芪芎左归颗粒通过上调BDNF/TrkB通路提高衰老大鼠突触可塑性

doi:10.12122/j.issn.1673-4254.2025.08.03

南方医科大学学报 ›› 2025, Vol. 45 ›› Issue (8): 1589-1598.doi: 10.12122/j.issn.1673-4254.2025.08.03

• • 上一篇

芪芎左归颗粒通过上调BDNF/TrkB通路提高衰老大鼠突触可塑性

王庆阁¹(), 赵晓慧², 何宇轩², 刘飞祥³, 张运克³()

^1.河南省中医院/河南中医药大学第二附属医院人才库，郑州 450000
^2.河南中医药大学第一临床医学院，郑州 450000
^3.河南中医药大学第一附属医院脑病科，郑州 450000

收稿日期:2025-03-01 出版日期:2025-08-20 发布日期:2025-09-05
通讯作者: 张运克 E-mail:826955610@qq.com;henanzyk@126.com
作者简介:王庆阁，主治医师，博士，E-mail: 826955610@qq.com
基金资助:
国家自然科学基金(81974564);国家自然科学基金(82104730);中原英才计划——科技创新领军人才项目(224200510027);河南省“双一流”创建学科中医学科学研究专项(HSRP-DFCTCM-2023-1-04);河南省中医药科学研究专项课题(2023ZY1030)

Qixiong Zuogui Granules enhance synaptic plasticity in aging rats by regulating the BDNF/TrkB signaling pathway

Qingge WANG¹(), Xiaohui ZHAO², Yuxuan HE², Feixiang LIU³, Yunke ZHANG³()

^1.Talent Pool of Henan Province Hospital of Traditional Chinese Medicine, Zhengzhou 450000, China
^2.First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou 450000, China
^3.Department of Encephalopathy, First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China

Received:2025-03-01 Online:2025-08-20 Published:2025-09-05
Contact: Yunke ZHANG E-mail:826955610@qq.com;henanzyk@126.com
Supported by:
National Natural Science Foundation of China(81974564)

摘要/Abstract

摘要：

目的探讨芪芎左归颗粒通过调控脑源性神经营养因子（BDNF）/酪氨酸激酶受体B（TrkB）通路对衰老大鼠突触可塑性的影响。方法将40只SD大鼠随机分为对照（Control）组、模型（Model）组、阳性药多奈哌齐（Don）组、中药芪芎左归颗粒（QXZG）组，10只/组。除对照组外，其余各组大鼠均连续腹腔注射D-半乳糖构建脑衰老大鼠模型；造模同时，Don组给予盐酸多奈哌齐混悬液（0.45 mg/kg灌胃）、QXZG组给予芪芎左归颗粒混悬液（7.97 g/kg灌胃），持续8周。干预结束后，评估各组大鼠的一般情况情况、行为学表现、血清中超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）活力及丙二醛（MDA）含量；HE及尼氏染色观察海马CA1区病理变化；免疫组化法检测细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A/p16INK4a）蛋白阳性表达、免疫荧光法观察突触可塑性蛋白突触素（SYN）、生长相关蛋白43（GAP43）的阳性表达、蛋白免疫印迹检测BDNF/TrkB通路相关蛋白及突触后致密蛋白95（PSD95）的表达情况。结果与对照组相比，模型组大鼠出现牙齿、毛发变黄，体质量减轻等衰老表型并表现出学习记忆能力的损伤；血清SOD、GSH-Px活力降低，MDA含量升高（P<0.001）；海马CA1区出现病理损伤，尼氏小体减少伴有p16蛋白升高（P<0.001）；BDNF/TrkB通路蛋白BDNF、TrkB、CREB及突触可塑性蛋白SYN、GAP43、PSD95表达量降低（P<0.01）。与模型组相比，芪芎左归颗粒能够一定程度上抑制大鼠衰老表型的发生，提高学习记忆能力；改善海马CA1区病理损伤，降低氧化应激反应及p16蛋白表达（P<0.05）；促进BDNF/TrkB通路蛋白及突触可塑性蛋白表达（P<0.05）。结论芪芎左归颗粒可能通过上调BDNF/TrkB信号通路相关蛋白的表达，提高衰老大鼠突触可塑性、降低体内氧化应激水平，发挥抗脑衰老及提高学习记忆能力的作用。

