梓醇对D-半乳糖衰老小鼠的神经保护作用研究
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摘要
梓醇是玄参科植物地黄(Rehmannia glutinosa Libosch)的主要成分,有保肝泻下,抗炎止痛,降血糖的功效。本实验室的前期研究证实:在细胞和动物模型上梓醇具有神经保护活性。然而梓醇是一种环烯醚萜类化合物,化学性质不稳定,分离工艺繁琐,来源有限,因此对现有工艺进行优化,对于梓醇的药理活性研究及产品开发具有现实意义。本研究旨在优化地黄中梓醇的提取纯化工艺,重点探讨梓醇在D-半乳糖致衰老小鼠模型中的神经保护作用及机制,主要研究内容与结果如下:
首先,将微波辅助提取与大孔吸附树脂柱层析技术相结合,对梓醇工艺进行了优化。
以高效液相色谱法为检测手段,考察冷浸、超声波辅助提取、微波辅助提取、热回流提取、索氏提取五种方法对梓醇提取率的影响。达到最大提取率时,微波辅助提取用时最短(4 min),说明微波辅助提取方法在提取效率上优于其它方法,综合评价选用微波辅助提取法进行梓醇的提取;考察九种不同极性大孔吸附树脂对梓醇的吸附性能,结果表明,D101树脂对梓醇的吸附量较大(76.1 mg/g干树脂),且对梓醇的解析率较高(92.1%)。该树脂对梓醇的吸附等温线符合Langmuir和Freundlich公式,为单分子层吸附,适于地黄醇提取液中梓醇的纯化。利用D101树脂层析柱,上样量为5 BV的地黄浓缩液(2 mg/ml),以水和不同浓度的乙醇洗脱。收集含梓醇的5%乙醇洗脱液,浓缩干燥后,得到梓醇含量大于50%的褐色粉末,将其进行硅胶柱层析,氯仿:甲醇(8∶2)梯度洗脱得到梓醇单体,纯度达90%以上,得率为600 mg/kg药材。
其次,建立皮下注射D-半乳糖致衰老小鼠模型,研究梓醇的神经保护作用及机制。
(1)利用旷场、跳台和Morris水迷宫,考察梓醇对D-半乳糖衰老模型小鼠认知能力的影响,发现D-半乳糖致衰老小鼠的自主活动和探究能力,被动学习记忆和空间认知能力下降,应用梓醇治疗两周后,明显改善衰老小鼠的学习记忆能力。病理切片苏木素-伊红(HE)染色发现D-半乳糖衰老小鼠神经元细胞稀疏,细胞核固缩;生化方法检测到大脑皮层和海马内胆碱酯酶(AChE)活力上升,免疫组织化学方法发现基底前脑乙酰胆碱转移酶(ChAT)表达量减少,免疫印迹方法发现脑组织乙酰胆碱M受体(mAChR)表达量降低。应用梓醇后,不仅能够减轻D-半乳糖所致的小鼠大脑病理损伤,而且通过抑制AChE的活力,提高ChAT和mAChR表达来保护乙酰胆碱系统,进而维持神经递质乙酰胆碱(Ach)的含量,改善模型小鼠的学习记忆能力。
(2)梓醇对D-半乳糖衰老模型小鼠体内抗氧化能力的研究表明:梓醇能显著提高大脑皮层、海马、肝和脾组织内超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、谷胱甘肽-S-转移酶(GSH-ST)活力,降低脂质过氧化产物丙二醛(MDA)含量。提示梓醇对衰老模型小鼠具有保护作用,其保护机制之一是提高机体内源性抗氧化酶活力,减轻脂质过氧化程度,保护机体免受氧化损伤。通过相关性分析,发现小鼠大脑皮层、海马内SOD和GSH-Px活力与小鼠水迷宫实验第五天逃避潜伏期呈负相关,MDA水平与第五天逃避潜伏期呈显著正相关,表明梓醇改善模型小鼠学习记忆能力可能与其提高大脑抗氧化能力有关。
(3)考察梓醇对D-半乳糖衰老模型小鼠大脑能量代谢的影响,发现梓醇能够降低模型小鼠大脑皮层和海马组织乳酸脱氢酶(LDH)活力,提高肌酸激酶(CK)、Na~+-K~+-ATP和Ca~(2+)-Mg~(2+)-ATP酶活力;梓醇治疗组小鼠大脑皮层和海马线粒体呼吸链复合酶Ⅰ、Ⅱ/Ⅲ、Ⅳ活性明显高于D-半乳糖衰老模型小鼠,梓醇不仅抑制线粒体活性氧(ROS)的产生和线粒体膜电位(MMP)的降低,而且抑制衰老小鼠皮层和海马细胞的凋亡,提高抑凋亡蛋白Bcl-2的表达,抑制凋亡通路关键蛋白caspase-3的活性。这说明梓醇可通过提高线粒体呼吸链复合酶的活性,抑制线粒体ROS的产生,阻止MMP的丧失,上调Bcl-2蛋白的表达及拮抗caspase-3的激活,从而保持线粒体功能的完整性,进而抑制氧化应激所致的细胞凋亡同时上调能量代谢相关酶的活力,保护脑组织能量代谢的平衡来发挥其抗衰老作用。
总之,本研究表明梓醇为地黄中主要的抗衰老活性成份之一,有可能在延缓衰老和与衰老相关的神经退行性疾病的预防和治疗中发挥作用。
Catalpol, one of the main active constituents of Rehmannia glutinosa Libosch, possesses many therapeutic effects such as protection of liver damage, anti-inflammation, reduction of pain and blood sugar. Catalpol has been verified to have neuroprotective effects in vitro and in vivo in our laboratory and be worth further studying. Due to its instable chemical property and complicated seperation technique, it is so difficult to obtain bulk of catalpol that an optimized seperation technique of catalpol becomes urgent. The purpose of this study mainly aims to optimize existed extraction and purification technique of catalpol and obtain enough catalpol to investigate its protective effects on senescent mice induced by D-galactose. The main results are summarized as following.
Firstly, an optimized technique for extraction and purification of catalpol had been established, including microwave-assisted extration and column chromatography with macroporpus adsorbent resins.
