent models of cerebral ischemia. Stroke,1989,20(12):1627-1642.
[4] 张成英,姚家庆,田鹤村,等. 大鼠脑动脉环的解剖学观察. 解剖学杂志,1996,19:506-508.
[5] Garcia JH. Experimental ischemic stroke:a review. Stroke,1984,15(1):5-14
[6] Zea Longa E,Weinstein PR,Carlson S,et al. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke,1989,20(1):84-97.
[7] 袁琼兰,李瑞祥,羊惠君. 改良的短暂局灶性大鼠脑缺血模型. 四川解剖学杂志,1998,6(2):65-68.
[8] 刘亢丁,苏志坚,李毅平,等. 实验性局灶性脑缺血再灌注动物模型的改进及评价.中风与神经疾病杂志,1997,14(2):87-89.
[9] Coyle P,Jokelainen PT. Dosal cerebral artery collaterals of the rat. TheAnatomical Record,1982,203:397-404.
[10] Coyle P. Middle cerebral artery occlusion in the young rat. Stroke,1982,13:855-859.
[11] Rubino GJ,Young W. Ischemic cortical lesions after permanent occlusion of individual middle cerebral artery branches in rats. Stroke 1988,19(7):870-877 .
[12] Menzies SA,Hoff JT,et al. Middle cerebral artery occlusion in rats:a neurological and pathological evaluation of a reproducibal model. Neurosurgery,1992,31(1):100-107.
[13] 邱红霞,陈惟昌. 大鼠局灶性脑缺血模型的 MRI、血管构筑及病理变化特点. 中日友好医院学报,1999,13(5):249-253.
[14] 何秋,刘美洁,朴英善,等. 栓线法制备大鼠局灶性脑缺血再灌注模型的研究. 中国医科大学学报,1998,27(4):343-345.
[15] 卞杰勇,周岱. 大鼠局灶性脑缺血再灌注模型的改进. 苏州医学院学报,1998,18(3):226-228.
[16] 李胜,雷征霖. 大鼠大脑中动脉阻断可逆性局灶脑缺血模型的研究. 脑与神经疾病杂志,1997,5:341-343.
[17] 陈春富,李劲松. 栓线法大鼠局灶性脑缺血模型的研究. 中风与神经疾病杂志,1996,13(1):18-19.
[18] Kawamura S,Yasui N,Shirasawa M,et al.Rat middle cerebral artery occlusion using a intraluminal thread technique. Acta Neurochir,1991,109:126-132.
[19] 褚晓凡,董家政,吴军. 颈内动脉线栓与环扎建立大鼠局灶脑缺血再灌注模型. 中风与神经疾病杂志,2000,17(3):152-154.
[20] 曹霞,曹秉振,赵玉武. 线栓法复制局灶性脑缺血模型影响因素探讨. 中国病理生理杂志,2000,16(2):157-159.
[21] 王耀明,童萼塘,肖学宏. MRI 评价改进的大鼠可逆性局灶性脑缺血模型. 卒中与神经疾病,1996,6(3):171-173.
[22] Li F,Omae T,Fisher M. Spontaneous hyperthermia and its mechanism in the intraluminal suture middle cerebral artery occlusion model of rats. Stroke,1999,30(11):2464-2470.
[23] Ozdemir YG,Bolay H,Erdem E,et al. Occlusion of the MCA by a intraluminal filament may cause disturbances in the hippocampal blood flow due to anomalies of circle of willis and filament thickness. Brain Res,1999,822(1-2):260-264.
[24] Kanemitsu H,Nakagomi T,Tamura A,et al. Differences in the extent of primary ischemic damage between middle cerebral artery coagulation and intraluminal occlusion models. J Cereb Blood Flow Metab,2002,22(10):1196-1204.
[25] 郑健,董为伟. 介绍一种大鼠大脑中动脉阻塞/再灌注模型. 中国应用生理学杂志,1996,12(4):359,373.
[26] 李光勤,董为伟. 高血压对大鼠脑缺血区白细胞浸润及梗死体积的影响. 中风与神经疾病杂志,2000,17(2):72-74.
[27] Kuge Y,Minematsu K,Yamaguchi T,et al. Nylon monofilament forintraluminal middle cerebral artery occlusion in rats. Stroke,1995,26(9):1655-1658.
[28] 马常升,马文领,戴维国. 插线法制备大鼠局灶性脑缺血再灌注模型的研究. 解剖学杂志,1999,22(3):209-211.
[29] Laing RJ,Jakubowski J,Laing RW. Middle cerebral artery occlusion without craniectomy in rats with methond workes best? Stroke,1993,24(2):294-298.
[30] 屈秋民,曹振林,杨剑波. 线栓法大鼠大脑中动脉闭塞局灶性脑缺血模型Longa 法和小泉法的比较. 中华神经科杂志,2000,33(5):289.
[31] Takano K,Tatlisumak T,Bergmann AG,et al. Reproducibility and reliability of middle cerebral artery occlusion using a silicone-coated suture(koizumi)in rats. J Neurol Sci, 1997,153(1):8-11.
