强力增智灵对血管性痴呆小鼠治疗机理的研究
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摘要
目的:血管性痴呆(Vascular Dementia,VD)是老年期疾病的重要类型之一。随着社会人口老龄化,VD的发病率越来越高,成为严重影响人们生活质量的重要因素。因此,深入探讨VD的病理机制,开发和研制防治VD的有效药物具有重要意义。根据中医学对VD的传统认识和现代研究成果,导师以活血通络、化痰降浊、益肾健脑为法研制成强力增智灵。实验采用双侧颈总动脉结扎的方法制备小鼠VD模型,观察此方药对小鼠行为学、海马组织病理形态学、脑组织SOD和MDA含量及脑组织单胺类神经递质等指标的影响,探讨其治疗VD的疗效及可能作用机制。
方法:实验采用双侧颈总动脉结扎的方法制备血管性痴呆小鼠模型。健康雄性昆明小鼠100只,随机分为假手术组、模型组、强力增智灵高剂量组(以下简称“高剂量组”)、强力增智灵低剂量组(以下简称“低剂量组”)、尼莫地平对照组(以下简称“尼莫地平组”)5组,每组20只。假手术组小鼠只分离颈总动脉,穿线但不结扎,尾部不放血,其余各组结扎双侧颈总动脉阻断血流加尾部放血,制备反复脑缺血再灌注VD模型。术后第2天开始治疗。高剂量组和低剂量组灌服强力增智灵液,尼莫地平组灌服尼莫地平液,假手术组和模型组均灌服生理盐水。分别于术后7、15d进行行为学测试(跳台实验、水迷宫实验)。行为学测试结束后断头处死小鼠,取左侧脑组织固定后切片,HE、Nissl染色,光镜下观察脑组织的形态变化。取大脑皮层组织制成匀浆,离心后取上清液,采用比色分析法进行脑组织超氧化物歧化酶(SOD)、丙二醛(MDA)的含量的测定及高效液相色谱法检测脑神经递质去甲肾上腺素(NE)和5-羟色胺(5-HT)的变化。
结果
1强力增智灵对VD小鼠行为学实验的影响
1.1跳台成绩术后各时段,模型组小鼠的反应时间延长,潜伏期缩短,错误次数增加,与假手术组比较,有统计学意义(P<0.01)。各给药组与模型组比较,反应时间缩短,潜伏期延长,错误次数减少,差异有统计学意义(P<0.05或P<0.01)。
1.2水迷宫成绩术后7、15d,小鼠的学习成绩与记忆成绩改变基本一致。模型组小鼠在水迷宫中游全程时间延长,错误次数增多,与假手术组比较差异具有统计学意义(P<0.05或P<0.01)。各给药组与模型组比较,小鼠游全程时间和错误次数均显著减少具有统计学意义(P<0.05或P<0.01),且高低剂量组优于低剂量组和尼莫地平组,低剂量组和尼莫地平组之间比较无显著性差异(P>0.05)。
2强力增智灵对VD小鼠病理形态学的影响光镜下观察各组小鼠脑组织的病理形态学变化,假手术组海马区锥体细胞排列紧密,细胞核大而较圆,核仁清晰;模型组海马组织病变范围涉及CA1、CA2及CA3区,尤以CA1区明显,呈缺血性病理改变。锥体细胞层次减少,排列稀疏,明显脱失,细胞核变小,结构不清。随着时间的推移,模型组小鼠脑组织病理改变逐步加重,相对而言,各用药组小鼠病变比模型组均有所改善。
3强力增智灵对VD小鼠脑组织中SOD、MDA含量的影响模型组与假手术组相比,小鼠脑组织中SOD活性明显减弱(P<0.01),MDA含量则明显增加(P<0.01);各用药组与模型组相比,小鼠脑组织中SOD活性明显增强(P<0.01),MDA含量则显著降低(P<0.01)。用药各组之间比较:高剂量组的SOD活性高于低剂量组与尼莫地平组(P<0.05),MDA含量低于低剂量组与尼莫地平组(P<0.05),低剂量组与尼莫地平组比较,差异无统计学意义(P>0.05)。
4强力增智灵对VD小鼠脑组织海马区NE、5-HT含量的影响模型组与假手术组比较,模型组小鼠海马组织NE和5-HT含量明显低于假手术组(P<0.01或P<0.05);各用药组与模型组比较,均能明显升高小鼠海马组织NE、5-HT的含量(P<0.01或P<0.05);各用药组间的比较:高剂量组的NE含量高于尼莫地平组,有统计学意义(P<0.05),而低剂量组与尼莫地平组比较,差异无统计学意义(P>0.05)。
结论
1脑缺血是引起VD的重要原因,其主要症状是造成学习记忆能力下降。强力增智灵可提高VD小鼠水迷宫与跳台实验的成绩,改善其学习记忆能力。
2海马锥体细胞的受损是血管性痴呆的病理学基础,强力增智灵对VD小鼠有治疗作用,可减轻脑缺血再灌注所造成的病理损害。
3强力增智灵可以提高VD小鼠脑组织中SOD活性,降低MDA含量,具有抗自由基损伤的作用。
4强力增智灵可升高VD小鼠脑组织海马区NE和5-HT的含量,减轻缺血再灌注损伤。
Objective: Vascular Dementia (called VD as follows) is one of the important types in senile disease. With the aging of the population, the incidence of VD is more and more higher; VD has become an important factor to affect seriously the people’s living quality. Therefore, it’s of great significance to make deeper research into its pathological mechanism and develop the effective treatment to prevent and cure the VD. Based on the conventional knowledge and the modern research achievements of Traditional Chinese medicine (TCM) on VD, my teacher developed QiangLiZengZhiLing with the function of promoting blood circulation to remove meridian obstruction, dissipating phlegm to descending the turbid, benefiting kidney and brain. In order to make probe into its treatment action mechanism, we adopted VD model of Kunming mice with the operation of ligating both side carotid artery, observed its effect on mice praxiology, hippocampus pathomorphology, the contents of SOD, MDA in brain tissue neurotransmitter, etc.