关键词: 脑衰老, BDNF/TrkB信号通路, 突触可塑性, 学习记忆, 芪芎左归颗粒

Abstract:

Objective To exple the mechanism of Qixiong Zuogui Granules (QXZG) for enhancing synaptic plasticity in aging rats. Method Forty SD rats were randomized into control group, aging model group, donepezil treatment group, and QXZG treatment group (n=10). Except for the control rats, all the rats were subjected to daily intraperitoneal injection of D-galactose for 8 consecutive weeks to induce brain aging, and donepezil hydrochloride and QXZG suspension were administered by gavage during modeling. After the interventions, the rats were evaluated for general conditions, behavioral changes, oxidative stress indicators, hippocampal pathologies, and expressions of the brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) pathway, p16, and synaptic plasticity-associated proteins. Results The rats in the model group exhibited obvious aging phenotypes such as yellowing of the teeth and hair, body weight loss, and impaired learning and memory abilities, with decreased serum SOD and GSH-Px activities and increased serum MDA level. The rat models also showed obvious pathological changes, reduced Nissl bodies, and elevated p16 protein expression in the hippocampal CA1 region, with significantly decreased expression levels of BDNF, TrkB, CREB and synaptic plasticity proteins SYN, GAP43, and PSD95. Treatment with QXZG alleviated the aging phenotypes in the rat models, improved their learning and memory abilities and pathological changes in the hippocampal CA1 region, reduced oxidative stress and p16 protein expression, and promoted the expressions of the BDNF/TrkB pathway proteins and synaptic plasticity proteins. Conclusion QXZG enhances synaptic plasticity and reduces oxidative stress in aging rats possibly by upregulating the BDNF/TrkB signaling pathway proteins, thereby delaying brain aging and improving learning and memory abilities of the rats.

Key words: brain aging, BDNF/TrkB signaling pathway, synaptic plasticity, learning and memory, Qixiong Zuogui Granules

王庆阁, 赵晓慧, 何宇轩, 刘飞祥, 张运克. 芪芎左归颗粒通过上调BDNF/TrkB通路提高衰老大鼠突触可塑性[J]. 南方医科大学学报, 2025, 45(8): 1589-1598.

Qingge WANG, Xiaohui ZHAO, Yuxuan HE, Feixiang LIU, Yunke ZHANG. Qixiong Zuogui Granules enhance synaptic plasticity in aging rats by regulating the BDNF/TrkB signaling pathway[J]. Journal of Southern Medical University, 2025, 45(8): 1589-1598.

图/表 6

图1 造模期间各组大鼠体质量情况

Fig.1 Changes in body mass of the rats in each group during modeling. Don: Donepezil treatment. QXZG: Qixiong Zuogui Granules.

表1 各组大鼠血清氧化应激指标结果

Tab.1 Comparison of serum oxidative stress indexes of the rats among the 4 groups

Group	SOD (U/mL)	MDA (nmol/mL)	GSH-Px (U/mL)
Control	142.91±9.22	3.88±0.32	1317.86±33.34
Model	115.30±6.80¹⁾	5.63±0.56¹⁾	1038.23±69.17¹⁾
Don	131.94±6.50²⁾	4.48±0.61³⁾	1212.83±56.60³⁾
QXZG	134.53±12.54²⁾	4.40±0.52³⁾	1244.88±83.56⁴⁾

图4 各组大鼠海马CA1区HE染色

Fig.4 HE staining of the hippocampal CA1 region of the rats in each group (Original magnification: ×200).

