四种达玛烷型三萜皂苷益智作用特点及机制研究
发布时间：2018-08-09 20:35
【摘要】：研究表明达玛烷型三萜皂苷具有显著的改善学习记忆能力作用,其中主要以原人参三醇型皂苷和原人参二醇型皂苷为主,尤为集中在对含量丰富的原人参三醇型皂苷代表性成分-Rg1和原人参二醇型皂苷代表性成分-Rb1这两种皂苷的益智作用探讨,对其代谢产物-稀有皂苷Rh1、Rh2、PPT和PPD的益智作用报道十分有限,而且Rg1和Rb1具有不同益智作用特点,因此对其代谢产物-Rh1、Rh2、PPT和PPD这四种达玛烷型三萜皂苷的益智作用特点及机制研究有利于更好理解和阐释达玛烷型三萜皂苷的药理作用,并能为寻找有效的认知功能障碍防护措施提供防护药物。本文主要研究成果如下:1.研究发现原人参三醇型皂苷Rh1和原人参二醇型皂苷Rh2具有不同益智作用特点。应用空场、物体认知、水迷宫和避暗实验研究原人参三醇型皂苷Rh1和原人参二醇型皂苷Rh2(20、40μmol/kg)经腹腔注射给药14天后对东莨胆碱和慢性睡眠干扰所致小鼠学习记忆障碍模型的影响。研究结果显示,Rh1和Rh2均能明显改善东莨菪碱和慢性睡眠干扰所致的学习记忆障碍。但Rh1有改善空间学习记忆能力作用更强的趋势,而Rh2则有改善短时、非空间记忆能力作用更优的趋势。2.首次发现原人参三醇型苷元PPT和原人参二醇型苷元PPD对记忆的获得、巩固和再现过程均具有明显促进作用,而且对慢性睡眠干扰所致学习记忆障碍亦具有显著改善作用,二者之间具有不同的益智作用特点和作用机制。物体认知和避暗实验结果显示:PPT和PPD(20、40μmol/kg)经腹腔给药14天后具有显著改善东莨菪碱所致记忆的获得、巩固和再现障碍作用。在对记忆的获得过程促进作用方面,原人参三醇型苷元PPT有改善空间记忆能力作用更强的趋势,原人参二醇型苷元PPD则显示出对非空间记忆能力改善作用更优的趋势。PPT主要影响与空间记忆密切相关的海马这一脑区内的生化指标,通过抑制AchE活性,促进Ach释放,提高胆碱能系统神经传递;对抗氧化应激损伤以及上调海马内CREB和即早基因c-Fos、c-Jun和Egr-1的表达;而PPD则主要调节皮层内的生化指标,通过升高ChAT活性,升高Ach含量从而促进胆碱能系统功能,具有显著的抗氧化作用以及上调海马内即早基因c-Fos和Egr-1的表达,但对CREB无影响,甚至下调了 c-Jun的表达。这些作用机制的差异使得PPT和PPD发挥益智作用特点有所不同。对记忆的巩固和再现过程促进作用方面,PPT和PPD未显示出显著差异。对慢性睡眠干扰所致学习记忆障碍,PPT和PPD同样具有显著改善作用,而且PPT表现出对空间参考记忆能力改善作用更优的趋势。3.证实了代谢产物PPT比其原形物Rh1的益智活性更强,而且二者的作用机制相似。应用东莨菪碱和慢性睡眠干扰所致学习记忆障碍模型,对Rh1及其代谢产物PPT的益智作用进行比较研究,结果发现,Rh1及其代谢产物PPT(20、40μmol/kg)经腹腔给药14天后确能显著提高模型小鼠的学习记忆能力,而且同剂量下相比,PPT的益智作用强于Rh1,并且二者均具有提高胆碱能系统功能和对抗氧化应激损伤作用,提示Rh1及其代谢产物PPT具有相似的作用机制发挥益智活性,而且代谢产物PPT的作用强于Rh1。4.首次发现代谢产物PPD及其原形物Rh2具有相似的作用机制,而且PPD的益智活性强于Rh2。应用东茛菪碱和慢性睡眠干扰所致学习记忆障碍模型,对Rh2及其代谢产物PPD的益智作用进行比较研究,结果发现,Rh2及其代谢产物PPD(20、40μmol/kg)经腹腔给药14天后,均可通过提高胆碱能神经传递和对抗氧化损伤发挥益智活性。而且同剂量下相比,PPD的益智作用强于Rh2。本研究论文从整体动物行为学、中枢胆碱能系统神经递质传递、氧化应激和学习记忆相关信号分子等角度,应用两种学习记忆障碍动物模型,对原人参三醇型皂苷和原人参二醇型皂苷之间、次苷及其代谢产物苷元之间的益智作用特点和作用机制进行了比较研究。结果表明,原人参三醇型皂苷和原人参二醇型皂苷在改善学习记忆方面具有不同的作用特点(前者改善空间学习记忆能力更强,后者则对非空间学习记忆能力改善作用更优);完全去糖基后的苷元具有与其原形物-次苷相似的作用机制,甚至苷元的益智活性强于次苷。本研究结果可为达玛烷型三萜皂苷用于防治学习记忆障碍相关疾病的研究提供理论基础和科学依据。
[Abstract]:The study shows that diterpane three terpene saponins have significant effect on improving learning and memory ability, mainly including propanax ginseng three alcohol saponins and propanax Panax saponins, especially in the two saponins, the representative components of the rich propanax ginseng three alcohol saponins -Rg1 and the propanediol saponins of the saponins, the two saponins. The intellectual function of the metabolites, rare saponins Rh1, Rh2, PPT and PPD, is very limited, and Rg1 and Rb1 have different beneficial characteristics. Therefore, the study on the beneficial characteristics and mechanism of the four kinds of diterpene saponins of its metabolites, -Rh1, Rh2, PPT and PPD, is beneficial to better understanding and interpreting the damanane type. The pharmacological effects of three terpenoid saponins can provide protective drugs for the effective protective measures for cognitive impairment. The main achievements of this paper are as follows: 1. the study found that the original ginseng three alcohol saponins Rh1 and the original Panax ginsenoside Rh2 have different beneficial characteristics. The application of empty field, object cognition, water maze and dark experiment study of ginseng The effects of three alcohol saponins Rh1 and propanpanediol saponins Rh2 (20,40 mu mol/kg) on the model of learning and memory impairment induced by scopoline and chronic sleep disturbance in mice after 14 days of intraperitoneal injection. The results showed that Rh1 and Rh2 could significantly improve the learning and memory impairment induced by scopolamine and chronic sleep disturbance. But Rh1 has improved empty space. The trend of the ability of learning and memory is stronger, while Rh2 has the tendency to improve short time, and the effect of non spatial memory ability is better..2. first found that the propanax ginseng three alcohol glycoside PPT and propanax glycoside PPD have an obvious promoting effect