摘要
目的：
观察人参川芎注射液对局灶性脑缺血模型大鼠神经的保护作用，并初步探讨其防治中风的作用机理。
方法：
通过电凝大脑中动脉建立脑缺血模型大鼠，设立假手术组、模型组、尼莫地平注射液组、川芎嗪注射液组、人参川芎注射液高、中、低剂量组，观察大鼠脑缺血后的神经功能、脑缺血梗死范围、缺血区形态学及超微结构的影响；以及血清中超氧化物岐化酶(SOD)的活性，丙二醛(MDA)含量，血浆中内皮素-1(ET-1)、脑组织肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)、纤溶酶原激活物抑制剂(PAI-1)、组织型纤溶酶原激活物(t-PA)的水平、脑组织EAA含量。
结果：
1、人参川芎注射液高、中、低剂量组均能显著改善局灶大鼠脑缺血的神经功能障碍，效果优于尼莫地平及川芎嗪(P＜0.05)；降低脑梗死范围，与尼莫地平和川芎嗪无明显差异(P＞0.05)；增加造模14天后大鼠的体重，疗效优于尼莫地平(P＜0.05)，与川芎嗪无明显差异(P＞0.05)。
2、模型组血清SOD活性显著降低、MDA含量显著升高(P＜0.01)。人参川芎注射液能提高血清中SOD的活性，作用优于尼莫地平和川芎嗪(P＜0.05)。降低血清中MDA的含量，与尼莫地平和川芎嗪组无明显差异(P＞0.05)。
3、模型组血浆ET-1含量显著高于假手术组(P＜0.01)，人参川芎注射液可以显著降低血浆ET-1水平，低剂量组与尼莫地平和川芎嗪无明显差异(P＞0.05)，中剂量组优于尼莫地平(P＜0.01)，与川芎嗪无明显差异，而高剂量组则优于尼莫地平(P＜0.01)和川芎嗪(P＜0.05)。
4、模型组脑组织TNF-α及IL-1β含量显著高于假手术组(P＜0.01)。人参川芎注射液可以显著降低脑组织TNF-α及IL-1β含量。人参川芎注射液高、中剂量组降低TNF-α含量优于尼莫地平及低剂量组(P＜0.01)，但与川芎嗪无明显差异(P＞0.05)，降低IL-1β与尼莫地平、川芎嗪无明显差异(P＞0.05)。
5、模型组血浆t-PA含量及活性显著低于假手术组(P＜0.01)，PAI-1显著高于假手术组(P＜0.01)。人参川芎注射液可以提高血浆t-PA含量及活性，降低PAI-1含量。人参川芎注射液提高t-PA含量及活性优于尼莫地平(P＜0.01)，但与川芎嗪无明显差异(P＞0.05)。
6、模型组大鼠脑组织Glu含量显著高于假手术组(P＜0.01)。人参川芎注射液可以降低脑组织中Glu的含量，与尼莫地平及川芎嗪相比，无明显差异(P＞0.05)。
7、人参川芎注射液可以促使缺血大鼠病理形态学改变及超微结构的改变。
溯，匕中医学陇
2001级硕士研究生毕业击文
结论:
人参川首注射液对对局灶性脑缺血损伤具有很好的保护作用，且其综合作
用优于临床常用的尼莫地平注射液组及川芍嗓注射液组。实验结果表明，人参
川首注射液可通过调节血管舒缩因子，减轻自由基损伤，平衡紊乱的纤溶系统，
减轻炎症反应，抑制兴奋性氨基酸含量，降低兴奋性毒性而达到治疗脑缺血损
伤的疗效。
Objective: To study the protective effect and the dose-dependence of Renshen Chuanxiong injection in treating focal cerebral ischemia in rats; and to explore the mechanism of preventing and curing the cerebral ischemia with the theory of Yi Qi Huo Xie of Traditional Chinese medicine.
Methods: Model rats of cerebral ischemia, which were prepared by electionic solidified the middle cerebral artery, were randomly divided into seven groups: the sham control, the model control, the Ligustrazine-treated control, Nimodipine treated control, and three experimental groups of varying injection dose of Renshen Chuanxiong. The neurologic function, the area of necrosis, changes of tissue morphology, and ultrastrcuture of ischemia area, and the level of ET-1, t-P, PAI-1 in plasma , TNF-α, IL-1β,EAA in brain tissue and SOD, MDA in serum were evaluated.