[32] 辛世萌,刘远红,聂志余. 栓线长度、直径及大鼠体重与栓线法大鼠局灶性脑缺血模型关系的研究. 大连医科大学学报,2000,22(2):105-107.
[33] 曹霞,曹秉振. 鼠须替代尼龙线栓塞大鼠大脑中动脉造成局灶性脑缺血模型研究.中国病理生理杂志,2001,17(4):381-382.
[34] 吴莹,陈文容,吴春泽,等. 线栓法大鼠局灶性脑缺血模型的建立与改进. 汕头大学医学院学报,1999,12(1):23-25.
[35] 徐旭东,刘文彦,孙秀丽,等. 大鼠局灶性脑缺血动物模型的实验研究. 济宁医学院学报,2000,23(1):9-11.
[36] 李小凤,孙圣刚,童萼塘. 大鼠可逆性脑缺血模型复制方法的改进. 华中医学杂志,2000,24(4):192-193.
[37] Wiebers DO,Adams HP Jr,Whisnant JP. Animal models of stroke:are they relevant to human disease? Stroke,1990,21(3):1-3.
[38] 施新猷,黄友恕,王泰清,等. 医学动物实验方法. 北京.人民卫生出版社:1980.
[39] Wang LG,Futrell N,Wang DZ,et al. A reproducibal model of middle cerebral infaction,compitabal with long-term survival,in aged rat. Stroke,1995,26:2087-2090.
[40] Duverger D,Mackenzie ET. The quantification of cerebral infarction following focal ischemia in the rat : influence of strain , arterial pressure , blood glucose concentration,and age. J Cereb Blood Flow Metab,1988,8:449-461.
[41] Markgraf CG,Kraydich S,Prado R,et al. Comparative histopathologic consequences of photothrombotic occlusion of the distal middle cerebral artery in Sprague-Dawley and Wistar rats. Stroke,1993,24(2):286-293.
[42] Oliff HS,Weber E,Eilon G,et al. The role of strain/vendor differences on the outcome of focal ischemia induced by intraluminal middle cerebral artery occlusion in the rat. Brain Research,1995,675:20-26.
[43] 庄心良,曾因明. 现代麻醉学. 北京. 人民卫生出版社:2003,25-29.
[44] 赵俊. 新编麻醉学. 北京. 人民军医出版社:2000,59-74.
[45]卜碧涛,王伟,张苏明. 大鼠脑缺血模型制作过程中麻醉方的选择与应用. 同济医科大学学报,1998,27(3):202-205.
[46] 田鹤邨,陈前芬,张成英,等. 氯胺酮对大鼠全脑缺血再灌注损伤的影响及其机理探讨. 蚌埠医学院学报,1994,19(2):83-86.
[47] 张洪,梅元武,孙圣刚,等. 脑缺血与高温关系的研究进展. 中华神经科杂志,2000,33(5):305-307.
[48] 陈春富,罗伟,范卫平,等. 亚低温对大鼠局灶性脑缺血的影响. 基础医学与临床,1997,17:51,52-54.
[49] 梅元武,张洪,孙圣刚. 不同药物麻醉后大鼠全脑缺血脑温的变化. 卒中与神经疾病,2001,8(5):282-285.
[50] Yamashta K,Busch E,Wiessner C,et al. Thread occlusion but not electrocoagulation of the middle cerebral artery cause hypothalamic damage with subsequent hyperthermia. Neuro Med Chir(Tokyo),1997,37:723-729.
[51] Siesjo BK,Ekholm A,Katsura K,et al. Acid-base changes during brain ischemia. Stroke,1990,21(Supple Ⅲ):Ⅲ-194.
[52] 刘建荣,胡大萌,赵瑜,等. 高血糖对大鼠局灶性缺血脑细胞外钙离子的影响. 上海第二医科大学学报,1997,17(3):201-203.
[53] 杨春水,陈涛. 高血糖加重大鼠局灶性脑缺血损伤中的自由基作用. 卒中与神经疾病,2000,7(2):95-97.
[54] 帅杰. 实验性高血糖大鼠缺血脑组织一氧化氮和中性白细胞浸润的变化. 中国神经精神疾病杂志,1998,24(增刊):9-10.
[55] 尹岭,田东华,朱克,等. 血糖水平及再灌流对大鼠局部脑缺血影响的实验研究.中国提视学与图象分析,1996,(3,4):44-46.
[56] Chileuitt L,Leber K,Mccalden T,et al. Induced hypertension during ischemia reduces infarct area after temporary middle cerebral artery occlusion in rats. Surg Neurol,1996,46(3):229-234.
[57] 李光勤,董为伟. 高血压对大鼠脑缺血区白细胞浸润及梗死体积的影响. 中风与神经疾病杂志,2000,17(2):72-74.
[58] 王伟. 严格控制实验条件,建立标准化脑缺血动物模型. 中华神经科杂志,1998,31(5):261-263.
