川芎嗪注射液改善血管性痴呆模型大鼠学习记忆及其作用机制研究
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摘要
目的:通过川芎嗪注射液对血管性痴呆模型大鼠的行为学、神经生化及病理形态指标的影响的实验研究,探讨川芎嗪注射液治疗血管性痴呆的相关作用机制。
方法:健康的雄性Wistar大鼠80只,随机分为八组,即正常组、假手术组、模型组、脑复康组、尼莫地平组、川芎嗪注射液低剂量组、川芎嗪注射液中剂量组、川芎嗪注射液高剂量组。采用腹腔注射硝普钠后反复夹闭双侧颈总动脉造成血管性痴呆大鼠模型。观察用药前后的变化:用跳台仪器检测大鼠行为学;用紫外分光光度计检测脑组织中SOD、MDA、NO、Ca2+的含量;运用放射免疫测定法(RIA)检测脑组织中的ET、CGRP的含量;同时用HE染色观察病理形态学变化。
结果:跳台试验显示,川芎嗪注射液可以改善血管性痴呆模型大鼠的学习记忆能力,指标检测发现提高模型大鼠脑组织SOD的活性,降低MDA的含量;能降低模型大鼠脑组织ET及Ca2+含量,增加CGRP含量,减少NO的产生,与模型组比较,差异有显著性(P<0.05或P<0.01)。川芎嗪注射液高剂量组大鼠脑组织中SOD活力明显高于脑复康组、尼莫地平组、川芎嗪注射液低剂量组(P<0.01);MDA含量明显低于脑复康组、尼莫地平组、川芎嗪注射液低、中剂量组(P<0.05或P<0.01);Ca2+含量明显低于川芎嗪注射液低、中剂量组(P<0.05);ET含量明显少于脑复康组、川芎嗪注射液低剂量组(P<0.05);CGRP含量明显高于脑复康组、川芎嗪注射液低、中剂量组(P<0.05或P<0.01)。川芎嗪注射液中剂量组大鼠脑组织中MDA含量明显低于脑复康组(P<0.05)。结论:川芎嗪注射液具有改善模型大鼠学习记忆的作用,其作用机制主要是增加SOD含量,减少MDA的产生,通过增强组织的抗氧化能力来改善脑损害;降低NO过量生成,减少神经细胞毒性因子的含量,避免细胞死亡;降低ET及Ca2+含量,增加CGRP含量,改善脑血管舒缩功能,保护脑缺血组织。从总体看川芎嗪注射液高剂量组的治疗效果要优于川芎嗪注射液中、低剂量组,在改善模型大鼠SOD、MDA、ET、CGRP生化指标的效果要优于脑复康组,同时比尼莫地平组有明显提高SOD活力,降低MDA的作用。
Objective: To investigate the effect mechanism of Chuanxiongqin injection for the treatment of vascular dementia in animal model by means of the experimental study on the effect of the behavioral experiment , some biochemical substance in brain tissue of rats and the pathology morphological changes of brain tissue.
Methods: 80 male Wistar rats were randomized into 8 groups which were categorized as follows: (1)normal group; (2)sham-operated group; (3)model group;(4) Piracetam treated group; (5) Nimodipine treated group; (6)low dose of Chuanxiongqin injection treated group; (7)middle dose of Chuanxiongqin injection treated group; (8) high dose of Chuanxiongqin injection treated group. After intraperitoneal injection of low dose of sodium nitroprusside, animal models of vascular dementia were established by clamping common carotid arteries repeatedly. After the use of medicine, some changes were observed: observe the performance record of learning and memory by the step-down avoidance test; the content of SOD、MDA、NO、Ca2+ in brain tissue were detected by means of UV spectrometer; the levels of ET、CGRP in brain tissue were detected by means of radioimmunassay(RIA); meanwhile the pathology morphological changes of brain tissue were observed under optical microscope in HE staining.
Result: After treated by Chuanxiongqin injection, the learning and memory ability could be improved by the test of step-down avodiance; Chuanxiongqin injection could significantly enhance the activity of SOD,reduce the content of MDA,reduce the levels of ET and Ca2+ obviously,increase the CGRP content and lower the content of NO,compared with model group. (P<0.05 or P<0.01). The level of SOD in brain tissue of high dose of Chuanxiongqin injection treated group was higher than Piracetam treated group, Nimodipine treated group and low dose of Chuanxiongqin injection treated group(P<0.01);MDA level of high dose group was lower than Piracetam treated group, Nimodipine treated group,low and middle dose of Chuanxiongqin injection treated group(P<0.05 or P<0.01);Ca2+ level of high dose group was lower than low and middle dose of Chuanxiongqin injection treated group(P<0.05);ET level of high dose group was lower than Piracetam treated group and low dose of Chuanxiongqin injection treated group(P<0.05);CGRP level of high dose group was higher than Piracetam treated group , low and middle dose of Chuanxiongqin injection treated group(P<0.05 or P<0.01). The level of MDA in brain tissue of middle dose of Chuanxiongqin injection treated group was lower than Piracetam treated group(P<0.05).