Different extraction methods including extraction at room temperature (ERT), heat reflux extraction, Soxhlet extraction, ultrasonic extraction and microwave-assisted extraction (MAE) to evaluat the percentage extraction of catapol from Rehmannia has been tested. The extracts were analyzed by high performance liquid chromatography (HPLC). The results showed that the percentage extraction of catalpol from Rehmannia by MAE (4 min) was more efficient in short time followed by Soxhlet extraction, heat reflux extraction, ultrasonic and ERT methods. The present results showed that the considerable saving of time by MAE was more competent than the other extraction techniques. Considering its time saving and higher percentage extraction of catalpol, we had choosed MAE technique for catalpol extraction from Rehmannia. Nine different kinds of macroporous adsorbent resins were evaluated by the static capacity of adsorption and desorption. The results showed that D101 resin had higher static adsorption capacity of 76.1mg/g dry resin and desorption ratio of 92.1%. Its isotherm curve can be well described by Langmuir and Freudlich equation and belong to monomolecular layer absorption. D101 resin was choosed for the purification of catalpol from the extraction solution of Rehmannia. After the extract containing 2mg/mL of catalpol was loaded onto the column, resins bed was eluted by 5BV (five folds volume of resin bed) water and different concentrations of ethanol, respectively. The 5% ethanol elution on removal of the solvent under reduced pressure provided a brown powder containing 50% catalpol, which was subjected to an open column chromatography on silica gel eluted with a CHCl_3-MeOH gradient. The fraction eluted with CHCl_3-MeOH (8:2) was identified as catalpol and the purity of the compound was more than 90% purity by HPLC analysis. The yield of this separation technique was 600mg/kg Rehmannia.
Secondly, the neuroprotective effects of catalpol on the senescent mice induced by subcutaneous injection of D-galactose were assessed and the mechanisms underlying its protective effects were studied.
(1) Effects of catalpol on the cognition ability of senescent mice induced by D-galactose were evaluated by open field test, step-down avoidance test and Morris water maze test. The results showed that injection of D-galactose caused not only degression of autonomic activities and novelty-induced exploratory behaviors but also passive and spacial cognition ability. Administration of catalpol for two weeks was capable of reversing the D-galactose induced behavioral impairment, indicating that catalpol has the effect of ameliorating cognition ability of senescent mice. Hematoxylin and eosin (HE) staining showed that pyramidal neurons either presented a densely stained shrunken appearance with minimal cytoplasm or had disappeared in the brain of D-galactose treated mice. In contrast, majority of the neurons were rescued in mice treated with catalpol. Moreover, catalpol decreased the elevated activity of acetylcholinesterase (AChE) in aging mice brain cortex and hippocampus, increased the positive neurons of choline acetyltransferase (ChAT) in aging mice basal forebrain revealed by immunohistochemical staining and the expression of Acetylcholine M receptor (mAChR) in aging mice brain determined by western blotting method, indicating that catalpol had protective effects on cholinergic impairment in aging model mice so as to maintain the content of acetylcholine (ACh) and eventually ameliorate cognition deficits of senescent mice.