[1] Payne RS, Ozan A, Norbert R, et al. Sevoflurane-induced preconditioning protects against cerebral ischemic neuronal damage in rats. Brain Research, 2005,1034(1-2):147-152.
[2] Bajgar R, Scetharaman S, Kowaitowski AG, et al. Identification and properties of a novel intracellular(mitochondrial) ATP-sensitive potassium channel in brain.J.Biol.Chem,2001, 276(36):33369-33374.
[3] Shimizu K, Lacza Z, Rajapakse N, et al. MitoK(ATP)opener, diazoxide, reduces neuronal damage after middle artery occlusion in the rat.Am.J.Physiol, 2002,283(3):H1005-H1011.
[4] Kehl F, Payne RS, Akca 0, et al. Sevoflurane-induced preconditioning of rat brain in vitro and the role of KATP channels. Brain Res, 2004,1021(l):76-81.
[5] Shake JG,Peck EA, Marban E, et al. Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection. Ann Thorac Surg, 2001, 72 (6):1849-1854
[6] Toner CC, Connelly K, Whelpton R, et al. Effects of sevoflurane on dopamine,glutamate and aspartate release in an in vitro model of cerebral ischemia. British Journal of Anaesthesia, 2001,86(4):550-554
[7] Stucke AG, Stuth EA, Tonkovic CV, et al. Effects of sevoflurane on excitatory neurotransmission to medullary expiratory neurons and on phrenic nerve activity in adecerebrate dog model. Anesthesiology, 2001, 95(2):485-491.
[8] Moe MC, Berg JJ, Larsen GA, et al. Sevoflurane reduces synaptic glutamate release in human synaptosomes. J Neurosurg Anesthesiol, 2002,14(3):180-186.
[9] Kudo M, Aono M, Lee Y, et al. Effects of volatile anesthetics on N-methyl-D-aspartate excitoxicity in primary rat neuronal-glial cultures.Anesthesiology, 2001,95(3)756-765
[10] Miyazaki H, Nakamura Y, Arai T, et al. Increase of glutamate uptake in astrocytes-a possible mechanism of action of volatile anesthetics. Anesthesiology,1997,86(6):1359-1366.
[11] Ohta K, Fukuuchi Y, Shimazu K, et al. Presynaptic glutamate receptors faciliate release of norepinephrine and 5-hydroxytryptamine as well as dopamine in the normal and ischemic striatum.J Auton Nerv Syst, 1994, 49 (suppl):195-202.
[12] Adachi Y, Taoda M, Uchihashi Y, et al. The effects of sevoflurane and isoflurane on striatal dopamine of awake freely moving rats observed in an in vivo microdialysis study. Masui,1999,48(9):960-965.
[13] Wei HF, Baobin K, Wei WL, et al. Isoflurane and sevoflurane affect cell survival and BCL-2/BAX ratio differently. Brain Research, 2005,1037(1-2):139-147.
[14] Engelhard K, Werner C, Eberspacher E, et al. Sevoflurane and propofol ingluence the expression of apoptosis regulation proteins after cerebral ischemia and reperfusion in rats.Eur J Anesthesiol,2004, 21(7):530-537.
[15] 张绍东,翟晶,张家瑾,等.异氟烷和七氟烷对缺血神经元的保护及对 bcl-2和 ice 基因表达的影响。中风与神经疾病杂志,2002, 19 (6): 323-325.
[16] Wise FL, Raizada MK, Sumners C. Desflurane and sevoflurane attenuate oxygen and glucose deprivation-induced neuronal cell death. Journal of Neurosurgical Anesthesiology, 2003, 15(3):193-199.
[17] Warner DS, Zhou J, Ramani R, et al. Reversible focal ischemia in the rat:effects of halothane, isoflurane,and methohexital anesthesia. Journal of Cerebral Blood Flow and Metabolism, 1991, 11(5):794-802.
[18] Sano T, Drummond JC, Patel PM, et al. A comparison of the cerebral protective effects of isoflurane and mild hypothermia in a model of incomplete forebrain ischemia in the rat. Anesthesiology, 1992, 76(2):221-228.
[19] Kushikata T, Hirota K, Kotani N, et al. Isoflurane increases norepinephine release in the rat preoptic area and the posterior hypothalamus in vivo and in vitro:Relevance to thermoregulation during anesthesia. Neuroscience, 2005, 131(1):79-86.36
[20] David S, Warner MD, Claude MF, et al. Sevoflurane and halothane reduce focal ischemic brain damage in the rat. Anesthesiology, 1993, 79(5):985-992.
[21] Werner C, Mollenberg O,Kochs E, et al. Sevoflurane improves neurological outcome after incomplete cerebral ischemia in rats. British Journal of Anaesthesia, 1995, 75 (6):756-760.
[2] Mehmet H., Edwards A. D. Hypoxia, ischaemia, and apoptosis[J]. Archives of disease in childhood, 1996, 75(2): F73-75.