on the acquisition, consolidation and reproduction of memory, and the learning and memory barrier caused by chronic sleep disturbance. The hindrance also has a significant improvement, and there are different characteristics and mechanisms of action between the two. The results of object cognition and dark experiment show that PPT and PPD (20,40 mu mol/kg) can significantly improve the acquisition of scopolamine induced memory after 14 days of intraperitoneal administration, and promote the effect on the acquisition of memory. On the other hand, the propanax ginseng three alcohol glycoside PPT has a stronger tendency to improve the spatial memory ability. The propanediol glycoside PPD shows a better tendency to improve the non spatial memory ability..PPT mainly affects the biochemical indexes in the hippocampus, which is closely related to spatial memory, and promotes the release of Ach by inhibiting the activity of AchE. High cholinergic system neurotransmitters; antagonism to oxidative stress damage and up regulation of the expression of CREB and c-Fos, c-Jun and Egr-1 in the hippocampus; while PPD mainly regulates the biochemical indexes in the cortex, increases the activity of ChAT, increases the Ach content and promotes the function of the cholinergic system. It has a significant antioxidant effect and an up regulation of the hippocampus as early as possible. The expression of gene c-Fos and Egr-1 has no effect on CREB, even down the expression of c-Jun. The differences in these mechanisms make PPT and PPD play a different role in the beneficial effects of the beneficial intelligence. There is no significant difference between PPT and PPD for the consolidation and reproduction of memory. The learning and memory impairment caused by chronic sleep disturbance, PPT and PP. D also has a significant improvement, and PPT shows a better improvement in the ability to improve the spatial reference memory ability.3. confirms that the metabolite PPT is more active than its original Rh1, and the mechanism of the two is similar. The use of scopolamine and chronic sleep disturbance caused by learning and memory impairment model, Rh1 and its metabolites A comparative study of the beneficial effect of PPT showed that Rh1 and its metabolite PPT (20,40 mu mol/kg) could significantly improve the learning and memory ability of the model mice after 14 days of intraperitoneal administration, and the effect of PPT was stronger than that of Rh1 at the same dose, and all of the two had the function of raising the high cholinergic system and the action against oxidative stress. It is suggested that Rh1 and its metabolite PPT have a similar mechanism of action, and the role of the metabolite PPT is stronger than the first discovery of Rh1.4. that the metabolite PPD and its protoplast Rh2 have a similar mechanism of action, and the beneficial activity of PPD is stronger than the Rh2. application of scopolamine and the model of learning and memory disorder caused by slow sleep disturbance, and the R A comparative study of the beneficial effects of H2 and its metabolite PPD was carried out. The results showed that Rh2 and its metabolite PPD (20,40 mu mol/kg) could improve the cholinergic transmission and antagonism to oxidative damage after 14 days of intraperitoneal administration. Moreover, compared with the same dose, the beneficial effect of PPD is stronger than that of the whole animal research paper of Rh2.. In order to learn from the angles of neurotransmitter transmission, oxidative stress and learning and memory related signal molecules in the central cholinergic system, two animal models of learning and memory disorders were used to compare the characteristics and mechanism of the beneficial effects between the propanax ginseng three alcohol saponins and the