Results: 1. In all three experimental groups, injection of Renshen Chuanxiong reduced the neurological deficits and brain-infracted areas and increased the weight of the rat with local brain ischemia. The results were better than Nimodipine and Ligustrazine-treated group.
2. In Renshen Chuanxiong injection groups, SOD activity significantly increased and MDA level considerably decreased, while in the model control group, the SOD activity decreased and the MDA level increased, the result was better than Nimodipine and Ligustrazine-treated group.
3.Injection of Renshen Chuanxiong significantly decreased ET-1 level in plasma and the result of highest-doze group was better than Nimodipine and Ligustrazine treated group, but there was no significantly difference between low-doze group and Nimodipine and Ligustrazine treated group. The plasma ET-1 level of the model control group was higher than that of the sham control group.
4.Injection of Renshen Chuanxiong significantly decreased TNF-α and IL-1β levels in brain tissue and the result was better than Nimodipine-treated group,
but there was no difference between injection of Renshen Chuanxiong and
Ligustrazine-treated group. The TNF-α and IL-1 β levels of the model control
group were higher than those of the sham control group.
5.Injection of Renshen Chuanxiong increased t-PA concention and activity and decreased PAI-1 concention. The t-PA concention and activity in the model control group was significantly lower than that of the sham control group, while the PAI-1 concention in the model control group was significantly higher than that of the sham control group.
6.Injection of Renshen Chuanxiong decreased Glu level in brain tissue, there was no significantly difference between it and other comparative groups. The Glu level in the model control group was lower than that of the sham control group.
7.Injection of Renshen Chuanxiong could lead to improvent of morphology and ultra-structure of rats with brain ischemia.
Conclusions: Renshen Chuanxiong injection may protect from cerebral ischemia injury in rats, its synthetical propective effect is better than ligustrazine injection and nimodipine injection which is often applied in clinic. Through adjusting the diastolic factor of blood vessel, reducing free radicals harm,EAA in brain tissue, blancing the disorder of plasmin system and lowering antiinflammation action, Renshen Chuanxiong injection attain the effect of treating cerebral ischemia injury.
引文
1．李世绰，程学铭，王文志，等．神经系统疾病流行病学．北京：人民卫生出版社，2000，4
2．蒲传强，郎森阳，吴卫平．脑血管病学．北京：人民军医出版社，1999，6：157
3. Yokozawa T, et al. Hyperlipemia—Improving effects of Ginsenoside—Rb_2 in cholesterol—fed Rats. Chem. Pharm. Bull. 1985;33(2):722
4．史大卓．川芎嗪的临床应用与药理研究．中国中西医结合杂志，2003；23(5)：378-379
5．刘天胤．益气活血法治疗脑中风50例疗效观察．黑龙江中医药 1997(6)14—15
6. Yanagisawa M, kurihara H, kimura S, et al. A novel potent vasoconstriction peptide produced by vascular endothelial cells. Nature, 1988, 322:411
7．张雨梅，谢恺舟，王以兰．桂枝茯苓丸加减方对脑缺血及再灌注过程中Ca~(2+)、氨基酸水平变化的研究．中国中药杂志，1998；23(9)：558．560
8．刘玮，吴华璞，祝晓光，等．白芍总苷对大鼠脑缺血的保护作用．安徽医科大学学报，2001；36(3)：186-188
9．王军，陈国华．脑缺血模型研究进展．中医研究2002，15(5)60-62
10．韩明向，丁灿东，周宜轩．人参皂甙与川芎嗪合用对家兔心肌缺血再灌注损伤的保护作用．中国中医基础医学杂志，2001；1：17-18
11. Wen S R, et al. Effect of ginsenoside Rbl and Rgl on the calcium antagonist receptor from rabbit skeletal muscle. The third China—Japan Joint Hecting on pharmacology. Programme and Abstracts Beijing China 1993 : 97
12．开丽，王中峰，肖家思，等．人参二醇皂甙抗离体大鼠脑缺氧损伤的L—型钙通道阻滞机制．中国药理学报，1998，19(5)：455—458
13．钟平，杨任民．中药川芎嗪治疗急性脑缺血的实验研究．实用全科医学，2003，1(1)：19-20
14．刘天胤．益气活血法治疗脑中风50例疗效观察．黑龙江中医药 1997，(6)：14—15
15．林松波，连祺周，梁晖，等．急性脑梗塞患者血管内皮细胞活性因子的变化和活血化淤对其影响的临床观察．中国中西医结合杂志，1998，18(7)：392—395
16．熊密，朱长庚，蔡秋云，等．脑缺血时大鼠海马及其生长抑素神经元的超微结构改变．解剖学报，1994；25(3)248-251
17. Shinmi O, kimura S, Yoshizawa T, et al. Presence of endotheline-1 in porcine spinal cord: isolation and sequence determination. Biochem Biophys Res Commun, 1989; 162: 340—346.