[3] Wise-Faberowski L., Raizada M. K., Sumners C. Oxygen and glucose deprivation-induced neuronal apoptosis is attenuated by halothane and isoflurane[J]. Anesthesia and analgesia, 2001, 93(5): 1281-1287.
[4] Kapinya K. J., Prass K., Dirnagl U. Isoflurane induced prolonged protection against cerebral ischemia in mice: a redox sensitive mechanism?[J]. Neuroreport, 2002, 13(11): 1431-1435.
[5] Kehl F., Payne R. S., Roewer N.et al. Sevoflurane-induced preconditioning of rat brain in vitro and the role of KATP channels[J]. Brain research, 2004, 1021(1): 76-81.
[6] Payne R. S., Akca O., Roewer N.et al. Sevoflurane-induced preconditioning protects against cerebral ischemic neuronal damage in rats[J]. Brain research, 2005, 1034(1-2): 147-152.
[7] Toner C. C., Connelly K., Whelpton R.et al. Effects of sevoflurane on dopamine, glutamate and aspartate release in an in vitro model of cerebral ischaemia[J]. British journal of anaesthesia, 2001, 86(4): 550-554.
[8] Zablocka B., Dluzniewska J., Zajac H.et al. Opposite reaction of ERK and JNK in ischemia vulnerable and resistant regions of hippocampus: involvement of mitochondria[J]. Brain Res Mol Brain Res, 2003, 110(2): 245-252.
[9] Zhou L., Del Villar K., Dong Z.et al. Neurogenesis response to hypoxia-induced cell death: map kinase signal transduction mechanisms[J]. Brain research, 2004, 1021(1): 8-19.
[10] Longa E. Z., Weinstein P. R., Carlson S.et al. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke; a journal of cerebral circulation, 1989, 20(1): 84-91.
[11] Tsuchidate R., He Q. P., Smith M. L.et al. Regional cerebral blood flow during and after 2 hours of middle cerebral artery occlusion in the rat[J]. J Cereb Blood Flow Metab, 1997, 17(10): 1066-1073.
[12] van Lookeren Campagne M., Thomas G. R., Thibodeaux H.et al. Secondary reduction in the apparent diffusion coefficient of water, increase in cerebral blood volume, and delayed neuronal death after middle cerebral artery occlusion and early reperfusion in the rat[J]. J Cereb Blood Flow Metab, 1999, 19(12): 1354-1364.
[13] Kitagawa K., Matsumoto M., Tagaya M.et al. 'Ischemic tolerance' phenomenon found in the brain[J]. Brain research, 1990, 528(1): 21-24.
[14] Kersten J. R., Schmeling T. J., Pagel P. S.et al. Isoflurane mimics ischemic preconditioning via activation of K(ATP) channels: reduction of myocardial infarct size with an acute memory phase[J]. Anesthesiology, 1997, 87(2): 361-370.
[15] Hengartner M. O. Apoptosis: corralling the corpses[J]. Cell, 2001, 104(3): 325-328.
[16] Li Y., Chopp M., Jiang N.et al. In situ detection of DNA fragmentation after focal cerebral ischemia in mice[J]. Brain Res Mol Brain Res, 1995, 28(1): 164-168.
[17] MacManus J. P., Buchan A. M., Hill I. E.et al. Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain[J]. Neuroscience letters, 1993, 164(1-2): 89-92.
[18] Hashiguchi H., Morooka H., Miyoshi H.et al. Isoflurane protects renal function against ischemia and reperfusion through inhibition of protein kinases, JNK and ERK[J]. Anesthesia and analgesia, 2005, 101(6): 1584-1589.
[19] Fukunaga K., Miyamoto E. Role of MAP kinase in neurons[J]. Molecular neurobiology, 1998, 16(1): 79-95.
[20] Impey S., Obrietan K., Storm D. R. Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity[J]. Neuron, 1999, 23(1): 11-14.
[21] Keyse S. M. An emerging family of dual specificity MAP kinase phosphatases[J]. Biochimica et biophysica acta, 1995, 1265(2-3): 152-160.
[22] Seger R., Krebs E. G. The MAPK signaling cascade[J]. Faseb J, 1995, 9(9): 726-735.
[23] Kyriakis J. M., Banerjee P., Nikolakaki E.et al. The stress-activated protein kinase subfamily of c-Jun kinases[J]. Nature, 1994, 369(6476): 156-160.
[24] Gao Y., Signore A. P., Yin W.et al. Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway[J]. J Cereb Blood Flow Metab, 2005, 25(6): 694-712.
[25] Lei K., Nimnual A., Zong W. X.et al. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase[J]. Molecular and cellular biology, 2002, 22(13): 4929-4942.
[26] Tournier C., Hess P., Yang D. D.et al. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway[J]. Science (New York, NY, 2000, 288(5467): 870-874.
[27] Sgambato V., Vanhoutte P., Pages C.et al. In vivo expression and regulation of Elk-1, a target of the extracellular-regulated kinase signaling pathway, in the adult rat brain[J]. J Neurosci, 1998, 18(1): 214-226.