Method: We duplicated the model of VD mice with the operation of ligating both side carotid arteries. 100 healthy male Kunming mice were divided into five groups with 20 mice in each group at random,which were sham-operation group, model group, high dose of QiangLiZengZhiLing group(called“High-dose group”as follows), low dose of QiangLiZengZhiLing group (called“Low-dose group”as follows),and Nimodipine control group (called“Nimodipine group”as follows). We duplicated the model of VD mice with the operation of cerebral ischem reperfusion through separating and ligating both side carotid arteries with putting blood from coda except sham-operation group. And then 5 groups were continuously filled medicine or saline through the stomach from the second day after the operation of cerebral ischem reperfusion. Sham-operation group and model group were filled saline and other groups were given medicine. We did the praxiology experiment On the 7th and 15th day after operation (jumping stand experiment, water-labyrinth experi- ment). The mice were cut head for obtaining cerebral tissue, the left part of which was fixed and cut into slices. The tissue was stained by HE (Hematoxylin) and Nissl dye. We observed constitutional morphologic changes of cerebral tissue under light microscope. Then we made the homogenate from cerebral cortex tissue, took the supernatant after centrifuging, measured the content of the SOD, MDA in the brain tissue with colorimetric analysis antigenic and examined the change of the brain neurotransmitter (NE and 5-HT) with high-performance liquid chromatography.
Results
1 The effect of QiangLiZengZhiLing on praxiology of VD mice.
1.1 The mice’s performance record of jumping stand
Every period after the operation, model group had longer reaction time, shorter latency time and more wrong times, there was different (P<0.01) compared with Sham-operation group. At the same time, other groups had shorter reaction time, longer latency time and less wrong times, there was different ( P<0.05 or P<0.01) compared with model group.
1.2 The mice’s performance record of water-labyrinth
Every period after the operation, there was no significant difference between the learning and memorizing performance. The wrong times and the time of swimming along the whole line of the model group were more than those of the sham-operation group (P<0.05 or P<0.01). There was different (P<0.01) compared with the Sham-operation group. At the same time,the swimming time and the wrong times of other groups were less than those of the model group (P<0.05 or P<0.01), and the performance of the High-dose group was better than that of the Low-dose group. There was no significant different between the Little-dose group and the Nimodipine group.
2 The effect of QiangLiZengZhiLing on cerebral pathomorph- ology of VD mice
The pathomorphology under light mirror lens indicated that pyramidal cells in the hippocampus of the sham-operation group were arranged closely, cell nucleuses were big and round, nucleoli were clear. The layers of the pyramidal cells in the hippocampus of the model group were reduced, the pyramidal cells were arranged sparse and missed obviously, the cell nucleuses diminished and the cell structure was vague The scope of the pathological changes in hippocampus of mice brain tissue involved CA1, CA2 and CA3 areas with CA1 area was especially obvious, hippocampus of mice brain tissue took on the pathological changes of ischem. As time went, the pathological changes of brain tissue in the model group was growing seriously. The pathological changes of each medical group were improved compared with the model group.
3 The effect of QiangLiZengZhiLing on the content of the SOD, MDA in the brain tissue of the VD mice.
The activity of the SOD in the brain tissue of the model group was lessoned compared with that of the sham-operation group (P<0.01), but the content of the MDA was increased obviously (P<0.01); The activity of the SOD in the brain tissue of the medical group was strengthened compared with that of the model group (P<0.01), but the content of the MDA was decreased obviously (P<0.01). The activity of the SOD in the brain tissue of high-dose group was higher than that of the low-dose group and the Nimodipine group (P<0.05), but the content of the MDA was decreased obviously (P<0.05). There was no different when other medical groups were compared with each other (P>0.05).
4 The effect of QiangLiZengZhiLing on the content of 5-HT and NE in the hippocampus brain tissue of the VD mice.
The content of the NE, 5-HT in the hippocampus brain tissue of the model group were lower obviously than those of the sham-operation group (P<0.01 or P<0.05); The content of the Ne and 5-HT in the hippocampus brain tissue of the medical groups were higher obviously than those of the model group (P<0.01 or P<0.05); The content of the NE in the hippocampus brain tissue of high-dose group was higher than that of the Nimodipine group (P<0.05); we could draw the conclusion that there was different, but there was no statistics significance in the difference between the low-dose group and the Nimodipine group (P>0.05).