(2) Effects of catalpol on the anti-oxidative ability of senescent mice induced by D-galactose were examined by biochemical method. The results showed that catalpol increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione S-transferase (GSH-ST), decreased the malondialdehyde (MDA) level in the cerebral cortex, hippocampus, liver and spleen of D-galactose treated mouse. These suggested that the antiaging effects of catalpol were partly mediated via enhancing endogenous antioxidant enzymatic activities, alleviating lipid peroxide and protecting organism from oxidative damage. Significant negative correlation was found between the mean latency to find the platform on fifth day in water maze test and the activities of SOD and GSH-Px in mice cortex and hippocampus. The levels of MDA were positive correlated with the mean latency in the two regions of mice brain. The data indicated that the oxidative damage may play a role in the cognitive decline of the senescent mice induced by D -galactose.
(3) Effects of catalpol on the brain neuron apotosis of senescent mice induced by D-galactose were studied utilizing ultraviolet spectrophotometer, fluorospectrophotometer and flow cytometry. The data revealed that catalpol could decreased the activity of lactate dehydrogenase (LDH), increased the activities of creatine kinase (CK), Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase in brain cortex and hippocampus of senescent mice induced by D-galactose. Further study found that catalpol could increase the activities of respiratory complex I, II /III, IV and mitochondrial membrane potential level, decrease reactive oxygen species (ROS) production in the brain cortex and hippocampus mitochondria of senescent mice. Flow cytometry analysis revealed that catalpol could inhibit apoptosis in the brain cortex and hippocampus of senescent mice via inhibting the production of ROS and the loss of membrane potential level, up-regulation of Bcl-2 and inactivation of caspase-3. These results suggested that catalpol could exert antiaging effects via maintaining the balance of energy metabolism in the brain of senescent mice by elevating the activities of respiratory complex, inhibting apoptosis and regulating the activities of energy-related enzymes.
In conclusion, the results suggest that catalpol may be one of the main antiaging components in the Rehmannia and may be an agent for senescence or neurodegenerative diseases.
首先,将微波辅助提取与大孔吸附树脂柱层析技术相结合,对梓醇工艺进行了优化。