[28] Shimizu N., Yoshiyama M., Omura T.et al. Activation of mitogen-activated protein kinases and activator protein-1 in myocardial infarction in rats[J]. Cardiovascular research, 1998, 38(1): 116-124.
[29] Kindy M. S. Inhibition of tyrosine phosphorylation prevents delayed neuronal death following cerebral ischemia[J]. J Cereb Blood Flow Metab, 1993, 13(3): 372-377.
[30] Hu B. R., Wieloch T. Tyrosine phosphorylation and activation of mitogen-activated protein kinase in the rat brain following transient cerebral ischemia[J]. Journal of neurochemistry, 1994, 62(4): 1357-1367.
[31] Alessandrini A., Namura S., Moskowitz M. A.et al. MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia[J]. Proceedings of the National Academy of Sciences of the United States of America, 1999, 96(22): 12866-12869.
[32] Kerr J. F., Wyllie A. H., Currie A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics[J]. British journal of cancer, 1972, 26(4): 239-257.
[33] Mehmet H., Yue X., Squier M. V.et al. Increased apoptosis in the cingulate sulcus of newborn piglets following transient hypoxia-ischaemia is related to the degree of high energy phosphate depletion during the insult[J]. Neuroscience letters, 1994, 181(1-2): 121-125.
[34] Guglielmo M. A., Chan P. T., Cortez S.et al. The temporal profile and morphologic features of neuronal death in human stroke resemble those observed in experimental forebrain ischemia: the potential role of apoptosis[J]. Neurological research, 1998, 20(4): 283-296.
[35] Martin L. J., Al-Abdulla N. A., Brambrink A. M.et al. Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: A perspective on the contributions of apoptosis and necrosis[J]. Brain research bulletin, 1998, 46(4): 281-309.
[36] Petito C. K., Torres-Munoz J., Roberts B.et al. DNA fragmentation follows delayed neuronal death in CA1 neurons exposed to transient global ischemia in the rat[J]. J Cereb Blood Flow Metab, 1997, 17(9): 967-976.
[37] Soriano S. G., Wang Y. F., Lipton S. A.et al. ICAM-1 dependent pathway is not involved in the development of neuronal apoptosis after transient focal cerebral ischemia[J]. Brain research, 1998, 780(2): 337-341.
[38] Lee S. H., Kim M., Kim Y. J.et al. Ischemic intensity influences the distribution of delayed infarction and apoptotic cell death following transient focal cerebral ischemia in rats[J]. Brain research, 2002, 956(1): 14-23.
[39] Gupta S., Barrett T., Whitmarsh A. J.et al. Selective interaction of JNK protein kinase isoforms with transcription factors[J]. The EMBO journal, 1996, 15(11): 2760-2770.
[40] Clarke N., Arenzana N., Hai T.et al. Epidermal growth factor induction of the c-jun promoter by a Rac pathway[J]. Molecular and cellular biology, 1998, 18(2): 1065-1073.
[41] Widmann C., Gibson S., Jarpe M. B.et al. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human[J]. Physiological reviews,1999, 79(1): 143-180.
[42] Takagi Y., Nozaki K., Sugino T.et al. Phosphorylation of c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinase after transient forebrain ischemia in mice[J]. Neuroscience letters, 2000, 294(2): 117-120.
[43] Davis R. J. Signal transduction by the JNK group of MAP kinases[J]. Cell, 2000, 103(2): 239-252.
[44] Dong C., Davis R. J., Flavell R. A. Signaling by the JNK group of MAP kinases. c-jun N-terminal Kinase[J]. Journal of clinical immunology, 2001, 21(4): 253-257.
[45] Lennmyr F., Karlsson S., Gerwins P.et al. Activation of mitogen-activated protein kinases in experimental cerebral ischemia[J]. Acta neurologica Scandinavica, 2002, 106(6): 333-340.
[46] Hayashi T., Sakai K., Sasaki C.et al. c-Jun N-terminal kinase (JNK) and JNK interacting protein response in rat brain after transient middle cerebral artery occlusion[J]. Neuroscience letters, 2000, 284(3): 195-199.
[47] Okuno S., Saito A., Hayashi T.et al. The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia[J]. J Neurosci, 2004, 24(36): 7879-7887.
[48] Asanuma T., Inanami O., Tabu K.et al. Protection against malonate-induced ischemic brain injury in rat by a cell-permeable peptidic c-Jun N-terminal kinase inhibitor, (L)-HIV-TAT48-57-PP-JBD20, observed by the apparent diffusion coefficient mapping magnetic resonance imaging method[J]. Neuroscience letters, 2004, 359(1-2): 57-60.
[49] Hirt L., Badaut J., Thevenet J.et al. D-JNKI1, a cell-penetrating c-Jun-N-terminal kinase inhibitor, protects against cell death in severe cerebral ischemia[J]. Stroke; a journal of cerebral circulation, 2004, 35(7): 1738-1743.
[1] Koizumi J,Yoshida Y,Nakazawa T. Experimental studies of ischemic brain edema,1:a new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemia area. Stroke,1986,8:1-8.