Conclusion
1 The descend of the study and memory ability resulted from the cerebral ischem is the important reason to cause VD, QiangLiZengZhiLing can raise the VD mice’s performance record of water-labyrinth and jumping stand experiment, and improve the study and memory ability.
2 The damage of the pyramidal cells in the hippocampus tissue is the import pathology change that will lead to VD, QiangLiZengZhiLing have treatment function to the VD mice, and can alleviate the pathology damage caused by the cerebral ischem.
3 QiangLiZengZhiLing can raise the activity of the SOD, lower the content of the MDA to resist the damage of the free radical. 4 QiangLiZengZhiLing can heighten the content of the NE and 5-HT in the the hippocampus tissue of VD mice, and allevite the damage of the cerebral ischem.
方法:实验采用双侧颈总动脉结扎的方法制备血管性痴呆小鼠模型。健康雄性昆明小鼠100只,随机分为假手术组、模型组、强力增智灵高剂量组(以下简称“高剂量组”)、强力增智灵低剂量组(以下简称“低剂量组”)、尼莫地平对照组(以下简称“尼莫地平组”)5组,每组20只。假手术组小鼠只分离颈总动脉,穿线但不结扎,尾部不放血,其余各组结扎双侧颈总动脉阻断血流加尾部放血,制备反复脑缺血再灌注VD模型。术后第2天开始治疗。高剂量组和低剂量组灌服强力增智灵液,尼莫地平组灌服尼莫地平液,假手术组和模型组均灌服生理盐水。分别于术后7、15d进行行为学测试(跳台实验、水迷宫实验)。行为学测试结束后断头处死小鼠,取左侧脑组织固定后切片,HE、Nissl染色,光镜下观察脑组织的形态变化。取大脑皮层组织制成匀浆,离心后取上清液,采用比色分析法进行脑组织超氧化物歧化酶(SOD)、丙二醛(MDA)的含量的测定及高效液相色谱法检测脑神经递质去甲肾上腺素(NE)和5-羟色胺(5-HT)的变化。
结果
1强力增智灵对VD小鼠行为学实验的影响
1.1跳台成绩术后各时段,模型组小鼠的反应时间延长,潜伏期缩短,错误次数增加,与假手术组比较,有统计学意义(P<0.01)。各给药组与模型组比较,反应时间缩短,潜伏期延长,错误次数减少,差异有统计学意义(P<0.05或P<0.01)。
1.2水迷宫成绩术后7、15d,小鼠的学习成绩与记忆成绩改变基本一致。模型组小鼠在水迷宫中游全程时间延长,错误次数增多,与假手术组比较差异具有统计学意义(P<0.05或P<0.01)。各给药组与模型组比较,小鼠游全程时间和错误次数均显著减少具有统计学意义(P<0.05或P<0.01),且高低剂量组优于低剂量组和尼莫地平组,低剂量组和尼莫地平组之间比较无显著性差异(P>0.05)。
2强力增智灵对VD小鼠病理形态学的影响光镜下观察各组小鼠脑组织的病理形态学变化,假手术组海马区锥体细胞排列紧密,细胞核大而较圆,核仁清晰;模型组海马组织病变范围涉及CA1、CA2及CA3区,尤以CA1区明显,呈缺血性病理改变。锥体细胞层次减少,排列稀疏,明显脱失,细胞核变小,结构不清。随着时间的推移,模型组小鼠脑组织病理改变逐步加重,相对而言,各用药组小鼠病变比模型组均有所改善。
3强力增智灵对VD小鼠脑组织中SOD、MDA含量的影响模型组与假手术组相比,小鼠脑组织中SOD活性明显减弱(P<0.01),MDA含量则明显增加(P<0.01);各用药组与模型组相比,小鼠脑组织中SOD活性明显增强(P<0.01),MDA含量则显著降低(P<0.01)。用药各组之间比较:高剂量组的SOD活性高于低剂量组与尼莫地平组(P<0.05),MDA含量低于低剂量组与尼莫地平组(P<0.05),低剂量组与尼莫地平组比较,差异无统计学意义(P>0.05)。
4强力增智灵对VD小鼠脑组织海马区NE、5-HT含量的影响模型组与假手术组比较,模型组小鼠海马组织NE和5-HT含量明显低于假手术组(P<0.01或P<0.05);各用药组与模型组比较,均能明显升高小鼠海马组织NE、5-HT的含量(P<0.01或P<0.05);各用药组间的比较:高剂量组的NE含量高于尼莫地平组,有统计学意义(P<0.05),而低剂量组与尼莫地平组比较,差异无统计学意义(P>0.05)。
结论
1脑缺血是引起VD的重要原因,其主要症状是造成学习记忆能力下降。强力增智灵可提高VD小鼠水迷宫与跳台实验的成绩,改善其学习记忆能力。
2海马锥体细胞的受损是血管性痴呆的病理学基础,强力增智灵对VD小鼠有治疗作用,可减轻脑缺血再灌注所造成的病理损害。
3强力增智灵可以提高VD小鼠脑组织中SOD活性,降低MDA含量,具有抗自由基损伤的作用。
4强力增智灵可升高VD小鼠脑组织海马区NE和5-HT的含量,减轻缺血再灌注损伤。
Objective: Vascular Dementia (called VD as follows) is one of the important types in senile disease. With the aging of the population, the incidence of VD is more and more higher; VD has become an important factor to affect seriously the people’s living quality. Therefore, it’s of great significance to make deeper research into its pathological mechanism and develop the effective treatment to prevent and cure the VD. Based on the conventional knowledge and the modern research achievements of Traditional Chinese medicine (TCM) on VD, my teacher developed QiangLiZengZhiLing with the function of promoting blood circulation to remove meridian obstruction, dissipating phlegm to descending the turbid, benefiting kidney and brain. In order to make probe into its treatment action mechanism, we adopted VD model of Kunming mice with the operation of ligating both side carotid artery, observed its effect on mice praxiology, hippocampus pathomorphology, the contents of SOD, MDA in brain tissue neurotransmitter, etc.