以高效液相色谱法为检测手段,考察冷浸、超声波辅助提取、微波辅助提取、热回流提取、索氏提取五种方法对梓醇提取率的影响。达到最大提取率时,微波辅助提取用时最短(4 min),说明微波辅助提取方法在提取效率上优于其它方法,综合评价选用微波辅助提取法进行梓醇的提取;考察九种不同极性大孔吸附树脂对梓醇的吸附性能,结果表明,D101树脂对梓醇的吸附量较大(76.1 mg/g干树脂),且对梓醇的解析率较高(92.1%)。该树脂对梓醇的吸附等温线符合Langmuir和Freundlich公式,为单分子层吸附,适于地黄醇提取液中梓醇的纯化。利用D101树脂层析柱,上样量为5 BV的地黄浓缩液(2 mg/ml),以水和不同浓度的乙醇洗脱。收集含梓醇的5%乙醇洗脱液,浓缩干燥后,得到梓醇含量大于50%的褐色粉末,将其进行硅胶柱层析,氯仿:甲醇(8∶2)梯度洗脱得到梓醇单体,纯度达90%以上,得率为600 mg/kg药材。
其次,建立皮下注射D-半乳糖致衰老小鼠模型,研究梓醇的神经保护作用及机制。
(1)利用旷场、跳台和Morris水迷宫,考察梓醇对D-半乳糖衰老模型小鼠认知能力的影响,发现D-半乳糖致衰老小鼠的自主活动和探究能力,被动学习记忆和空间认知能力下降,应用梓醇治疗两周后,明显改善衰老小鼠的学习记忆能力。病理切片苏木素-伊红(HE)染色发现D-半乳糖衰老小鼠神经元细胞稀疏,细胞核固缩;生化方法检测到大脑皮层和海马内胆碱酯酶(AChE)活力上升,免疫组织化学方法发现基底前脑乙酰胆碱转移酶(ChAT)表达量减少,免疫印迹方法发现脑组织乙酰胆碱M受体(mAChR)表达量降低。应用梓醇后,不仅能够减轻D-半乳糖所致的小鼠大脑病理损伤,而且通过抑制AChE的活力,提高ChAT和mAChR表达来保护乙酰胆碱系统,进而维持神经递质乙酰胆碱(Ach)的含量,改善模型小鼠的学习记忆能力。
(2)梓醇对D-半乳糖衰老模型小鼠体内抗氧化能力的研究表明:梓醇能显著提高大脑皮层、海马、肝和脾组织内超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)、谷胱甘肽-S-转移酶(GSH-ST)活力,降低脂质过氧化产物丙二醛(MDA)含量。提示梓醇对衰老模型小鼠具有保护作用,其保护机制之一是提高机体内源性抗氧化酶活力,减轻脂质过氧化程度,保护机体免受氧化损伤。通过相关性分析,发现小鼠大脑皮层、海马内SOD和GSH-Px活力与小鼠水迷宫实验第五天逃避潜伏期呈负相关,MDA水平与第五天逃避潜伏期呈显著正相关,表明梓醇改善模型小鼠学习记忆能力可能与其提高大脑抗氧化能力有关。
(3)考察梓醇对D-半乳糖衰老模型小鼠大脑能量代谢的影响,发现梓醇能够降低模型小鼠大脑皮层和海马组织乳酸脱氢酶(LDH)活力,提高肌酸激酶(CK)、Na~+-K~+-ATP和Ca~(2+)-Mg~(2+)-ATP酶活力;梓醇治疗组小鼠大脑皮层和海马线粒体呼吸链复合酶Ⅰ、Ⅱ/Ⅲ、Ⅳ活性明显高于D-半乳糖衰老模型小鼠,梓醇不仅抑制线粒体活性氧(ROS)的产生和线粒体膜电位(MMP)的降低,而且抑制衰老小鼠皮层和海马细胞的凋亡,提高抑凋亡蛋白Bcl-2的表达,抑制凋亡通路关键蛋白caspase-3的活性。这说明梓醇可通过提高线粒体呼吸链复合酶的活性,抑制线粒体ROS的产生,阻止MMP的丧失,上调Bcl-2蛋白的表达及拮抗caspase-3的激活,从而保持线粒体功能的完整性,进而抑制氧化应激所致的细胞凋亡同时上调能量代谢相关酶的活力,保护脑组织能量代谢的平衡来发挥其抗衰老作用。
总之,本研究表明梓醇为地黄中主要的抗衰老活性成份之一,有可能在延缓衰老和与衰老相关的神经退行性疾病的预防和治疗中发挥作用。
Catalpol, one of the main active constituents of Rehmannia glutinosa Libosch, possesses many therapeutic effects such as protection of liver damage, anti-inflammation, reduction of pain and blood sugar. Catalpol has been verified to have neuroprotective effects in vitro and in vivo in our laboratory and be worth further studying. Due to its instable chemical property and complicated seperation technique, it is so difficult to obtain bulk of catalpol that an optimized seperation technique of catalpol becomes urgent. The purpose of this study mainly aims to optimize existed extraction and purification technique of catalpol and obtain enough catalpol to investigate its protective effects on senescent mice induced by D-galactose. The main results are summarized as following.
Firstly, an optimized technique for extraction and purification of catalpol had been established, including microwave-assisted extration and column chromatography with macroporpus adsorbent resins.
