五脏温阳化瘀汤对动脉粥样硬化血管性痴呆大鼠作用机理的研究
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摘要
血管性痴呆(vascular dementia,ⅤD)是由于各种脑血管病变最终引脑组织的损伤,以获得性智能损害和认知障碍为主要表现的综合征。血管性痴呆为各种脑血管疾病导致的,其中各种疾病导致动脉粥样硬化,最终导致脑血管出现缺血或者缺血再灌注损伤,而致痴呆的发生。因此,我们在动脉粥样硬化的基础上制作血管性痴呆的动物模型,高度模仿了人类临床血管性痴呆的发病机理。
从中医的理论来看,我们根据中医理论中“阳化气,阴成形”认为动脉粥样硬化属阳气虚衰,气化不足,阴成形太过的表现。因此我们运用临床经验方“五脏温阳化瘀汤”对动脉粥样硬化血管性痴呆进行研究和机理探讨。在由动脉粥样硬化导致的血管性痴呆中,氧化应激反应可能是血管性痴呆发病机制中的一个重要的环节。本实验从氧化应激反应中Nrf2/ARE蛋白通路入手,观察五脏温阳化瘀汤对血管性痴呆的保护作用,研究五脏温阳化瘀汤对动脉粥样硬化血管性痴呆的作用机理。
目的：首先建立动脉粥样硬化血管性痴呆大鼠模型,观察不同剂量的五脏温阳化瘀汤对动脉粥样硬化血管性痴呆大鼠的治疗作用,并从氧化应激反应中Nrf2/ARE蛋白通路入手,观察五脏温阳化瘀汤对血管性痴呆的神经保护机制。
方法：首先制作动脉粥样硬化血管性痴呆大鼠模型,健康SD大鼠,雌雄各半,随机分为空白对照组、假手术组、模型组。高脂饲料喂养大鼠,同时在喂食开始时一次性腹腔注射维生素D370IU/kg,造成动脉粥样硬化的模型,之后采用反复夹闭大鼠双侧颈总动脉方法制备血管性痴呆大鼠模型。之后用Morris水迷宫检测大鼠记忆功能,HE染色观察大鼠海马区。手术4周后将大鼠随机分为假手术组、模型组、中药低剂量组、中医药中剂量组、中药高剂量组、脑复康组,灌胃给药。持续4周,进行Morris水迷宫行为学检测,观察各组大鼠空间学习及记忆能力,用生化检测大鼠海马区SOD、MDA、LPO、GSH-PX、 T-AOC等指标,western blot检测大鼠海马区Nrf2蛋白细胞核与细胞浆内的表达,同时检测下游蛋白HO-1蛋白的表达。RT-PCR检测HO-1mRNA的表达,EMSA检测胞核内Nrf2与ARE蛋白的结合力。
结果：(1)五脏温阳化瘀汤中剂量组和高剂量组从第3天开始可以明显缩短动脉粥样硬化血管性痴呆大鼠Morris水迷宫的逃避潜伏期,低剂量组和脑复康阳性药物对照组则没有明显差异,空间搜索实验中药中剂量组和高剂量组有效停留时间和有效停留距离明显延长,低剂量组和脑复康阳性药物对照组则没有明显差异。(2)动脉粥样硬血管性痴呆造模完成后,大鼠海马区产生一系列氧化应激损伤,五脏温阳化瘀汤和脑复康对治疗氧化应激损伤均有一定的效果,但是以中药高剂量组和中剂量组效果显著,能够提高大鼠海马区GSH-PX、 SOD.T-AOC6勺含量,降低LPO、MDA的含量,以保护大鼠海马区氧化应激的损伤。(3)动脉粥样硬化血管性痴呆大鼠海马区Nrf2-ARE通路被激活,Western blot检测显示五脏温阳化瘀汤可以使Nrf2蛋白由胞浆转移到胞核内,并激活下游蛋白HO-1,使其表达增强。RT-PCR检测HO-1mRNA表达增强。(4)用EMSA法测定胞核内Nrf2-ARE的结合力,结果显示五脏温阳化瘀汤能够使胞核内Nrf2/ARE结合力增强。
结论：五脏温阳化瘀汤能改善动脉粥样硬化血管性痴呆大鼠学习记忆能力,其作用机理可能与抑制动脉粥样硬化血管性痴呆大鼠的氧化应激反应,增强脑组织的抗氧化防御机制有关,其中剂量组和高剂量组作用显著。
Vascular dementia(VD),resulting from brain loss caused by varieties of cerebrovascular diseases, is an acquired intelligent damage syndrome and cognitive function defect.Cerebrovascular diseases lead to atherosclerosis, and ischemia or ischemia-reperfusion injury will appear, which results in dementia. In this case, VD animal models,based on atherosclerosis, were made in our research, to highly imitate the pathogenesis of VD.