Conclusion: Chuanxiongqin injection has the function of improving the learing-memory ability in model rats, its function mechanism mainly increases the SOD content, reduces the production of MDA,and improve brain injury by strengthening the ability of brain tissue anti-oxidation;decreasing the level of NO so that toxic factors which followed were alleviated in the nerve cells and avoided the death of cell;lessen the contents of ET and Ca2+ and enhance the content of CGRP in brain tissue so that the cerebrovascular function could be amended. On the whole the effect of high dose of Chuanxiongqin injection treated vascular dementia in animal model was better than the effect of low and middle dose group. The effect of improving the level of SOD、MDA、ET、CGRP in rats treated by high dose of Chuanxiongqin injection was better than in rats treated by Piracetam.At the same time compared with Nimodipine treated group, high dose of Chuanxiongqin injection treated group could increase the SOD content and lower the level of MDA obviously.
方法:健康的雄性Wistar大鼠80只,随机分为八组,即正常组、假手术组、模型组、脑复康组、尼莫地平组、川芎嗪注射液低剂量组、川芎嗪注射液中剂量组、川芎嗪注射液高剂量组。采用腹腔注射硝普钠后反复夹闭双侧颈总动脉造成血管性痴呆大鼠模型。观察用药前后的变化:用跳台仪器检测大鼠行为学;用紫外分光光度计检测脑组织中SOD、MDA、NO、Ca2+的含量;运用放射免疫测定法(RIA)检测脑组织中的ET、CGRP的含量;同时用HE染色观察病理形态学变化。
结果:跳台试验显示,川芎嗪注射液可以改善血管性痴呆模型大鼠的学习记忆能力,指标检测发现提高模型大鼠脑组织SOD的活性,降低MDA的含量;能降低模型大鼠脑组织ET及Ca2+含量,增加CGRP含量,减少NO的产生,与模型组比较,差异有显著性(P<0.05或P<0.01)。川芎嗪注射液高剂量组大鼠脑组织中SOD活力明显高于脑复康组、尼莫地平组、川芎嗪注射液低剂量组(P<0.01);MDA含量明显低于脑复康组、尼莫地平组、川芎嗪注射液低、中剂量组(P<0.05或P<0.01);Ca2+含量明显低于川芎嗪注射液低、中剂量组(P<0.05);ET含量明显少于脑复康组、川芎嗪注射液低剂量组(P<0.05);CGRP含量明显高于脑复康组、川芎嗪注射液低、中剂量组(P<0.05或P<0.01)。川芎嗪注射液中剂量组大鼠脑组织中MDA含量明显低于脑复康组(P<0.05)。结论:川芎嗪注射液具有改善模型大鼠学习记忆的作用,其作用机制主要是增加SOD含量,减少MDA的产生,通过增强组织的抗氧化能力来改善脑损害;降低NO过量生成,减少神经细胞毒性因子的含量,避免细胞死亡;降低ET及Ca2+含量,增加CGRP含量,改善脑血管舒缩功能,保护脑缺血组织。从总体看川芎嗪注射液高剂量组的治疗效果要优于川芎嗪注射液中、低剂量组,在改善模型大鼠SOD、MDA、ET、CGRP生化指标的效果要优于脑复康组,同时比尼莫地平组有明显提高SOD活力,降低MDA的作用。
Objective: To investigate the effect mechanism of Chuanxiongqin injection for the treatment of vascular dementia in animal model by means of the experimental study on the effect of the behavioral experiment , some biochemical substance in brain tissue of rats and the pathology morphological changes of brain tissue.
Methods: 80 male Wistar rats were randomized into 8 groups which were categorized as follows: (1)normal group; (2)sham-operated group; (3)model group;(4) Piracetam treated group; (5) Nimodipine treated group; (6)low dose of Chuanxiongqin injection treated group; (7)middle dose of Chuanxiongqin injection treated group; (8) high dose of Chuanxiongqin injection treated group. After intraperitoneal injection of low dose of sodium nitroprusside, animal models of vascular dementia were established by clamping common carotid arteries repeatedly. After the use of medicine, some changes were observed: observe the performance record of learning and memory by the step-down avoidance test; the content of SOD、MDA、NO、Ca2+ in brain tissue were detected by means of UV spectrometer; the levels of ET、CGRP in brain tissue were detected by means of radioimmunassay(RIA); meanwhile the pathology morphological changes of brain tissue were observed under optical microscope in HE staining.