Different extraction methods including extraction at room temperature (ERT), heat reflux extraction, Soxhlet extraction, ultrasonic extraction and microwave-assisted extraction (MAE) to evaluat the percentage extraction of catapol from Rehmannia has been tested. The extracts were analyzed by high performance liquid chromatography (HPLC). The results showed that the percentage extraction of catalpol from Rehmannia by MAE (4 min) was more efficient in short time followed by Soxhlet extraction, heat reflux extraction, ultrasonic and ERT methods. The present results showed that the considerable saving of time by MAE was more competent than the other extraction techniques. Considering its time saving and higher percentage extraction of catalpol, we had choosed MAE technique for catalpol extraction from Rehmannia. Nine different kinds of macroporous adsorbent resins were evaluated by the static capacity of adsorption and desorption. The results showed that D101 resin had higher static adsorption capacity of 76.1mg/g dry resin and desorption ratio of 92.1%. Its isotherm curve can be well described by Langmuir and Freudlich equation and belong to monomolecular layer absorption. D101 resin was choosed for the purification of catalpol from the extraction solution of Rehmannia. After the extract containing 2mg/mL of catalpol was loaded onto the column, resins bed was eluted by 5BV (five folds volume of resin bed) water and different concentrations of ethanol, respectively. The 5% ethanol elution on removal of the solvent under reduced pressure provided a brown powder containing 50% catalpol, which was subjected to an open column chromatography on silica gel eluted with a CHCl_3-MeOH gradient. The fraction eluted with CHCl_3-MeOH (8:2) was identified as catalpol and the purity of the compound was more than 90% purity by HPLC analysis. The yield of this separation technique was 600mg/kg Rehmannia.
Secondly, the neuroprotective effects of catalpol on the senescent mice induced by subcutaneous injection of D-galactose were assessed and the mechanisms underlying its protective effects were studied.
(1) Effects of catalpol on the cognition ability of senescent mice induced by D-galactose were evaluated by open field test, step-down avoidance test and Morris water maze test. The results showed that injection of D-galactose caused not only degression of autonomic activities and novelty-induced exploratory behaviors but also passive and spacial cognition ability. Administration of catalpol for two weeks was capable of reversing the D-galactose induced behavioral impairment, indicating that catalpol has the effect of ameliorating cognition ability of senescent mice. Hematoxylin and eosin (HE) staining showed that pyramidal neurons either presented a densely stained shrunken appearance with minimal cytoplasm or had disappeared in the brain of D-galactose treated mice. In contrast, majority of the neurons were rescued in mice treated with catalpol. Moreover, catalpol decreased the elevated activity of acetylcholinesterase (AChE) in aging mice brain cortex and hippocampus, increased the positive neurons of choline acetyltransferase (ChAT) in aging mice basal forebrain revealed by immunohistochemical staining and the expression of Acetylcholine M receptor (mAChR) in aging mice brain determined by western blotting method, indicating that catalpol had protective effects on cholinergic impairment in aging model mice so as to maintain the content of acetylcholine (ACh) and eventually ameliorate cognition deficits of senescent mice.
(2) Effects of catalpol on the anti-oxidative ability of senescent mice induced by D-galactose were examined by biochemical method. The results showed that catalpol increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione S-transferase (GSH-ST), decreased the malondialdehyde (MDA) level in the cerebral cortex, hippocampus, liver and spleen of D-galactose treated mouse. These suggested that the antiaging effects of catalpol were partly mediated via enhancing endogenous antioxidant enzymatic activities, alleviating lipid peroxide and protecting organism from oxidative damage. Significant negative correlation was found between the mean latency to find the platform on fifth day in water maze test and the activities of SOD and GSH-Px in mice cortex and hippocampus. The levels of MDA were positive correlated with the mean latency in the two regions of mice brain. The data indicated that the oxidative damage may play a role in the cognitive decline of the senescent mice induced by D -galactose.
(3) Effects of catalpol on the brain neuron apotosis of senescent mice induced by D-galactose were studied utilizing ultraviolet spectrophotometer, fluorospectrophotometer and flow cytometry. The data revealed that catalpol could decreased the activity of lactate dehydrogenase (LDH), increased the activities of creatine kinase (CK), Na~+-K~+-ATPase and Ca~(2+)-Mg~(2+)-ATPase in brain cortex and hippocampus of senescent mice induced by D-galactose. Further study found that catalpol could increase the activities of respiratory complex I, II /III, IV and mitochondrial membrane potential level, decrease reactive oxygen species (ROS) production in the brain cortex and hippocampus mitochondria of senescent mice. Flow cytometry analysis revealed that catalpol could inhibit apoptosis in the brain cortex and hippocampus of senescent mice via inhibting the production of ROS and the loss of membrane potential level, up-regulation of Bcl-2 and inactivation of caspase-3. These results suggested that catalpol could exert antiaging effects via maintaining the balance of energy metabolism in the brain of senescent mice by elevating the activities of respiratory complex, inhibting apoptosis and regulating the activities of energy-related enzymes.
In conclusion, the results suggest that catalpol may be one of the main antiaging components in the Rehmannia and may be an agent for senescence or neurodegenerative diseases.
引文
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