中国新药杂志

二甲双胍联合小檗碱对db/db小鼠糖尿病认知功能障碍的改善作用

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曹月盈 ¹^,² , 孟祥宝 ³^,⁴^,⁵ , 孙桂波 ³^,⁴^,⁵ , 孙晓波 ³^,⁴^,⁵ , 孙懿 ¹^,² , 赵欣 ¹^,² , 蒲小平 ¹^,²

中国新药杂志 | 重大新药创制专项巡礼 2021,30(8): 690-700

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中国新药杂志 |重大新药创制专项巡礼 2021 , 30 (8) : 690 -700

二甲双胍联合小檗碱对db/db小鼠糖尿病认知功能障碍的改善作用

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曹月盈¹^,², 孟祥宝³^,⁴^,⁵, 孙桂波³^,⁴^,⁵, 孙晓波³^,⁴^,⁵, 孙懿¹^,², 赵欣¹^,², 蒲小平¹^,²

作者信息

¹北京大学　药学院分子与细胞药理学系，北京　100191

²北京大学　天然药物及仿生药物国家重点实验室，北京　100191

³中国医学科学院北京协和医学院　药用植物研究所，北京　100193

⁴中国医学科学院北京协和医学院　中草药生物活性物质及资源利用重点实验室，北京　100193

⁵中国医学科学院北京协和医学院　国家中医药管理局中药抗糖脂代谢紊乱疗效评估重点实验室，北京　100193

通讯作者:

蒲小平，女，教授，博士生导师，主要从事神经药理学研究。联系电话：（010）82802431，E-mail：puxi-aopingbj@163.com。

赵欣，女，博士，讲师，主要从事神经药理学研究。联系电话：（010）82802648，E-mail：zhaoxin2010@bjmu.edu.cn。

作者简介:

曹月盈，女，硕士研究生，主要从事药理学研究工作。E-mail：bingyingbjsz@163.com。

Metformin plus berberine alleviates cognitive dysfunction in db/db mice

Yue-ying CAO¹^,², Xiang-bao MENG³^,⁴^,⁵, Gui-bo SUN³^,⁴^,⁵, Xiao-bo SUN³^,⁴^,⁵, Yi SUN¹^,², Xin ZHAO¹^,², Xiao-ping PU¹^,²

Affiliations

¹Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

²State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China

³Institute of Medicinal Plants, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China

⁴Key Laboratory of Bioactive Substances and Resource Utilization of Chinese Herbal Medicine, Ministry of Education, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China

⁵Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100193, China

出版时间: 2021-04-30

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摘要

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目的：

利用db/db转基因小鼠模型探究二甲双胍联合小檗碱对糖尿病认知功能障碍的改善作用。

方法：

将db/db小鼠随机分为模型组（M）、二甲双胍给药组（Mt）、小檗碱给药组（Bb）和二甲双胍联合小檗碱给药组（MB），将同窝出生的db/m小鼠设为空白对照组（C）。分别灌胃给药二甲双胍（300 mg·kg^-1）、小檗碱（135 mg·kg^-1）、二甲双胍联合小檗碱（300 mg·kg^-1+135 mg·kg^-1）10周，测定各组db/db小鼠体重、血糖及其相关指标、行为学、氧化应激和炎症因子相关指标；并用苏木素-伊红染色处理脑组织切片，光镜观察病理学改变；利用基质辅助激光解析电离质谱成像（matrix-assisted laser desorption ionization time-of-flight mass spectrometry imaging，MALDI-TOF-MSI）技术观察小鼠脑组织代谢小分子含量的变化。

结果：

MB组小鼠空腹血糖值明显低于M组，且低于Mt和Bb组小鼠血糖。水迷宫实验中，和M组小鼠比较，MB组小鼠逃避潜伏期和从对侧象限入水找到平台的时间明显变短；90 s内穿台次数和在目标象限中停留时间明显增多。在外周血清ELISA测定中，MB组小鼠对比M组小鼠HbA1c，8-OHdG，PCO，TNF-α，NLRP3和IL-1β水平均明显降低，IL-6水平明显升高。在HE染色实验中，和M组小鼠比较，MB组小鼠脑海马区中神经细胞排列整齐，形态较完整，核染色清晰，细胞间界限清楚。在质谱成像实验中，和M组小鼠比较，MB组小鼠脑天冬氨酸、N-乙酰-天冬氨酸、谷氨酸水平明显上升且高于Mt和Bb组；牛磺酸、葡萄糖水平明显降低且低于Mt和Bb组。

结论：

本实验证明了二甲双胍联合小檗碱口服给药对糖尿病认知功能障碍有改善作用，且比单独给药二甲双胍或小檗碱效果更明显，其作用机制或与抗炎、抗氧化应激、改善TCA循环以及提高兴奋性氨基酸水平等相关。

关键词

db/db小鼠 / 糖尿病认知功能障碍 / 二甲双胍 / 小檗碱 / 基质辅助激光解析电离质谱成像

Abstract

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Objective:

To explore the protective effects of metformin plus berberine against diabetes-induced cognitive dysfunction in db/db mice.