[2] 李毅平,张雅洁,罗毅男,等. 应用改良的血管内栓线技术制造大鼠局灶脑缺血模型. 中国神经精神疾病杂志,1995,21(2):107-108.
[3] Ginsberg MD,Busto R. Rodent models of cerebral ischemia. Stroke,1989,20(12):1627-1642.
[4] 张成英,姚家庆,田鹤村,等. 大鼠脑动脉环的解剖学观察. 解剖学杂志,1996,19:506-508.
[5] Garcia JH. Experimental ischemic stroke:a review. Stroke,1984,15(1):5-14
[6] Zea Longa E,Weinstein PR,Carlson S,et al. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke,1989,20(1):84-97.
[7] 袁琼兰,李瑞祥,羊惠君. 改良的短暂局灶性大鼠脑缺血模型. 四川解剖学杂志,1998,6(2):65-68.
[8] 刘亢丁,苏志坚,李毅平,等. 实验性局灶性脑缺血再灌注动物模型的改进及评价.中风与神经疾病杂志,1997,14(2):87-89.
[9] Coyle P,Jokelainen PT. Dosal cerebral artery collaterals of the rat. TheAnatomical Record,1982,203:397-404.
[10] Coyle P. Middle cerebral artery occlusion in the young rat. Stroke,1982,13:855-859.
[11] Rubino GJ,Young W. Ischemic cortical lesions after permanent occlusion of individual middle cerebral artery branches in rats. Stroke 1988,19(7):870-877 .
[12] Menzies SA,Hoff JT,et al. Middle cerebral artery occlusion in rats:a neurological and pathological evaluation of a reproducibal model. Neurosurgery,1992,31(1):100-107.
[13] 邱红霞,陈惟昌. 大鼠局灶性脑缺血模型的 MRI、血管构筑及病理变化特点. 中日友好医院学报,1999,13(5):249-253.
[14] 何秋,刘美洁,朴英善,等. 栓线法制备大鼠局灶性脑缺血再灌注模型的研究. 中国医科大学学报,1998,27(4):343-345.
[15] 卞杰勇,周岱. 大鼠局灶性脑缺血再灌注模型的改进. 苏州医学院学报,1998,18(3):226-228.
[16] 李胜,雷征霖. 大鼠大脑中动脉阻断可逆性局灶脑缺血模型的研究. 脑与神经疾病杂志,1997,5:341-343.
[17] 陈春富,李劲松. 栓线法大鼠局灶性脑缺血模型的研究. 中风与神经疾病杂志,1996,13(1):18-19.
[18] Kawamura S,Yasui N,Shirasawa M,et al.Rat middle cerebral artery occlusion using a intraluminal thread technique. Acta Neurochir,1991,109:126-132.
[19] 褚晓凡,董家政,吴军. 颈内动脉线栓与环扎建立大鼠局灶脑缺血再灌注模型. 中风与神经疾病杂志,2000,17(3):152-154.
[20] 曹霞,曹秉振,赵玉武. 线栓法复制局灶性脑缺血模型影响因素探讨. 中国病理生理杂志,2000,16(2):157-159.
[21] 王耀明,童萼塘,肖学宏. MRI 评价改进的大鼠可逆性局灶性脑缺血模型. 卒中与神经疾病,1996,6(3):171-173.
[22] Li F,Omae T,Fisher M. Spontaneous hyperthermia and its mechanism in the intraluminal suture middle cerebral artery occlusion model of rats. Stroke,1999,30(11):2464-2470.
[23] Ozdemir YG,Bolay H,Erdem E,et al. Occlusion of the MCA by a intraluminal filament may cause disturbances in the hippocampal blood flow due to anomalies of circle of willis and filament thickness. Brain Res,1999,822(1-2):260-264.
[24] Kanemitsu H,Nakagomi T,Tamura A,et al. Differences in the extent of primary ischemic damage between middle cerebral artery coagulation and intraluminal occlusion models. J Cereb Blood Flow Metab,2002,22(10):1196-1204.
[25] 郑健,董为伟. 介绍一种大鼠大脑中动脉阻塞/再灌注模型. 中国应用生理学杂志,1996,12(4):359,373.
[26] 李光勤,董为伟. 高血压对大鼠脑缺血区白细胞浸润及梗死体积的影响. 中风与神经疾病杂志,2000,17(2):72-74.
[27] Kuge Y,Minematsu K,Yamaguchi T,et al. Nylon monofilament forintraluminal middle cerebral artery occlusion in rats. Stroke,1995,26(9):1655-1658.
[28] 马常升,马文领,戴维国. 插线法制备大鼠局灶性脑缺血再灌注模型的研究. 解剖学杂志,1999,22(3):209-211.
[29] Laing RJ,Jakubowski J,Laing RW. Middle cerebral artery occlusion without craniectomy in rats with methond workes best? Stroke,1993,24(2):294-298.