Method: We duplicated the model of VD mice with the operation of ligating both side carotid arteries. 100 healthy male Kunming mice were divided into five groups with 20 mice in each group at random,which were sham-operation group, model group, high dose of QiangLiZengZhiLing group(called“High-dose group”as follows), low dose of QiangLiZengZhiLing group (called“Low-dose group”as follows),and Nimodipine control group (called“Nimodipine group”as follows). We duplicated the model of VD mice with the operation of cerebral ischem reperfusion through separating and ligating both side carotid arteries with putting blood from coda except sham-operation group. And then 5 groups were continuously filled medicine or saline through the stomach from the second day after the operation of cerebral ischem reperfusion. Sham-operation group and model group were filled saline and other groups were given medicine. We did the praxiology experiment On the 7th and 15th day after operation (jumping stand experiment, water-labyrinth experi- ment). The mice were cut head for obtaining cerebral tissue, the left part of which was fixed and cut into slices. The tissue was stained by HE (Hematoxylin) and Nissl dye. We observed constitutional morphologic changes of cerebral tissue under light microscope. Then we made the homogenate from cerebral cortex tissue, took the supernatant after centrifuging, measured the content of the SOD, MDA in the brain tissue with colorimetric analysis antigenic and examined the change of the brain neurotransmitter (NE and 5-HT) with high-performance liquid chromatography.
Results
1 The effect of QiangLiZengZhiLing on praxiology of VD mice.
1.1 The mice’s performance record of jumping stand
Every period after the operation, model group had longer reaction time, shorter latency time and more wrong times, there was different (P<0.01) compared with Sham-operation group. At the same time, other groups had shorter reaction time, longer latency time and less wrong times, there was different ( P<0.05 or P<0.01) compared with model group.
1.2 The mice’s performance record of water-labyrinth
Every period after the operation, there was no significant difference between the learning and memorizing performance. The wrong times and the time of swimming along the whole line of the model group were more than those of the sham-operation group (P<0.05 or P<0.01). There was different (P<0.01) compared with the Sham-operation group. At the same time,the swimming time and the wrong times of other groups were less than those of the model group (P<0.05 or P<0.01), and the performance of the High-dose group was better than that of the Low-dose group. There was no significant different between the Little-dose group and the Nimodipine group.
2 The effect of QiangLiZengZhiLing on cerebral pathomorph- ology of VD mice
The pathomorphology under light mirror lens indicated that pyramidal cells in the hippocampus of the sham-operation group were arranged closely, cell nucleuses were big and round, nucleoli were clear. The layers of the pyramidal cells in the hippocampus of the model group were reduced, the pyramidal cells were arranged sparse and missed obviously, the cell nucleuses diminished and the cell structure was vague The scope of the pathological changes in hippocampus of mice brain tissue involved CA1, CA2 and CA3 areas with CA1 area was especially obvious, hippocampus of mice brain tissue took on the pathological changes of ischem. As time went, the pathological changes of brain tissue in the model group was growing seriously. The pathological changes of each medical group were improved compared with the model group.
3 The effect of QiangLiZengZhiLing on the content of the SOD, MDA in the brain tissue of the VD mice.
The activity of the SOD in the brain tissue of the model group was lessoned compared with that of the sham-operation group (P<0.01), but the content of the MDA was increased obviously (P<0.01); The activity of the SOD in the brain tissue of the medical group was strengthened compared with that of the model group (P<0.01), but the content of the MDA was decreased obviously (P<0.01). The activity of the SOD in the brain tissue of high-dose group was higher than that of the low-dose group and the Nimodipine group (P<0.05), but the content of the MDA was decreased obviously (P<0.05). There was no different when other medical groups were compared with each other (P>0.05).