Methods:

Mice were randomly divided into model, metformin, berberine, and metformin plus berberine (MB) groups. Db/m mice born in the same litter were used as the control group. Metformin (300 mg·kg^-1) and berberine (135 mg·kg^-1), either alone or in combination, were administered orally for 10 weeks. Body weight, blood glucose and related indices, and behavioral, oxidative stress-related, and inflammatory factor-related indexes of db/db mice were measured. Brain tissue sections were subjected to hematoxylin-eosin (HE) staining, and pathological changes were observed via light microscopy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to observe changes in the levels of small molecules in the brain tissue.

Results:

Fasting blood glucose levels were significantly lower in the MB group than in the model, metformin, and berberine groups after 8 and 10 weeks of dosing. In the Morris water maze test, escape latency and time to find the platform from the contralateral quadrant were significantly shorter in the MB group than in the model group. The number of target crossings in 90 s and residence time in the target quadrant significantly increased in the metformin plus berberine group. According to ELISA, glycated hemoglobin, 8-hydroxydeoxyguanosine, protein carbonyl, tumor necrosis factor-α, NLRP3, and interleukin-1β levels were significantly lower in the MB group than in the model group, whereas interleukin-6 levels significantly increased. In HE staining experiments, compared with the model group, the neurons in the hippocampal region in the metformin plus berberine group were arranged neatly, with more complete shape, clear nuclear staining, and clear cell boundaries. In mass spectrometry imaging experiments, brain aspartate, N-acetyl-aspartate, and glutamate levels were significantly higher in the MB group than in the model group, whereas taurine and glucose levels significantly decreased.

Conclusion:

Oral administration of MB has protective effects on diabetes-induced cognitive dysfunction and stronger effects than using either drug alone. The mechanism of action may be related to anti-inflammatory and antioxidative stress effects and increase in excitatory amino acids levels.

Key words

db/db mice / diabetes-induced cognitive dysfunction / metformin / berberine / matrix-assisted laser desorption/ionization time-of-flight mass spectrometry imaging

引用本文

曹月盈, 孟祥宝, 孙桂波, 孙晓波, 孙懿, 赵欣, 蒲小平. 二甲双胍联合小檗碱对db/db小鼠糖尿病认知功能障碍的改善作用. 中国新药杂志, 2021 , 30 (8) : 690 -700 .

Yue-ying CAO, Xiang-bao MENG, Gui-bo SUN, Xiao-bo SUN, Yi SUN, Xin ZHAO, Xiao-ping PU. Metformin plus berberine alleviates cognitive dysfunction in db/db mice[J]. Chinese Journal of New Drugs, 2021 , 30 (8) : 690 -700 .

基金

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国家“重大新药创制”科技重大专项资助项目(2017ZX09101003-009-006)

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2021年第30卷第8期

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首发时间：2026-10-28
出版时间：2021-04-30

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录用日期：2020-05-20

基金

国家“重大新药创制”科技重大专项资助项目(2017ZX09101003-009-006)

作者信息

¹北京大学　药学院分子与细胞药理学系，北京　100191

²北京大学　天然药物及仿生药物国家重点实验室，北京　100191

³中国医学科学院北京协和医学院　药用植物研究所，北京　100193

⁴中国医学科学院北京协和医学院　中草药生物活性物质及资源利用重点实验室，北京　100193

⁵中国医学科学院北京协和医学院　国家中医药管理局中药抗糖脂代谢紊乱疗效评估重点实验室，北京　100193

通讯作者:

蒲小平，女，教授，博士生导师，主要从事神经药理学研究。联系电话：（010）82802431，E-mail：puxi-aopingbj@163.com。

赵欣，女，博士，讲师，主要从事神经药理学研究。联系电话：（010）82802648，E-mail：zhaoxin2010@bjmu.edu.cn。

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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