[30] 屈秋民,曹振林,杨剑波. 线栓法大鼠大脑中动脉闭塞局灶性脑缺血模型Longa 法和小泉法的比较. 中华神经科杂志,2000,33(5):289.
[31] Takano K,Tatlisumak T,Bergmann AG,et al. Reproducibility and reliability of middle cerebral artery occlusion using a silicone-coated suture(koizumi)in rats. J Neurol Sci, 1997,153(1):8-11.
[32] 辛世萌,刘远红,聂志余. 栓线长度、直径及大鼠体重与栓线法大鼠局灶性脑缺血模型关系的研究. 大连医科大学学报,2000,22(2):105-107.
[33] 曹霞,曹秉振. 鼠须替代尼龙线栓塞大鼠大脑中动脉造成局灶性脑缺血模型研究.中国病理生理杂志,2001,17(4):381-382.
[34] 吴莹,陈文容,吴春泽,等. 线栓法大鼠局灶性脑缺血模型的建立与改进. 汕头大学医学院学报,1999,12(1):23-25.
[35] 徐旭东,刘文彦,孙秀丽,等. 大鼠局灶性脑缺血动物模型的实验研究. 济宁医学院学报,2000,23(1):9-11.
[36] 李小凤,孙圣刚,童萼塘. 大鼠可逆性脑缺血模型复制方法的改进. 华中医学杂志,2000,24(4):192-193.
[37] Wiebers DO,Adams HP Jr,Whisnant JP. Animal models of stroke:are they relevant to human disease? Stroke,1990,21(3):1-3.
[38] 施新猷,黄友恕,王泰清,等. 医学动物实验方法. 北京.人民卫生出版社:1980.
[39] Wang LG,Futrell N,Wang DZ,et al. A reproducibal model of middle cerebral infaction,compitabal with long-term survival,in aged rat. Stroke,1995,26:2087-2090.
[40] Duverger D,Mackenzie ET. The quantification of cerebral infarction following focal ischemia in the rat : influence of strain , arterial pressure , blood glucose concentration,and age. J Cereb Blood Flow Metab,1988,8:449-461.
[41] Markgraf CG,Kraydich S,Prado R,et al. Comparative histopathologic consequences of photothrombotic occlusion of the distal middle cerebral artery in Sprague-Dawley and Wistar rats. Stroke,1993,24(2):286-293.
[42] Oliff HS,Weber E,Eilon G,et al. The role of strain/vendor differences on the outcome of focal ischemia induced by intraluminal middle cerebral artery occlusion in the rat. Brain Research,1995,675:20-26.
[43] 庄心良,曾因明. 现代麻醉学. 北京. 人民卫生出版社:2003,25-29.
[44] 赵俊. 新编麻醉学. 北京. 人民军医出版社:2000,59-74.
[45]卜碧涛,王伟,张苏明. 大鼠脑缺血模型制作过程中麻醉方的选择与应用. 同济医科大学学报,1998,27(3):202-205.
[46] 田鹤邨,陈前芬,张成英,等. 氯胺酮对大鼠全脑缺血再灌注损伤的影响及其机理探讨. 蚌埠医学院学报,1994,19(2):83-86.
[47] 张洪,梅元武,孙圣刚,等. 脑缺血与高温关系的研究进展. 中华神经科杂志,2000,33(5):305-307.
[48] 陈春富,罗伟,范卫平,等. 亚低温对大鼠局灶性脑缺血的影响. 基础医学与临床,1997,17:51,52-54.
[49] 梅元武,张洪,孙圣刚. 不同药物麻醉后大鼠全脑缺血脑温的变化. 卒中与神经疾病,2001,8(5):282-285.
[50] Yamashta K,Busch E,Wiessner C,et al. Thread occlusion but not electrocoagulation of the middle cerebral artery cause hypothalamic damage with subsequent hyperthermia. Neuro Med Chir(Tokyo),1997,37:723-729.
[51] Siesjo BK,Ekholm A,Katsura K,et al. Acid-base changes during brain ischemia. Stroke,1990,21(Supple Ⅲ):Ⅲ-194.
[52] 刘建荣,胡大萌,赵瑜,等. 高血糖对大鼠局灶性缺血脑细胞外钙离子的影响. 上海第二医科大学学报,1997,17(3):201-203.
[53] 杨春水,陈涛. 高血糖加重大鼠局灶性脑缺血损伤中的自由基作用. 卒中与神经疾病,2000,7(2):95-97.
[54] 帅杰. 实验性高血糖大鼠缺血脑组织一氧化氮和中性白细胞浸润的变化. 中国神经精神疾病杂志,1998,24(增刊):9-10.
[55] 尹岭,田东华,朱克,等. 血糖水平及再灌流对大鼠局部脑缺血影响的实验研究.中国提视学与图象分析,1996,(3,4):44-46.
[56] Chileuitt L,Leber K,Mccalden T,et al. Induced hypertension during ischemia reduces infarct area after temporary middle cerebral artery occlusion in rats. Surg Neurol,1996,46(3):229-234.