18. Yanagisawa M, kurihara H, kimura S, et al. A novel potent vasoconstriction peptide produced by vascular endothelial cells. Nature, 1988, 322:411
19. Rakagi H, Tabuchi Y, Nakamani M. Endothelin activates vascular rennin-angiotensin system in rat mesenteric arteries. Biochem Biophys Res
Commun, 1990; 21(5): 867—872
20．谭盛．内皮素与缺血性脑血管病．国外医学·内科学分册，1996；23(3)：107—109
21. Ziv I, Fleminger G, Djaldetti R, et al. Increased Plasma endotheline-1 in acute ischemic stroke. Stroke, 1992; 23:1014—1016
22．汪卫，王立祥，于正龙，等．老年脑梗塞患者血浆内皮素水平的变化及意义．实用老年医学，1996；10(5)：215—216
23．廖春来，佟丽，沈建刚．补阳还五汤抗脑缺血的实验研究进展．中国药物与临床，2003；3(3)：176-178
24. Dashwood M, Turner, M, Tacobs M, et al. Endothelin-1 contractile response and autoradiographic locolization of recepters in rabbit blood vessels. J Cardiovasc Pharmocol, 1989;13(Suppl 5): 183
25. Prasad K, Lee P, Kalra J, et al. Influence of endothelin on cardiovascular function, oxygen free radials and blood chemistry. Am Heart J, 1991;121(1):178
26. Yushida S, Inoh S, Asano T, et al. Effect of transient ischemia on free fatty acids and phospholipids in the gerbil brain[J]. J Neurosurg, 1980,53(3): 323-331
27．张勇，陈金全，吴凯，等．单味川芎治疗脑缺血的研究进展．河北中医，2003：25(6)：471-473
28．陈民利，胡福良，应华忠，等．工蜂虫蛹对大鼠脑、肝、血中SOD活性和MDA含量的影响．浙江中医学院学报，1997；21(3)：30-31
29．禹志领，张广钦，赵红旗．葛根总黄酮对脑缺血的保护作用．中国药科大学学报，1997；28(1)：310-312
30．苏立觊，王淑仙，代瑞亭等．大黄素甲醚对杀土鼠脑缺血损伤时肿瘤坏死因子、白介素表达的影响．中国中西医结合急救杂志。2000；7(1)：46-48
31．陈兴洲，陆兵勋．局灶性脑缺血后再灌注损伤的炎症机制与治疗前景．国外医学脑血管疾病分册；1999；7(3)：136-140
32. Satio K, Suyama K., Nishida K, et al. Early increases in TNF a, IL-6 and IL-1 beta levels following transient cerebral ischemia in gerbil brain. Neurosci Lett 1996; 206:149-152
33. Tetsumei U, Kenichi S, Masaki N. Fluctuation oft-PA and PAI-1 antigen level in plasma: difference of their fluctation patterns between male and female. Thromb Res, 1990;60(2): 133-139
34．曲辉．组织型纤溶酶原激活物及其抑制物与缺血性脑血管病．国外医学·脑血管疾病分册，1997；5(5)：290-293
35．张津，魏岗之，周茗．缺血性脑血管病患者纤溶激活系统系列观察及临床意义．综合临床医学，1995：11(3)：126-128
36．张琦，张颖冬，陈月琴．脑梗死患者血纤溶系统活性指标的改变和预后的关系．临床神经病学杂志，2000；13(2)86-88
37．徐仁四，黄怀均，王凤霞．兴奋性氨基酸与缺血性损伤的研究概况．国外医学神经病学神经外科学分册，1998；25(2)：62-64
38. Salinska E, Lazarexicz JW. NMDA receptor-mediated calcium fluxes in the hippocampus: relevance to ischemia brain pathology. Neurol Neurochir Pol 1996;30 Suppl 2:35-42
39．赵卫国，张天锡．细胞内钙超载与脑缺血损害．上海第二医科大学学报，1990：10(3)：259-263
40. Kristian T, Siesjo BK. Calcium-related damages in ischemia. Life Sci, 1996;59(5-6): 357-367