According to "yang transforming qi while yin constituting form" in Chinese traditional medical, atherosclerosis is caused by the inadequacy of yang and yang transforming and the over dose of yin. Therefore,"wu zang wen yang hua yu tang" was applied in the study of atherosclerosis VD. Oxidative stress is probably an important factor of VD. In the experiment, the researcher began with Nrf2/ARE pathway to observe therapeutic the effect of Visceral Wenyang Huayu Decoction on VD and the mechanism.
Objective:firs, develope a rat model of VD and observe therapeutic effect of different doses of Visceral Wenyang Huayu Decoction on these rats; second, from the aspect of Nrf2/ARE pathway in oxidative stress, examine the decoction's defense mechanism against VD nerves.
Method:Healthy SD rats with half males and half females were divided randomly into a sedentary control group, a sham-operated group and a model group, and fed on high-fat diet with an intraperitoneal injection of70IU/kg vitamin D3. Then the VD rat models were established by repeatedly cerebral ischemia. Then Morris water maze was applied to testing the memories of rats, HE staining was used to observe their hippocampus.Four weeks later, these rats were divided randomly into a sham-operated group, a sedentary control group, a low-doses group, a middle-dose group, a high-dose group, and a Piracetam treated group. After4weeks'gastric perfusion, their spatial learning and memory function were tested by the Morris water maze. Biochemical detection was used to examine the standards of their SOD, MDA, LPO, GSH-PX, and T-AOC, while western blot to examine the expression of Nrf2protein in the nucleus and cytoplasm, and the expression of HO-1protein. RT-PCR was used to test the expression of HO-1mRNA, and EMS A to combining power between Nrf2and ARE.
Result:(1) In the middle-dose group and the high-dose group, the rats'escape latent periods in Morris maze were shortened from the third day on, while in the low-doses group and the Piracetam treated group, no obvious change appeared. In spatial search test, the stay and distance were lengthened, while in low-doses group and the Piracetam treated group there was no significant difference.(2) In the treatment, Visceral Wenyang Huayu Decoction had active effect on the oxidative stress damage in the hippocampus of rats, especially for high-doses and low-dose groups. It could increase GSH-PX. SOD、T-AOC and lower in the hippocampus to protect it from oxidative stress damage.(3) Nrf2/ARE pathway in hippocampus of VD rats were activated. In Western blot test, it was found that Visceral Wenyang Huayu Decoction could transport Nrf2protein from cytoplasm to nucleus. The decoction could also activate HO-1and strengthen its expression, according to RT-PCR test in HO-1mRNA.(4) In the EMS A test, it was showed that the decoction could also strengthen the combining power between Nrf2and ARE.
Conclusion:Visceral Wenyang Huayu Decoction can improve the learning and memory ability of VD rats. It may concern the oxidative stress reaction and antioxidant mechanism in VD rats, especially in high-doses and low-dose groups.
从中医的理论来看,我们根据中医理论中“阳化气,阴成形”认为动脉粥样硬化属阳气虚衰,气化不足,阴成形太过的表现。因此我们运用临床经验方“五脏温阳化瘀汤”对动脉粥样硬化血管性痴呆进行研究和机理探讨。在由动脉粥样硬化导致的血管性痴呆中,氧化应激反应可能是血管性痴呆发病机制中的一个重要的环节。本实验从氧化应激反应中Nrf2/ARE蛋白通路入手,观察五脏温阳化瘀汤对血管性痴呆的保护作用,研究五脏温阳化瘀汤对动脉粥样硬化血管性痴呆的作用机理。
目的：首先建立动脉粥样硬化血管性痴呆大鼠模型,观察不同剂量的五脏温阳化瘀汤对动脉粥样硬化血管性痴呆大鼠的治疗作用,并从氧化应激反应中Nrf2/ARE蛋白通路入手,观察五脏温阳化瘀汤对血管性痴呆的神经保护机制。
方法：首先制作动脉粥样硬化血管性痴呆大鼠模型,健康SD大鼠,雌雄各半,随机分为空白对照组、假手术组、模型组。高脂饲料喂养大鼠,同时在喂食开始时一次性腹腔注射维生素D370IU/kg,造成动脉粥样硬化的模型,之后采用反复夹闭大鼠双侧颈总动脉方法制备血管性痴呆大鼠模型。之后用Morris水迷宫检测大鼠记忆功能,HE染色观察大鼠海马区。手术4周后将大鼠随机分为假手术组、模型组、中药低剂量组、中医药中剂量组、中药高剂量组、脑复康组,灌胃给药。持续4周,进行Morris水迷宫行为学检测,观察各组大鼠空间学习及记忆能力,用生化检测大鼠海马区SOD、MDA、LPO、GSH-PX、 T-AOC等指标,western blot检测大鼠海马区Nrf2蛋白细胞核与细胞浆内的表达,同时检测下游蛋白HO-1蛋白的表达。RT-PCR检测HO-1mRNA的表达,EMSA检测胞核内Nrf2与ARE蛋白的结合力。