Result: After treated by Chuanxiongqin injection, the learning and memory ability could be improved by the test of step-down avodiance; Chuanxiongqin injection could significantly enhance the activity of SOD,reduce the content of MDA,reduce the levels of ET and Ca2+ obviously,increase the CGRP content and lower the content of NO,compared with model group. (P<0.05 or P<0.01). The level of SOD in brain tissue of high dose of Chuanxiongqin injection treated group was higher than Piracetam treated group, Nimodipine treated group and low dose of Chuanxiongqin injection treated group(P<0.01);MDA level of high dose group was lower than Piracetam treated group, Nimodipine treated group,low and middle dose of Chuanxiongqin injection treated group(P<0.05 or P<0.01);Ca2+ level of high dose group was lower than low and middle dose of Chuanxiongqin injection treated group(P<0.05);ET level of high dose group was lower than Piracetam treated group and low dose of Chuanxiongqin injection treated group(P<0.05);CGRP level of high dose group was higher than Piracetam treated group , low and middle dose of Chuanxiongqin injection treated group(P<0.05 or P<0.01). The level of MDA in brain tissue of middle dose of Chuanxiongqin injection treated group was lower than Piracetam treated group(P<0.05).
Conclusion: Chuanxiongqin injection has the function of improving the learing-memory ability in model rats, its function mechanism mainly increases the SOD content, reduces the production of MDA,and improve brain injury by strengthening the ability of brain tissue anti-oxidation;decreasing the level of NO so that toxic factors which followed were alleviated in the nerve cells and avoided the death of cell;lessen the contents of ET and Ca2+ and enhance the content of CGRP in brain tissue so that the cerebrovascular function could be amended. On the whole the effect of high dose of Chuanxiongqin injection treated vascular dementia in animal model was better than the effect of low and middle dose group. The effect of improving the level of SOD、MDA、ET、CGRP in rats treated by high dose of Chuanxiongqin injection was better than in rats treated by Piracetam.At the same time compared with Nimodipine treated group, high dose of Chuanxiongqin injection treated group could increase the SOD content and lower the level of MDA obviously.
引文
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6 Emsley HC, Tyrrell PJ, Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab, 2002, 22(12): 1399-1419.
7 Shen XJ, Han GY, Lu XQ, et al. The effect of Jiangzhitongmai on atheroscle- rosis. XiandaiKangfu, 2001, 5(6A): 71.
8 Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res, 2001, 89(9): 63-71.
9 Paterson JR, Lawrence JR. Endogenous salicylates, asprin, and inflammation. Arch Intern Med, 2002, 162(13): 1531-1532.
10 Kharbanda RK, Walton B, Allen M, et al. Prevention of inflammation-induced endothelial dysfunction: a novel vasculo-protective action of aspirin. Circulation, 2002, 105(22): 2600-2604.
11 Tick H,zhomberg GL,Jick SS, et al. Statins and the risk of dementia Lancet, 2000, 356: 1627-1631.
12 Rockwood K, Kirkland S, Hogan DB, et al. Use of lip id-lowe ring agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol, 2002, 59: 223-227.
13 Blauw GJ, Laggay AM, Smelt AH, et al. Stroke, statins and cholesterol A meta-analysis of randomized placebo-controlled double-blind trials with HMG-CoA reductase inhibitios. Stroke, 1997, 28: 946-950.
14 Keamey D, Fizgerald D. The anti-thrombotic effect of statins. J Am Cardiol, 1999, 33: 1305-1307.
15 Law MR, Wald NJ, Rudnicka AR, et al. Quantifying effect of statins on low density lipoprote in cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ, 2003, 326: 1423.
16 Bostom AG, Rosenherg IH,Silbershatz H,et al. Nonfasting plasma total homocysteinelevels and stroke incidence in elderlv persons: the Framingham study[J]. Ann Intern Med, 1999. 131: 352-355.
17 Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalam in deficiency in the absence of anemia or macrocytosis[J]. N Engl J Med, 1988, 318: 1720-1728.
18 常林,唐朝枢.高同型半胱氨酸血症与动脉粥样硬化[M]//杨永宗.动脉粥样硬化性心血管病基础与临床.北京:科学出版社, 2004:563-571.