4 The effect of QiangLiZengZhiLing on the content of 5-HT and NE in the hippocampus brain tissue of the VD mice.
The content of the NE, 5-HT in the hippocampus brain tissue of the model group were lower obviously than those of the sham-operation group (P<0.01 or P<0.05); The content of the Ne and 5-HT in the hippocampus brain tissue of the medical groups were higher obviously than those of the model group (P<0.01 or P<0.05); The content of the NE in the hippocampus brain tissue of high-dose group was higher than that of the Nimodipine group (P<0.05); we could draw the conclusion that there was different, but there was no statistics significance in the difference between the low-dose group and the Nimodipine group (P>0.05).
Conclusion
1 The descend of the study and memory ability resulted from the cerebral ischem is the important reason to cause VD, QiangLiZengZhiLing can raise the VD mice’s performance record of water-labyrinth and jumping stand experiment, and improve the study and memory ability.
2 The damage of the pyramidal cells in the hippocampus tissue is the import pathology change that will lead to VD, QiangLiZengZhiLing have treatment function to the VD mice, and can alleviate the pathology damage caused by the cerebral ischem.
3 QiangLiZengZhiLing can raise the activity of the SOD, lower the content of the MDA to resist the damage of the free radical. 4 QiangLiZengZhiLing can heighten the content of the NE and 5-HT in the the hippocampus tissue of VD mice, and allevite the damage of the cerebral ischem.
引文
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3 许士凯 . 抗衰老药物学 [M]. 北京 : 中国医药科技出版社,1994:285
4 姚泰,罗自强.生理学.北京:人民卫生出版社,2001:435~439
5 Mani PB.Hippocampal pyramidal cells and aging in the human :Aquantttative study of neuronal loss in sectors CA1 to CA4[J].Exp Neurol ,1986,94:29~40
6 张雪朝,贺志光,吕明庄,等.血管性痴呆大鼠记忆障碍与海马 Bcl-2 蛋 白 表 达 的 研 究 [J]. 中 国 病 理 生 理 杂志,2002,18(10):1295
7 秦震.神经病学.上海:上海医科大学出版社,2000:193~196
8 赵建新,田元祥,李国明,等.脑缺血再灌注拟血管性痴呆小鼠皮层及海马细胞病理形态学动态观察[J].中风与神经疾病杂志,2000,17(4):200~202
9 Schmidley JW.Free radicals in central nervous system is chaem ia [J].Stroke,1990,21:1086~1091
10 丁克祥 .SOD 临床研究集 [M]. 北京 : 原子能出版社,1992:67~68
11 梁勇.氧自由基与脑损伤和脑水肿[J].国外医学.神经病学神经外科分册,1995,22(20):81~84
12 贾建平,贾健民.阿尔茨海默病和血管性痴呆患者脑脊液中乙酰胆碱和胆碱检测及其临床意义.中华神经科杂志,2002,35(3):168~169
13 Weinberger J, Rosa JN, Cohen G. Nerve terminal damage in cerebral ischemia: Protective effect of alpha-methyl- paratryrosine. Stroke ,1985,16(5):864
14 Harik SI, Yoshida S,Busto R, Monoamine neurotransmitters in diffuse reversible forbrain ischemia and early recirculation: Increased dopaminergic activity. Neurology1986,36:971
15 Bielenberg GW, Burkharct M. 5-hydroxytryptamine agonists. A new therapeutic principle for stroke treatment.Stroke, 1990,21(12): 161
16 陈光辉,饶明俐,韩漫本,等.大鼠可逆性全脑缺血再灌注过程中几个脑区儿茶酚胺递质的动态变化.中风与神经疾病杂志, 1996,13(3):133~136