图5 各组大鼠海马CA1区尼氏染色

Fig.5 Nissl staining of the hippocampal CA1 region of the rats in each group (×200). Black arrows indicate Nissl bodies.

图7 各组大鼠海马SYN、GAP43蛋白比较

Fig.7 Comparison of SYN and GAP43 proteins in the hippocampus of the rats in the 4 groups. A: Expression of SYN proteins in the hippocampal CA1 region (×200). B: Expression of GAP43 proteins in the hippocampal CA1 region (×200). C, D: Mean fluorescence intensity of SYN and GAP43 proteins. ***P<0.001 vs Control group; ##P<0.01, ###P<0.001 vs Model group.

图8 各组大鼠海马组织中BDNF/TrkB通路蛋白及PSD95蛋白相对表达量

Fig.8 Comparison of BDNF/TrkB pathway proteins and PSD95 proteins in the hippocampus of the rats among the 4 groups. A: Protein bands in Western blotting. B-E: Relative expression levels of BDNF, TrkB, CREB, and PSD95 proteins. **P<0.01, ***P<0.001 vs Control group; #P<0.05, ##P<0.01 vs Model group.

参考文献 47

[1]	Guerville F, De Souto Barreto P, Ader I, et al. Revisiting the hallmarks of aging to identify markers of biological age[J]. J Prev Alzheimers Dis, 2020, 7(1): 56-64. doi：10.14283/jpad.2019.50
[2]	Case SL, Frazier HN, Anderson KL, et al. Falling short: the contribution of central insulin receptors to gait dysregulation in brain aging[J]. Biomedicines, 2022, 10(8): 1923. doi：10.3390/biomedicines10081923
[3]	Hajam YA, Rani R, Ganie SY, et al. Oxidative stress in human pathology and aging: molecular mechanisms and perspectives[J]. Cells, 2022, 11(3): 552. doi：10.3390/cells11030552
[4]	You H, Lu B. Diverse functions of multiple Bdnf transcripts driven by distinct Bdnf promoters[J]. Biomolecules, 2023, 13(4): 655. doi：10.3390/biom13040655
[5]	Numakawa T, Odaka H. The role of neurotrophin signaling in age-related cognitive decline and cognitive diseases[J]. Int J Mol Sci, 2022, 23(14): 7726. doi：10.3390/ijms23147726
[6]	Magee JC, Grienberger C. Synaptic plasticity forms and functions[J]. Annu Rev Neurosci, 2020, 43: 95-117. doi：10.1146/annurev-neuro-090919-022842
[7]	Fernández de Sevilla D, Nuñez A, Araque A, et al. Metabotropic regulation of synaptic plasticity[J]. Neuroscience, 2021, 456: 1-3. doi：10.1016/j.neuroscience.2020.10.006
[8]	张欣蕾, 王家传, 赵红. 中医药抗衰老的研究进展[J]. 深圳中西医结合杂志, 2023, 33(2): 129-33.
[9]	薄文集, 石和元, 王平. 《本草纲目》对衰老的认识及其防治老年病的思想特点[J]. 湖北中医药大学学报, 2018, 20(2): 47-50. doi：10.3969/j.issn.1008-987x.2018.02.11