propanediol saponins, secondary glycosides and their metabolite glycosides. The results showed that the propanax ginseng three alcohol saponins and propanax Panax saponins have different functions in improving learning and memory (the former improves the learning and memory ability of the former stronger, the latter is better in improving the ability of non spatial learning and memory), and the glycosides after the complete glycosyl group have the mechanism similar to those of their protoplast glucoside. Even the glycosides of the glycosides are stronger than those of the secondary glycosides. The results of this study can provide a theoretical basis and scientific basis for the study of diterpene type three terpenoid saponins in the prevention and treatment of learning and memory disorders related diseases.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R285.5
，
本文编号：2175240
[Abstract]:The study shows that diterpane three terpene saponins have significant effect on improving learning and memory ability, mainly including propanax ginseng three alcohol saponins and propanax Panax saponins, especially in the two saponins, the representative components of the rich propanax ginseng three alcohol saponins -Rg1 and the propanediol saponins of the saponins, the two saponins. The intellectual function of the metabolites, rare saponins Rh1, Rh2, PPT and PPD, is very limited, and Rg1 and Rb1 have different beneficial characteristics. Therefore, the study on the beneficial characteristics and mechanism of the four kinds of diterpene saponins of its metabolites, -Rh1, Rh2, PPT and PPD, is beneficial to better understanding and interpreting the damanane type. The pharmacological effects of three terpenoid saponins can provide protective drugs for the effective protective measures for cognitive impairment. The main achievements of this paper are as follows: 1. the study found that the original ginseng three alcohol saponins Rh1 and the original Panax ginsenoside Rh2 have different beneficial characteristics. The application of empty field, object cognition, water maze and dark experiment study of ginseng The effects of three alcohol saponins Rh1 and propanpanediol saponins Rh2 (20,40 mu mol/kg) on the model of learning and memory impairment induced by scopoline and chronic sleep disturbance in mice after 14 days of intraperitoneal injection. The results showed that Rh1 and Rh2 could significantly improve the learning and memory impairment induced by scopolamine and chronic sleep disturbance. But Rh1 has improved empty space. The trend of the ability of learning and memory is stronger, while Rh2 has the tendency to improve short time, and the effect of non spatial memory ability is better..2. first found that the propanax ginseng three alcohol glycoside PPT and propanax glycoside PPD have an obvious promoting effect on the acquisition, consolidation and reproduction of memory, and the learning and memory barrier caused by chronic sleep disturbance. The hindrance also has a significant improvement, and there are different characteristics and mechanisms of action between the two. The results of object cognition and dark experiment show that PPT and PPD (20,40 mu mol/kg) can significantly improve the acquisition of scopolamine induced memory after 14 days of intraperitoneal administration, and promote the effect on the acquisition of memory. On the other hand, the propanax ginseng three alcohol glycoside PPT has a stronger tendency to improve the spatial memory ability. The propanediol glycoside PPD shows a better tendency to improve the non spatial memory ability..PPT mainly affects the biochemical indexes in the hippocampus, which is closely related to spatial memory, and promotes the release of Ach by inhibiting the activity of AchE. High cholinergic system