17 Gustafson I,Westerberg E,Wieloch T.Protection against ischemia-induced neuronal damage by the alpha- adrenoceptor antagonist idazoxan:influence of time of administration and possible mechanisms of action. Cereb Blood Flow Metab,1990,10(6):885
18 吴继全,张力,杨晓晖等.启神胶囊对全脑反复缺血再灌注大鼠脑内单胺类神经递质含量的影响.山东生物医学工程,2002,21(2):31~33
19 张云岭,梅建勋.近10年来中医对血管性痴呆的临床研究进展.北京中医药大学学报,1997,20(3):52~55
20 王永炎,刘金民,谢颖桢.中风病智能障碍的中医康复.北京中医药大学校庆40周年论文汇编.北京:学苑出版社,1996:561~566
21 谢颖桢,邹忆怀,张云岭.血管性痴呆病因病机探讨.北京中医药大学学报,2000,23(6):1
22 王永炎,刘金民,谢颖桢.中风智能障碍的中医康复.北京中医药大学校庆40周年论文汇编.北京:学苑出版社,1996:561
23 唐启盛,王永炎,黄启福.浊毒闭阻脑络对老年期痴呆的影响.北京中医药大学学报,1997,20(6):24
24 雷燕,黄启福,王永炎.论瘀毒阻络是络病形成的病理基础.北京中医药大学学报,1999,22(2):8
25 颜德馨,吕立言.老年性痴呆与瘀血的关系.辽宁中医杂志,1991,18(8):37
26 夏泉,张平,李绍平,等.当归的药理作用研究进展.时珍国医国药,2004,15(3):164~165
27 So Young Kang, Ki Yong Lee, Mi Jung Park, et al. Decursin from A ngelica gigas mitigates mnesia induced by scopo lamine in mice[J]. Neurobiology of Learning and Memory, 2003, 79: 11~18
28 杨 勤 , 赵 朝 伟 . 丹 参 的 药 理 作 用 研 究 现 状 . 中 国 药业,2003,12(10):78
29 吁文贵,徐理纳.乙酰丹酚酸A对血小板花生四烯酸代谢的影响[J].药学学报,1998,33(1):62
30 杨怡静,王玲.丹参、藻酸双酯钠、低分子右旋糖酐、甘露醇对红细胞悬浮液粘弹特性的影响[J].华西医科大学学报,1993,24(2):143
31 尹宝光.水蛭对实验性脑水肿及皮下血肿的影响[J].中西医结合杂志,1986,6(7):407
32 周金黄,王筠默.中药药理学[M].上海:上海科学技术出版社,1986,(1):181
33 方永奇,匡忠生,谢宇辉,等.石菖蒲对缺血再灌注脑损伤大鼠 神 经 细 胞 凋 亡 的 影 响 . 现 代 中 西 医 结 合 杂志,2002,11(17):1647~1649
34 景玉宏,冯慎远,汤晓琴.石菖蒲对学习记忆的影响及突触机制.中国中医基础医学杂志,2002,8(6):38~41
35 唐洪梅,席萍,吴敏,等.石菖蒲对小鼠脑组织氨基酸类神经递质的影响.中药新药与临床药理,2004,15(5):310~311
36 刘治军,张丽,李林.中药何首乌的药理作用研究进展.中华名医论坛,2004,5(6):6~7
37 楚晋,叶翠飞,李林.《二苯乙烯苷对痴呆小鼠学习记2003,9(11):643~645
38 刘治军,李林,叶翠飞,王育琴《.二苯乙烯苷对脑缺血再灌注沙土鼠学习记忆功能及NMDA受体亲合力的影响》,《中国新药杂志》,2004,13(3):223~226
39 KiyoharaY. Prevalence , incidence, and risk factors of vascular dementia: the Hisayama study. Clin Neurol, 1999, 39:47~49
40 WooJ I, LeeJH, Yoo KY, etal. Prevalence estimation of dementia in a rural area of Korea. J American GeriatricsSociety,1998,46:983~987
41 盛树力.老年性痴呆的治疗和护理.北京:科学技术文献出版社,2000:176~185
42 周兰兰,明亮,江勤.银杏叶提取物对反复脑缺血再灌注损伤的保护作用.中国中西医结合杂志,2000,20(5):356~358
1 王兴华,李露斯.两种大鼠2-VO模型制作方法的比较[J].第三军医大学学报,2004,24(12):1496
2 李巍,张世仪,赵惠敏,等.小鼠缺血性学习记忆障碍模型的建立[J].基础医学与临床,1995,15(6):46
3 王蕊,杨秦飞,唐一鹏,等.大鼠拟“血管性痴呆”模型的改进[J].中国病理生理杂志,2000,16(10):914
4 唐启盛,黄启福,郭建文.高脂血症大鼠脑缺血再灌流诱发行为 学 障 碍 模 型 的 实 验 研 究 [J]. 北 京 中 医 药 大 学 学报,1997,20(5):34
5 Pulsinelli WA, Brierley JB. A new model of bilateral hemispheric ischemia in the unanesthetized rat [J]. Stroke, 1979,10:267~272
6 Lestage P, Lockhart B, Roger A. In vivo exploration of cerebral ischemia:use of neuroprotective agents in animal studies [J]. Therapie, 2002,57:554~563
7 Longa EZ, Weinstein in PR, Carlson S, etal. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke,1989,20(1):84~91
8 Yamamoto M, Tamura A, Krino T, etal. Behavioral changesafter focal cerebral ischemia by left middle cerebral artery occlusion in rats[J]. Brain Res,1988,452(12):323~328