19 Pantoni L, del Ser T, Soglian AG, et al. Efficacy and safety of nimodipine in subcortical vascular dementia: a randomized placebo-controlled trial[J]. Stroke, 2005, 36(3): 619- 624.
20 Rother M, Erkinjuntti T, Roessner M, et al. Propentofllin in the treatment of Alzheimer`s disease and vascular dementia [J]. Dement Geriatr Cogn Disord, 1998, 9 [Suppl]: 36-43.
21 平井俊策.诊断痴呆的进程[J].日本医学介绍, 2005, 26(3): 107-110.
22 Rogers Sl, Farlow MR, Doody RS, et al. A 24- week, double blinded, placebo-controlled trial of donepezil in patients with Alzheimer’s Disease[J]. Neurology, 1998, 50: 136-145.
23 David SG, Clinical experience with donepezil hydrochloride: a case study perspective[J]. Adv Therapy, 1997, 14: 305-311.
24 Togashi H, Matsumoto M, Yoshioka M, et al. Neurochemical profiles in cerebrospinal fluid of stroke-prone spontaneously hypertensive rats. Neurosci Lett, 1994, 166(1): 117-120.
25 Wilcock G, Mobius HJ, Stoffler A. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol, 2002, 17(6): 297-305.
26 Orgogozo J-M, Rigaud A-S, Staffler A, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-con- trolled trial (MMM300). Stroke, 2002, 33(7): 1834-1839.
27 Wilcock G, Mcbius HJ, Staffler A. on behalf of the MMM500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Internat Clin Psychopharmacol, 2002, 17(16): 297-305.
28 MAINAG, FIORIL, TORTAR, et al. Oxiracetam in the treatment of primary degenerative and multi-infarct dementia: a double blind, placebo-controlled study[J]. Neuropsychobiology, 1989, 21(3): 141-145.
29 BOTTINIG, VALLAR G, CAPPA S, et al. Oxiracetam in dementia: a double-blind, placebo-controlled study [J]. Acta Neurol Scand, 1992, 86(3): 237-241.
30 PARNETTI L, MECOCCI P, PETRINI A, et al. Neuropsychobiological results of long-term therapy with oxiracetam in patients with dementia of Alzheimer type and multi-infarct dementia in comparison with a control group[J]. Neuropsycho- biology, 1989, 22(2): 97-100.
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34 Amenta F, Di-Tullio MA, Tomassoni D. The cholinergic approach for the treatment of vascular dementia: evidence from pre-clinical and clinical studies. Clin Exp Hypertens, 2002, 24: 697.
35 D`Orlando KJ, Sandage BW. Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury. Neurol Res, 1995, 17: 281.
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1 Tang W K, Chan SS, Chiu HF, et al. Frequency and determinants of poststroke dementia in Chinese. Stroke, 2004, 35: 930-935.
2 Paul RH, Cohen RA, Moser DJ, et al. Clinical correlates of cognitive decline in vascular dementia. Cogn Behav Neurol, 2003, 16:40-46.
3 Pohjasvaara T, Erkinjuntti T, Vataja R, et al. Dementia three months after stroke. Baseline frequency and effect of different definitions of dementia in the Helsinki Stroke Aging Memory Study (SAM) cohort. Stroke, 1997, 28: 785-792.
4 Gorelick PB. Status of risk factors for dementia associated with stroke. Stroke, 1997, 28(2): 459-463.
5 Tzourio C, Anderson C, Chapman N, et al. Effects of blood pressure lowing with perindopil and indapamide therapy on dementia and cognitive decline in patient with cerebrovasular disease. Arch Interm Med, 2003, 163(9): 1069-1075.
6 Emsley HC, Tyrrell PJ, Inflammation and infection in clinical stroke. J Cereb Blood Flow Metab, 2002, 22(12): 1399-1419.
7 Shen XJ, Han GY, Lu XQ, et al. The effect of Jiangzhitongmai on atheroscle- rosis. XiandaiKangfu, 2001, 5(6A): 71.
8 Blake GJ, Ridker PM. Novel clinical markers of vascular wall inflammation. Circ Res, 2001, 89(9): 63-71.
9 Paterson JR, Lawrence JR. Endogenous salicylates, asprin, and inflammation. Arch Intern Med, 2002, 162(13): 1531-1532.
10 Kharbanda RK, Walton B, Allen M, et al. Prevention of inflammation-induced endothelial dysfunction: a novel vasculo-protective action of aspirin. Circulation, 2002, 105(22): 2600-2604.
