【作者】 张吉仲；

【导师】 彭成；

【作者基本信息】 成都中医药大学 ， 方剂学， 2009， 博士

【摘要】 目的：研究益智五海胶囊对血管性痴呆动物模型学习记忆行为学的影响；对模型动物的学习记忆相关神经递质——海马的Ach、AchE,大脑皮层单胺类递质5-HT、DA、NE的影响；对模型动物神经毒性相关递质——海马Glu、Gly、GABA、Asp的影响；对影响血液循环的相关血管活性物质ET、CGRP、TXB₂、6-Keto-PGF_1α以及血液流变性的影响；对肾精亏虚动物模型和记忆障碍动物模型的学习记忆的行为学的影响及体重增长、游泳时间、血液中ChE的影响,进而探求益智五海胶囊治疗血管性痴呆的的作用机制。方法：在结扎双侧颈总动脉（CCA）的基础上建立改良的缺血再灌注血管性痴呆大鼠模型、脉络瘀滞合并缺血再灌注血管性痴呆大鼠模型；建立老年肾精亏虚大鼠模型和氢化可的松肾虚小鼠模型；建立记忆获得障碍小鼠模型、记忆巩固障碍大鼠模型、记忆再现缺失小鼠模型。用跳台法、Morris水迷宫法、避暗法检测空间学习记忆的行为学指标；用ELISA法测定海马中Ach的含量,分光光度法测定海马中AchE的含量,荧光分光光度法测定大脑皮层5-HT、DA、NE的含量；用毛细管电泳法测定海马中Glu、Gly、GABA、Asp含量；放射免疫法测定血液ET、CGRP、TXB₂、6-Keto-PGF_1α的含量；测定血液流变性；测定氢化可的松肾虚小鼠游泳时间、脏器指数等。用喜得镇作阳性对照药物。采用SPSS11.5进行单因素方差分析法统计实验结果。结果：益智五海胶囊高剂量组的模型动物海马内Ach含量明显升高,与模型组比较差异显著（p＜0.05）：益智五海胶囊中、高剂量组对缺血再灌注血管性痴呆大鼠模型的NE的升高作用显著（P＜0.05）；益智五海胶囊各给药组升高CGRP、6-Keto PGF_1α的作用显著（P＜0.05）；益智五海胶囊中、高剂量组降低TXB2作用显著（P＜0.05）；但是对ET的降低效果不显著（P＞0.05）；益智五海胶囊各给药组降低全血低切还原粘度,全血低切相对粘度,血浆粘度（P＜0.05）；降低海马Glu、Asp的含量,升高Gly的海量（P＜0.05）；益智五海胶囊各给药组延长肾虚小鼠的游泳时间（P＜0.05）；益智五海胶囊各给药组行为学检测的逃避潜伏期等具较模型组有显著差异（P＜0.05）。结论：益智五海胶囊具有补肾益智、通脉活络,通过补肾精、通瘀滞、化痰浊、通经络、舒滞气,使肾精得补,脑髓得养,瘀血得化,痰浊可除,玄府得开,脉络得通,智力得复。可以改善动物模型空间学习记忆功能,提高动物模型的智力,其机制可能为：增加海马Ach的含量和大脑皮层的NE含量,同时,可降低血液中ChE的含量,维持海马神经元的信息传递和胆碱能神经功能的完整性,降低动物模型海马Glu、Asp的含量,提高Gly的含量,减轻氨基酸毒性对海马的损伤,从而维持神经组织功能的完整性。调节血管活性物质CGRP和ET、TXA₂和PGI₂含量,即升高CGRP、PGI₂含量,降低ET、TXA₂的含量；扩张血管,提高血液的流变性,改善血液循环,从而改善脑组织的血供和氧供,减轻脑组织因缺血缺氧造成的损伤。更多还原

【Abstract】 Objective:To investigate the Yizhiwuhai capsules treat animal model of vascular dementia study learning and memory in the hippocampus of the intervention and of Ach, AchE, Glu, Gly, GABA, Asp impact; of monoamine neurotransmitters in the cerebral cortex 5-HT, DA, NE impact; of related vasoactive substances ET, CGRP, TXB2,6-Keto-PGF1αimpact; on Hemorheology; on the effects of ChE in blood, and then to explore the Yizhiwuhai capsules in treatment of vascular dementia of the mechanism of action.Methods:The establishment of an improved bilateral ligation of carotid artery (CCA) of the result of ischemia-reperfusion rat model of vascular dementia, Mailuoning stasis combined ischemia-reperfusion rat model of vascular dementia, senile rat model of essence and memory deficiency mouse model of access barriers, obstacles to the consolidation of memory in rat model, loss of memory in mice model of reproduction, with Morris water maze method, platform method, to avoid detection dark spatial learning and memory behavior of the indicators; measured by capillary electrophoresis in the hippocampus Glu, Gly, GABA, Asp content, ELISA method in the Ach content of the hippocampus, the hippocampus in the Determination of the content of AchE, fluorescence spectrophotometric determination of the cerebral cortex 5-HT, DA, NE content. Blood measured by radioimmunoassay ET, CGRP, TXB2,6-Keto-PGF1αcontent. Kidney hydrocortisone injection to establish a mouse model to determine their swimming time, organ index. Hydergine used for positive control drug.SPSS11.5 conducted using one-way ANOVA statistical analysis of experimental results.Results:The model and the control group, Yizhiwuhai capsule high dose of acetylcholine in hippocampus were significantly increased compared with the model group significantly different (p<0.05); middle-and high-dose group of vascular ischemia-reperfusion dementia rat model of the role of NE significantly increased (P <0.05); the treatment group increased CGRP,6-Keto PGFla significant role (P< 0.05); middle-and high-dose group TXB2 significantly lower (P<0.05); However, lowering the effect of ET was not significant (P>0.05); of drug-treated to reduce whole blood low-shear reduced viscosity, a relatively low shear whole blood viscosity (P<0.05), plasma viscosity (P<0.05); Reduce hippocampal Glu, Asp content increased Gly mass (P<0.05), of drug-treated to extend the swimming time in mice Kidney; study of the treatment group behavior, such as detection of the escape latency differences were significant (P<0.05).Conclusions:The Yizhiwuhai capsule with Bushen Yizhi, Tongmai active through the kidney essence, Qualcomm stasis, and phlegm, pass the meridian, Shu Qi stagnation, so that a premium essence, brains were raised, was of blood, turbidity can be eliminated, too Xuanfu open, pass a context, a resumption of intelligence. Animal models can improve.spatial learning and memory functions, improve the animal model of intelligence, which may be as follows:increasing seahorse Ach content and the cerebral cortex NE content, simultaneously, may reduce in the blood the ChE content, the maintenance seahorse neuron information transmission and the choline can the nerve function integrity, reduces animal model seahorse Glu, the Asp content, enhances Gly the content, reduces the amino acid toxicity to seahorse’s damage, thus maintenance nervous tissue function integrity.Adjustment blood vessel active material CGRP and ET, TXA2 and the PGI2 content, namely elevates CGRP, the PGI2 content, reduces ET, the TXA2 content; The expansion blood vessel, the improvement blood circulation, guaranteed the brain organizes because the blood supply, reduces the brain organization to lack the damage which the anoxemia creates; Enhances the blood the rheological property, thus improves the blood which the brain organizes for with the oxygen to supply.更多还原