9 尹军祥,田金洲,黄启福,等.MCAO拟血管性痴呆大鼠模型的建立[J].中国病理生理杂志,2003,19(8):1144~1147
10 Nagasawa H, K. Correlation between cerebral blood flow and histologic changes in a new rat modle of middle cerebral artery occlusion[J]. Stroke,1989,20(8):1037~1043
11 梅建勋,张云岭,张伯礼,等.多发梗塞性痴呆大鼠模型的改进与应用[J].中国中西医结合杂志,2000,20(2):113
12 吴忧,贾建平.脑缺血动物模型的制备及影响因素[J].中国脑血管杂志,2007,4(1):43
13 Takagi K, Takeo S. The model of stroke induced by microsphere embolism in rats[J]. Nippon Yakurigaku Zasshi, 2003,121(6):440
14 吴忧,贾建平.脑缺血动物模型的制备及影响因素[J].中国脑血管杂志,2007,4(1):43
15 滕晶.康脑灵Ⅱ号治疗血管性痴呆实验与临床研究[J].山东中医药大学学报,2000,21(1):48~51
16 杨养贤,李锐,陈松盛,等.补肾化瘀法改善缺血性认知障碍作用机理研究[J].中国中医基础医学杂志,2001,7(1):15~17
17 陈忠义,李寅超,柳文科.血管性痴呆危险因素研究进展[J].实用医药杂志,2006,23(4):490
18 Sabbatini M, Catalani A, Consoli C, et al. The hippocampus in spontaneously hypertensive rats: an animal model of vascular demential [J]. Mech Ageing Dev, 2002,123(5):5475
19 赵勇,崔淑芳,汤球.血管性痴呆动物模型研究进展[J].上海实验动物科学,2005,25(1):56
20 韩冬,廖福龙,李文,等.冷光源光化学诱导局灶性脑梗塞及血管损伤半暗带大鼠模型[J].中国微循环,2001,5(1):71
21 蔡晶,杜建.光化学反应法建立拟血管性痴呆大鼠模型的改进[J].中国神经免疫学和神经病学杂志,2005,12(5):295
22 刘石梅,苏南湘,何明大.血管性痴呆动物模型实验研究进展[J].中医药导报,2005,11(9):78
23 王蕊,杨秦飞,唐一鹏,等.大鼠拟VD模型的建立及中药9602防治作用初探[J].北京中医药大学学报,2000,23(5):30
24 封银曼,龙旭阳,郑攀.血管性痴呆的中医实验研究近况[J].河南中医学院学报,2004,19(110):78~79
25 张力.化呆醒神汤对大鼠血管性痴呆模型病理变化及胆碱能纤维的影响[J].北京中医药大学学报,2001,24(3):23~25
26 冀宏,李澎涛,黄启福.解毒通络方抗大鼠脑缺血再灌后脂质过 氧 化 损 伤 的 实 验 研 究 [J]. 北 京 中 医 药 大 学 学报,2000:23(6):21~23
27 张孟仁,郭赛珊.补肾活血方对拟VD小鼠脑NMDA受体和一氧化氮合酶的影响[J].中医杂志,2000,41(12):745
28 孙莉,吴江,郝小淑.血管性痴呆大鼠脑血流量及细胞凋亡的研究[J].中华老年心脑血管病杂志,2001,3(6):40
29 封银曼,龙旭阳,郑攀.血管性痴呆的中医实验研究近况[J].河南中医学院学报,2004,19(110):78~79
30 梅建勋.健脑益智冲剂对多发梗塞性大鼠脑缺血再灌注模型血液流变学的影响[J].天津中医,1998,15(6):26
2 徐淑云,卞如濂,陈修.药理实验方法学,北京:人民卫生出版社,2002,22
3 许士凯 . 抗衰老药物学 [M]. 北京 : 中国医药科技出版社,1994:285
4 姚泰,罗自强.生理学.北京:人民卫生出版社,2001:435~439
5 Mani PB.Hippocampal pyramidal cells and aging in the human :Aquantttative study of neuronal loss in sectors CA1 to CA4[J].Exp Neurol ,1986,94:29~40
6 张雪朝,贺志光,吕明庄,等.血管性痴呆大鼠记忆障碍与海马 Bcl-2 蛋 白 表 达 的 研 究 [J]. 中 国 病 理 生 理 杂志,2002,18(10):1295
7 秦震.神经病学.上海:上海医科大学出版社,2000:193~196
8 赵建新,田元祥,李国明,等.脑缺血再灌注拟血管性痴呆小鼠皮层及海马细胞病理形态学动态观察[J].中风与神经疾病杂志,2000,17(4):200~202
9 Schmidley JW.Free radicals in central nervous system is chaem ia [J].Stroke,1990,21:1086~1091
10 丁克祥 .SOD 临床研究集 [M]. 北京 : 原子能出版社,1992:67~68
11 梁勇.氧自由基与脑损伤和脑水肿[J].国外医学.神经病学神经外科分册,1995,22(20):81~84
12 贾建平,贾健民.阿尔茨海默病和血管性痴呆患者脑脊液中乙酰胆碱和胆碱检测及其临床意义.中华神经科杂志,2002,35(3):168~169
13 Weinberger J, Rosa JN, Cohen G. Nerve terminal damage in cerebral ischemia: Protective effect of alpha-methyl- paratryrosine. Stroke ,1985,16(5):864
14 Harik SI, Yoshida S,Busto R, Monoamine neurotransmitters in diffuse reversible forbrain ischemia and early recirculation: Increased dopaminergic activity. Neurology1986,36:971
15 Bielenberg GW, Burkharct M. 5-hydroxytryptamine agonists. A new therapeutic principle for stroke treatment.Stroke, 1990,21(12): 161
