【摘要】：研究表明達瑪烷型三萜皂苷具有顯著的改善學習記憶能力作用,其中主要以原人參三醇型皂苷和原人參二醇型皂苷為主,尤為集中在對含量豐富的原人參三醇型皂苷代表性成分-Rg1和原人參二醇型皂苷代表性成分-Rb1這兩種皂苷的益智作用探討,對其代謝產(chǎn)物-稀有皂苷Rh1、Rh2、PPT和PPD的益智作用報道十分有限,而且Rg1和Rb1具有不同益智作用特點,因此對其代謝產(chǎn)物-Rh1、Rh2、PPT和PPD這四種達瑪烷型三萜皂苷的益智作用特點及機制研究有利于更好理解和闡釋達瑪烷型三萜皂苷的藥理作用,并能為尋找有效的認知功能障礙防護措施提供防護藥物。本文主要研究成果如下:1.研究發(fā)現(xiàn)原人參三醇型皂苷Rh1和原人參二醇型皂苷Rh2具有不同益智作用特點。應用空場、物體認知、水迷宮和避暗實驗研究原人參三醇型皂苷Rh1和原人參二醇型皂苷Rh2(20、40μmol/kg)經(jīng)腹腔注射給藥14天后對東莨膽堿和慢性睡眠干擾所致小鼠學習記憶障礙模型的影響。研究結果顯示,Rh1和Rh2均能明顯改善東莨菪堿和慢性睡眠干擾所致的學習記憶障礙。但Rh1有改善空間學習記憶能力作用更強的趨勢,而Rh2則有改善短時、非空間記憶能力作用更優(yōu)的趨勢。2.首次發(fā)現(xiàn)原人參三醇型苷元PPT和原人參二醇型苷元PPD對記憶的獲得、鞏固和再現(xiàn)過程均具有明顯促進作用,而且對慢性睡眠干擾所致學習記憶障礙亦具有顯著改善作用,二者之間具有不同的益智作用特點和作用機制。物體認知和避暗實驗結果顯示:PPT和PPD(20、40μmol/kg)經(jīng)腹腔給藥14天后具有顯著改善東莨菪堿所致記憶的獲得、鞏固和再現(xiàn)障礙作用。在對記憶的獲得過程促進作用方面,原人參三醇型苷元PPT有改善空間記憶能力作用更強的趨勢,原人參二醇型苷元PPD則顯示出對非空間記憶能力改善作用更優(yōu)的趨勢。PPT主要影響與空間記憶密切相關的海馬這一腦區(qū)內(nèi)的生化指標,通過抑制AchE活性,促進Ach釋放,提高膽堿能系統(tǒng)神經(jīng)傳遞;對抗氧化應激損傷以及上調(diào)海馬內(nèi)CREB和即早基因c-Fos、c-Jun和Egr-1的表達;而PPD則主要調(diào)節(jié)皮層內(nèi)的生化指標,通過升高ChAT活性,升高Ach含量從而促進膽堿能系統(tǒng)功能,具有顯著的抗氧化作用以及上調(diào)海馬內(nèi)即早基因c-Fos和Egr-1的表達,但對CREB無影響,甚至下調(diào)了 c-Jun的表達。這些作用機制的差異使得PPT和PPD發(fā)揮益智作用特點有所不同。對記憶的鞏固和再現(xiàn)過程促進作用方面,PPT和PPD未顯示出顯著差異。對慢性睡眠干擾所致學習記憶障礙,PPT和PPD同樣具有顯著改善作用,而且PPT表現(xiàn)出對空間參考記憶能力改善作用更優(yōu)的趨勢。3.證實了代謝產(chǎn)物PPT比其原形物Rh1的益智活性更強,而且二者的作用機制相似。應用東莨菪堿和慢性睡眠干擾所致學習記憶障礙模型,對Rh1及其代謝產(chǎn)物PPT的益智作用進行比較研究,結果發(fā)現(xiàn),Rh1及其代謝產(chǎn)物PPT(20、40μmol/kg)經(jīng)腹腔給藥14天后確能顯著提高模型小鼠的學習記憶能力,而且同劑量下相比,PPT的益智作用強于Rh1,并且二者均具有提高膽堿能系統(tǒng)功能和對抗氧化應激損傷作用,提示Rh1及其代謝產(chǎn)物PPT具有相似的作用機制發(fā)揮益智活性,而且代謝產(chǎn)物PPT的作用強于Rh1。4.首次發(fā)現(xiàn)代謝產(chǎn)物PPD及其原形物Rh2具有相似的作用機制,而且PPD的益智活性強于Rh2。應用東茛菪堿和慢性睡眠干擾所致學習記憶障礙模型,對Rh2及其代謝產(chǎn)物PPD的益智作用進行比較研究,結果發(fā)現(xiàn),Rh2及其代謝產(chǎn)物PPD(20、40μmol/kg)經(jīng)腹腔給藥14天后,均可通過提高膽堿能神經(jīng)傳遞和對抗氧化損傷發(fā)揮益智活性。而且同劑量下相比,PPD的益智作用強于Rh2。本研究論文從整體動物行為學、中樞膽堿能系統(tǒng)神經(jīng)遞質(zhì)傳遞、氧化應激和學習記憶相關信號分子等角度,應用兩種學習記憶障礙動物模型,對原人參三醇型皂苷和原人參二醇型皂苷之間、次苷及其代謝產(chǎn)物苷元之間的益智作用特點和作用機制進行了比較研究。結果表明,原人參三醇型皂苷和原人參二醇型皂苷在改善學習記憶方面具有不同的作用特點(前者改善空間學習記憶能力更強,后者則對非空間學習記憶能力改善作用更優(yōu));完全去糖基后的苷元具有與其原形物-次苷相似的作用機制,甚至苷元的益智活性強于次苷。本研究結果可為達瑪烷型三萜皂苷用于防治學習記憶障礙相關疾病的研究提供理論基礎和科學依據(jù)。
[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.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R285.5
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本文編號：2175240