结果：(1)五脏温阳化瘀汤中剂量组和高剂量组从第3天开始可以明显缩短动脉粥样硬化血管性痴呆大鼠Morris水迷宫的逃避潜伏期,低剂量组和脑复康阳性药物对照组则没有明显差异,空间搜索实验中药中剂量组和高剂量组有效停留时间和有效停留距离明显延长,低剂量组和脑复康阳性药物对照组则没有明显差异。(2)动脉粥样硬血管性痴呆造模完成后,大鼠海马区产生一系列氧化应激损伤,五脏温阳化瘀汤和脑复康对治疗氧化应激损伤均有一定的效果,但是以中药高剂量组和中剂量组效果显著,能够提高大鼠海马区GSH-PX、 SOD.T-AOC6勺含量,降低LPO、MDA的含量,以保护大鼠海马区氧化应激的损伤。(3)动脉粥样硬化血管性痴呆大鼠海马区Nrf2-ARE通路被激活,Western blot检测显示五脏温阳化瘀汤可以使Nrf2蛋白由胞浆转移到胞核内,并激活下游蛋白HO-1,使其表达增强。RT-PCR检测HO-1mRNA表达增强。(4)用EMSA法测定胞核内Nrf2-ARE的结合力,结果显示五脏温阳化瘀汤能够使胞核内Nrf2/ARE结合力增强。
结论：五脏温阳化瘀汤能改善动脉粥样硬化血管性痴呆大鼠学习记忆能力,其作用机理可能与抑制动脉粥样硬化血管性痴呆大鼠的氧化应激反应,增强脑组织的抗氧化防御机制有关,其中剂量组和高剂量组作用显著。
Vascular dementia(VD),resulting from brain loss caused by varieties of cerebrovascular diseases, is an acquired intelligent damage syndrome and cognitive function defect.Cerebrovascular diseases lead to atherosclerosis, and ischemia or ischemia-reperfusion injury will appear, which results in dementia. In this case, VD animal models,based on atherosclerosis, were made in our research, to highly imitate the pathogenesis of VD.
According to "yang transforming qi while yin constituting form" in Chinese traditional medical, atherosclerosis is caused by the inadequacy of yang and yang transforming and the over dose of yin. Therefore,"wu zang wen yang hua yu tang" was applied in the study of atherosclerosis VD. Oxidative stress is probably an important factor of VD. In the experiment, the researcher began with Nrf2/ARE pathway to observe therapeutic the effect of Visceral Wenyang Huayu Decoction on VD and the mechanism.
Objective:firs, develope a rat model of VD and observe therapeutic effect of different doses of Visceral Wenyang Huayu Decoction on these rats; second, from the aspect of Nrf2/ARE pathway in oxidative stress, examine the decoction's defense mechanism against VD nerves.
Method:Healthy SD rats with half males and half females were divided randomly into a sedentary control group, a sham-operated group and a model group, and fed on high-fat diet with an intraperitoneal injection of70IU/kg vitamin D3. Then the VD rat models were established by repeatedly cerebral ischemia. Then Morris water maze was applied to testing the memories of rats, HE staining was used to observe their hippocampus.Four weeks later, these rats were divided randomly into a sham-operated group, a sedentary control group, a low-doses group, a middle-dose group, a high-dose group, and a Piracetam treated group. After4weeks'gastric perfusion, their spatial learning and memory function were tested by the Morris water maze. Biochemical detection was used to examine the standards of their SOD, MDA, LPO, GSH-PX, and T-AOC, while western blot to examine the expression of Nrf2protein in the nucleus and cytoplasm, and the expression of HO-1protein. RT-PCR was used to test the expression of HO-1mRNA, and EMS A to combining power between Nrf2and ARE.
Result:(1) In the middle-dose group and the high-dose group, the rats'escape latent periods in Morris maze were shortened from the third day on, while in the low-doses group and the Piracetam treated group, no obvious change appeared. In spatial search test, the stay and distance were lengthened, while in low-doses group and the Piracetam treated group there was no significant difference.(2) In the treatment, Visceral Wenyang Huayu Decoction had active effect on the oxidative stress damage in the hippocampus of rats, especially for high-doses and low-dose groups. It could increase GSH-PX. SOD、T-AOC and lower in the hippocampus to protect it from oxidative stress damage.(3) Nrf2/ARE pathway in hippocampus of VD rats were activated. In Western blot test, it was found that Visceral Wenyang Huayu Decoction could transport Nrf2protein from cytoplasm to nucleus. The decoction could also activate HO-1and strengthen its expression, according to RT-PCR test in HO-1mRNA.(4) In the EMS A test, it was showed that the decoction could also strengthen the combining power between Nrf2and ARE.
Conclusion:Visceral Wenyang Huayu Decoction can improve the learning and memory ability of VD rats. It may concern the oxidative stress reaction and antioxidant mechanism in VD rats, especially in high-doses and low-dose groups.
引文
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