16 陈光辉,饶明俐,韩漫本,等.大鼠可逆性全脑缺血再灌注过程中几个脑区儿茶酚胺递质的动态变化.中风与神经疾病杂志, 1996,13(3):133~136
17 Gustafson I,Westerberg E,Wieloch T.Protection against ischemia-induced neuronal damage by the alpha- adrenoceptor antagonist idazoxan:influence of time of administration and possible mechanisms of action. Cereb Blood Flow Metab,1990,10(6):885
18 吴继全,张力,杨晓晖等.启神胶囊对全脑反复缺血再灌注大鼠脑内单胺类神经递质含量的影响.山东生物医学工程,2002,21(2):31~33
19 张云岭,梅建勋.近10年来中医对血管性痴呆的临床研究进展.北京中医药大学学报,1997,20(3):52~55
20 王永炎,刘金民,谢颖桢.中风病智能障碍的中医康复.北京中医药大学校庆40周年论文汇编.北京:学苑出版社,1996:561~566
21 谢颖桢,邹忆怀,张云岭.血管性痴呆病因病机探讨.北京中医药大学学报,2000,23(6):1
22 王永炎,刘金民,谢颖桢.中风智能障碍的中医康复.北京中医药大学校庆40周年论文汇编.北京:学苑出版社,1996:561
23 唐启盛,王永炎,黄启福.浊毒闭阻脑络对老年期痴呆的影响.北京中医药大学学报,1997,20(6):24
24 雷燕,黄启福,王永炎.论瘀毒阻络是络病形成的病理基础.北京中医药大学学报,1999,22(2):8
25 颜德馨,吕立言.老年性痴呆与瘀血的关系.辽宁中医杂志,1991,18(8):37
26 夏泉,张平,李绍平,等.当归的药理作用研究进展.时珍国医国药,2004,15(3):164~165
27 So Young Kang, Ki Yong Lee, Mi Jung Park, et al. Decursin from A ngelica gigas mitigates mnesia induced by scopo lamine in mice[J]. Neurobiology of Learning and Memory, 2003, 79: 11~18
28 杨 勤 , 赵 朝 伟 . 丹 参 的 药 理 作 用 研 究 现 状 . 中 国 药业,2003,12(10):78
29 吁文贵,徐理纳.乙酰丹酚酸A对血小板花生四烯酸代谢的影响[J].药学学报,1998,33(1):62
30 杨怡静,王玲.丹参、藻酸双酯钠、低分子右旋糖酐、甘露醇对红细胞悬浮液粘弹特性的影响[J].华西医科大学学报,1993,24(2):143
31 尹宝光.水蛭对实验性脑水肿及皮下血肿的影响[J].中西医结合杂志,1986,6(7):407
32 周金黄,王筠默.中药药理学[M].上海:上海科学技术出版社,1986,(1):181
33 方永奇,匡忠生,谢宇辉,等.石菖蒲对缺血再灌注脑损伤大鼠 神 经 细 胞 凋 亡 的 影 响 . 现 代 中 西 医 结 合 杂志,2002,11(17):1647~1649
34 景玉宏,冯慎远,汤晓琴.石菖蒲对学习记忆的影响及突触机制.中国中医基础医学杂志,2002,8(6):38~41
35 唐洪梅,席萍,吴敏,等.石菖蒲对小鼠脑组织氨基酸类神经递质的影响.中药新药与临床药理,2004,15(5):310~311
36 刘治军,张丽,李林.中药何首乌的药理作用研究进展.中华名医论坛,2004,5(6):6~7
37 楚晋,叶翠飞,李林.《二苯乙烯苷对痴呆小鼠学习记2003,9(11):643~645
38 刘治军,李林,叶翠飞,王育琴《.二苯乙烯苷对脑缺血再灌注沙土鼠学习记忆功能及NMDA受体亲合力的影响》,《中国新药杂志》,2004,13(3):223~226
39 KiyoharaY. Prevalence , incidence, and risk factors of vascular dementia: the Hisayama study. Clin Neurol, 1999, 39:47~49
40 WooJ I, LeeJH, Yoo KY, etal. Prevalence estimation of dementia in a rural area of Korea. J American GeriatricsSociety,1998,46:983~987
41 盛树力.老年性痴呆的治疗和护理.北京:科学技术文献出版社,2000:176~185
42 周兰兰,明亮,江勤.银杏叶提取物对反复脑缺血再灌注损伤的保护作用.中国中西医结合杂志,2000,20(5):356~358
1 王兴华,李露斯.两种大鼠2-VO模型制作方法的比较[J].第三军医大学学报,2004,24(12):1496
2 李巍,张世仪,赵惠敏,等.小鼠缺血性学习记忆障碍模型的建立[J].基础医学与临床,1995,15(6):46
3 王蕊,杨秦飞,唐一鹏,等.大鼠拟“血管性痴呆”模型的改进[J].中国病理生理杂志,2000,16(10):914
4 唐启盛,黄启福,郭建文.高脂血症大鼠脑缺血再灌流诱发行为 学 障 碍 模 型 的 实 验 研 究 [J]. 北 京 中 医 药 大 学 学报,1997,20(5):34
5 Pulsinelli WA, Brierley JB. A new model of bilateral hemispheric ischemia in the unanesthetized rat [J]. Stroke, 1979,10:267~272
6 Lestage P, Lockhart B, Roger A. In vivo exploration of cerebral ischemia:use of neuroprotective agents in animal studies [J]. Therapie, 2002,57:554~563
7 Longa EZ, Weinstein in PR, Carlson S, etal. Reversible middle cerebral artery occlusion without craniectomy in rats[J]. Stroke,1989,20(1):84~91
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