neurotransmitters; antagonism to oxidative stress damage and up regulation of the expression of CREB and c-Fos, c-Jun and Egr-1 in the hippocampus; while PPD mainly regulates the biochemical indexes in the cortex, increases the activity of ChAT, increases the Ach content and promotes the function of the cholinergic system. It has a significant antioxidant effect and an up regulation of the hippocampus as early as possible. The expression of gene c-Fos and Egr-1 has no effect on CREB, even down the expression of c-Jun. The differences in these mechanisms make PPT and PPD play a different role in the beneficial effects of the beneficial intelligence. There is no significant difference between PPT and PPD for the consolidation and reproduction of memory. The learning and memory impairment caused by chronic sleep disturbance, PPT and PP. D also has a significant improvement, and PPT shows a better improvement in the ability to improve the spatial reference memory ability.3. confirms that the metabolite PPT is more active than its original Rh1, and the mechanism of the two is similar. The use of scopolamine and chronic sleep disturbance caused by learning and memory impairment model, Rh1 and its metabolites A comparative study of the beneficial effect of PPT showed that Rh1 and its metabolite PPT (20,40 mu mol/kg) could significantly improve the learning and memory ability of the model mice after 14 days of intraperitoneal administration, and the effect of PPT was stronger than that of Rh1 at the same dose, and all of the two had the function of raising the high cholinergic system and the action against oxidative stress. It is suggested that Rh1 and its metabolite PPT have a similar mechanism of action, and the role of the metabolite PPT is stronger than the first discovery of Rh1.4. that the metabolite PPD and its protoplast Rh2 have a similar mechanism of action, and the beneficial activity of PPD is stronger than the Rh2. application of scopolamine and the model of learning and memory disorder caused by slow sleep disturbance, and the R A comparative study of the beneficial effects of H2 and its metabolite PPD was carried out. The results showed that Rh2 and its metabolite PPD (20,40 mu mol/kg) could improve the cholinergic transmission and antagonism to oxidative damage after 14 days of intraperitoneal administration. Moreover, compared with the same dose, the beneficial effect of PPD is stronger than that of the whole animal research paper of Rh2.. In order to learn from the angles of neurotransmitter transmission, oxidative stress and learning and memory related signal molecules in the central cholinergic system, two animal models of learning and memory disorders were used to compare the characteristics and mechanism of the beneficial effects between the propanax ginseng three alcohol saponins and the propanediol saponins, secondary glycosides and their metabolite glycosides. The results showed that the propanax ginseng three alcohol saponins and propanax Panax saponins have different functions in improving learning and memory (the former improves the learning and memory ability of the former stronger, the latter is better in improving the ability of non spatial learning and memory), and the glycosides after the complete glycosyl group have the mechanism similar to those of their protoplast glucoside. Even the glycosides of the glycosides are stronger than those of the secondary glycosides. The results of this study can provide a theoretical basis and scientific basis for the study of diterpene type three terpenoid saponins in the prevention and treatment of learning and memory disorders related diseases.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R285.5
，
本文编号：2175240
本文链接：https://www.wllwen.com/shoufeilunwen/yxlbs/2175240.html
教材专著