[57] 李光勤,董为伟. 高血压对大鼠脑缺血区白细胞浸润及梗死体积的影响. 中风与神经疾病杂志,2000,17(2):72-74.
[58] 王伟. 严格控制实验条件,建立标准化脑缺血动物模型. 中华神经科杂志,1998,31(5):261-263.
[1] Payne RS, Ozan A, Norbert R, et al. Sevoflurane-induced preconditioning protects against cerebral ischemic neuronal damage in rats. Brain Research, 2005,1034(1-2):147-152.
[2] Bajgar R, Scetharaman S, Kowaitowski AG, et al. Identification and properties of a novel intracellular(mitochondrial) ATP-sensitive potassium channel in brain.J.Biol.Chem,2001, 276(36):33369-33374.
[3] Shimizu K, Lacza Z, Rajapakse N, et al. MitoK(ATP)opener, diazoxide, reduces neuronal damage after middle artery occlusion in the rat.Am.J.Physiol, 2002,283(3):H1005-H1011.
[4] Kehl F, Payne RS, Akca 0, et al. Sevoflurane-induced preconditioning of rat brain in vitro and the role of KATP channels. Brain Res, 2004,1021(l):76-81.
[5] Shake JG,Peck EA, Marban E, et al. Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection. Ann Thorac Surg, 2001, 72 (6):1849-1854
[6] Toner CC, Connelly K, Whelpton R, et al. Effects of sevoflurane on dopamine,glutamate and aspartate release in an in vitro model of cerebral ischemia. British Journal of Anaesthesia, 2001,86(4):550-554
[7] Stucke AG, Stuth EA, Tonkovic CV, et al. Effects of sevoflurane on excitatory neurotransmission to medullary expiratory neurons and on phrenic nerve activity in adecerebrate dog model. Anesthesiology, 2001, 95(2):485-491.
[8] Moe MC, Berg JJ, Larsen GA, et al. Sevoflurane reduces synaptic glutamate release in human synaptosomes. J Neurosurg Anesthesiol, 2002,14(3):180-186.
[9] Kudo M, Aono M, Lee Y, et al. Effects of volatile anesthetics on N-methyl-D-aspartate excitoxicity in primary rat neuronal-glial cultures.Anesthesiology, 2001,95(3)756-765
[10] Miyazaki H, Nakamura Y, Arai T, et al. Increase of glutamate uptake in astrocytes-a possible mechanism of action of volatile anesthetics. Anesthesiology,1997,86(6):1359-1366.
[11] Ohta K, Fukuuchi Y, Shimazu K, et al. Presynaptic glutamate receptors faciliate release of norepinephrine and 5-hydroxytryptamine as well as dopamine in the normal and ischemic striatum.J Auton Nerv Syst, 1994, 49 (suppl):195-202.
[12] Adachi Y, Taoda M, Uchihashi Y, et al. The effects of sevoflurane and isoflurane on striatal dopamine of awake freely moving rats observed in an in vivo microdialysis study. Masui,1999,48(9):960-965.
[13] Wei HF, Baobin K, Wei WL, et al. Isoflurane and sevoflurane affect cell survival and BCL-2/BAX ratio differently. Brain Research, 2005,1037(1-2):139-147.
[14] Engelhard K, Werner C, Eberspacher E, et al. Sevoflurane and propofol ingluence the expression of apoptosis regulation proteins after cerebral ischemia and reperfusion in rats.Eur J Anesthesiol,2004, 21(7):530-537.
[15] 张绍东,翟晶,张家瑾,等.异氟烷和七氟烷对缺血神经元的保护及对 bcl-2和 ice 基因表达的影响。中风与神经疾病杂志,2002, 19 (6): 323-325.
[16] Wise FL, Raizada MK, Sumners C. Desflurane and sevoflurane attenuate oxygen and glucose deprivation-induced neuronal cell death. Journal of Neurosurgical Anesthesiology, 2003, 15(3):193-199.
[17] Warner DS, Zhou J, Ramani R, et al. Reversible focal ischemia in the rat:effects of halothane, isoflurane,and methohexital anesthesia. Journal of Cerebral Blood Flow and Metabolism, 1991, 11(5):794-802.
[18] Sano T, Drummond JC, Patel PM, et al. A comparison of the cerebral protective effects of isoflurane and mild hypothermia in a model of incomplete forebrain ischemia in the rat. Anesthesiology, 1992, 76(2):221-228.
[19] Kushikata T, Hirota K, Kotani N, et al. Isoflurane increases norepinephine release in the rat preoptic area and the posterior hypothalamus in vivo and in vitro:Relevance to thermoregulation during anesthesia. Neuroscience, 2005, 131(1):79-86.36
[20] David S, Warner MD, Claude MF, et al. Sevoflurane and halothane reduce focal ischemic brain damage in the rat. Anesthesiology, 1993, 79(5):985-992.
[21] Werner C, Mollenberg O,Kochs E, et al. Sevoflurane improves neurological outcome after incomplete cerebral ischemia in rats. British Journal of Anaesthesia, 1995, 75 (6):756-760.