11 Tick H,zhomberg GL,Jick SS, et al. Statins and the risk of dementia Lancet, 2000, 356: 1627-1631.
12 Rockwood K, Kirkland S, Hogan DB, et al. Use of lip id-lowe ring agents, indication bias, and the risk of dementia in community-dwelling elderly people. Arch Neurol, 2002, 59: 223-227.
13 Blauw GJ, Laggay AM, Smelt AH, et al. Stroke, statins and cholesterol A meta-analysis of randomized placebo-controlled double-blind trials with HMG-CoA reductase inhibitios. Stroke, 1997, 28: 946-950.
14 Keamey D, Fizgerald D. The anti-thrombotic effect of statins. J Am Cardiol, 1999, 33: 1305-1307.
15 Law MR, Wald NJ, Rudnicka AR, et al. Quantifying effect of statins on low density lipoprote in cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ, 2003, 326: 1423.
16 Bostom AG, Rosenherg IH,Silbershatz H,et al. Nonfasting plasma total homocysteinelevels and stroke incidence in elderlv persons: the Framingham study[J]. Ann Intern Med, 1999. 131: 352-355.
17 Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalam in deficiency in the absence of anemia or macrocytosis[J]. N Engl J Med, 1988, 318: 1720-1728.
18 常林,唐朝枢.高同型半胱氨酸血症与动脉粥样硬化[M]//杨永宗.动脉粥样硬化性心血管病基础与临床.北京:科学出版社, 2004:563-571.
19 Pantoni L, del Ser T, Soglian AG, et al. Efficacy and safety of nimodipine in subcortical vascular dementia: a randomized placebo-controlled trial[J]. Stroke, 2005, 36(3): 619- 624.
20 Rother M, Erkinjuntti T, Roessner M, et al. Propentofllin in the treatment of Alzheimer`s disease and vascular dementia [J]. Dement Geriatr Cogn Disord, 1998, 9 [Suppl]: 36-43.
21 平井俊策.诊断痴呆的进程[J].日本医学介绍, 2005, 26(3): 107-110.
22 Rogers Sl, Farlow MR, Doody RS, et al. A 24- week, double blinded, placebo-controlled trial of donepezil in patients with Alzheimer’s Disease[J]. Neurology, 1998, 50: 136-145.
23 David SG, Clinical experience with donepezil hydrochloride: a case study perspective[J]. Adv Therapy, 1997, 14: 305-311.
24 Togashi H, Matsumoto M, Yoshioka M, et al. Neurochemical profiles in cerebrospinal fluid of stroke-prone spontaneously hypertensive rats. Neurosci Lett, 1994, 166(1): 117-120.
25 Wilcock G, Mobius HJ, Stoffler A. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol, 2002, 17(6): 297-305.
26 Orgogozo J-M, Rigaud A-S, Staffler A, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-con- trolled trial (MMM300). Stroke, 2002, 33(7): 1834-1839.
27 Wilcock G, Mcbius HJ, Staffler A. on behalf of the MMM500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Internat Clin Psychopharmacol, 2002, 17(16): 297-305.
28 MAINAG, FIORIL, TORTAR, et al. Oxiracetam in the treatment of primary degenerative and multi-infarct dementia: a double blind, placebo-controlled study[J]. Neuropsychobiology, 1989, 21(3): 141-145.
29 BOTTINIG, VALLAR G, CAPPA S, et al. Oxiracetam in dementia: a double-blind, placebo-controlled study [J]. Acta Neurol Scand, 1992, 86(3): 237-241.
30 PARNETTI L, MECOCCI P, PETRINI A, et al. Neuropsychobiological results of long-term therapy with oxiracetam in patients with dementia of Alzheimer type and multi-infarct dementia in comparison with a control group[J]. Neuropsycho- biology, 1989, 22(2): 97-100.
31 江一帆.奥拉西坦[A].江一帆.世界最新药物手册[M].北京:中国医药科技出版社,1994,381.
32 Rao AM, Hatcher JF, Dempsey RJ. CDP choline: neuroprotection in transient forebrain ischemia of gerbils[J]. Neurisci Res, 1999, 58: 697.
33 Drago F, Mauceri F, Nardo L, et al. Effects of cytidine-diphosphocho- line on acetylcholinemediated behaviors in the rat. Brain Res Bull, 1993, 31: 485.
34 Amenta F, Di-Tullio MA, Tomassoni D. The cholinergic approach for the treatment of vascular dementia: evidence from pre-clinical and clinical studies. Clin Exp Hypertens, 2002, 24: 697.
35 D`Orlando KJ, Sandage BW. Citicoline (CDP-choline): mechanisms of action and effects in ischemic brain injury. Neurol Res, 1995, 17: 281.