[10]	魏智慧. 芪芎左归饮治疗老年颈动脉粥样硬化患者(肾虚血瘀型)的临床观察及对血清P53、P21的影响[D]. 郑州: 河南中医药大学, 2023.
[11]	孙世标. 芪芎左归饮治疗脑动脉粥样硬化的临床疗效观察及其对NF-κB相关级联因子的影响[D]. 郑州: 河南中医药大学, 2023.
[12]	李少康. 衰老后脑卒中血瘀证与神经血管单元SIRT1/NF-κB通路相关性研究[D]. 郑州: 河南中医药大学, 2023.
[13]	要莹莹, 樊飞燕, 李少康, 等. 芪芎左归复方干预骨髓间充质干细胞外泌体对缺血性脑卒中大鼠血脑屏障通透性的影响及抗衰老作用[J]. 中国中药杂志, 2024, 49(18): 5016-24. doi：10.19540/j.cnki.cjcmm.20240524.501
[14]	魏伟, 吴希美, 李元建. 药理实验方法学[M]. 4版. 北京: 人民卫生出版社, 2010.
[15]	韩诚, 张俊龙. 从“肾脑相关” 论衰老学习记忆功能障碍[J]. 中华中医药杂志, 2020, 35(10): 5112-6.
[16]	Villeda SA, Plambeck KE, Middeldorp J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice[J]. Nat Med, 2014, 20(6): 659-63. doi：10.1038/nm.3569
[17]	江晶晶, 江励华, 黄臻, 等. 补肾活血法在延缓大脑衰老过程中的应用[J]. 长春中医药大学学报, 2014, 30(6): 1064-7. doi：10.13463/j.cnki.cczyy.2014.06.039
[18]	陈珞珈. 黄帝内经[M]. 长春: 吉林大学出版社, 2009.
[19]	尹佳婷. 黄芪对自然衰老小鼠肠道功能及菌群稳态的调控作用研究[D]. 南京: 南京中医药大学, 2022.
[20]	董昱, 葛伟. 中药菟丝子抗衰老作用研究进展[J]. 实用老年医学, 2024, 38(3): 219-22. doi：10.3969/j.issn.1003-9198.2024.03.002
[21]	张继雅. 山桃仁水提物延缓线虫衰老及其机制研究[D]. 太原: 山西大学, 2023.
[22]	杨芊芊. 牛膝拮抗衰老小鼠及衰老神经干细胞的药效物质基础研究[D]. 北京: 北京中医药大学, 2020.
[23]	袁荣献, 代欣, 封帆, 等. 新工艺炮制的熟地黄对D-半乳糖致衰老小鼠学习记忆障碍的作用及机制研究[J]. 江苏中医药, 2024, 56(11): 72-7.
[24]	杨雁, 孙羽灵, 孙建梅, 等. 山药活性成分药理作用研究进展[J]. 中国野生植物资源, 2022, 41(12): 55-60. doi：10.3969/j.issn.1006-9690.2022.12.011
[25]	Qin XD, Hua J, Lin SJ, et al. Astragalus polysaccharide alleviates cognitive impairment and β-amyloid accumulation in APP/PS1 mice via Nrf2 pathway[J]. Biochem Biophys Res Commun, 2020, 531(3): 431-7. doi：10.1016/j.bbrc.2020.07.122
[26]	紫仰, 吴慧珍, 李安哲, 等. 山茱萸化学成分及药理作用研究[J]. 广州化工, 2023, 51, 3: 20-2.
[27]	朱紫悦, 金美玲, 许翔月, 等. D-半乳糖诱导脑老化模型机制的研究进展[J]. 中国比较医学杂志, 2024, 34(10): 104-10, 117.
[28]	刘建亚, 冯文静, 王仁萍, 等. D-半乳糖致衰老动物模型及其机制研究进展[J]. 中华老年多器官疾病杂志, 2018, 17(3): 224-7. doi：10.11915/j.issn.1671-5403.2018.03.049
[29]	Azman KF, Zakaria R. D-Galactose-induced accelerated aging model: an overview[J]. Biogerontology, 2019, 20(6): 763-82. doi：10.1007/s10522-019-09837-y
[30]	Shwe T, Pratchayasakul W, Chattipakorn N, et al. Role of D-galactose-induced brain aging and its potential used for therapeutic interventions[J]. Exp Gerontol, 2018, 101: 13-36. doi：10.1016/j.exger.2017.10.029
[31]	Wang BS, Han J, Elisseeff JH, et al. The senescence-associated secretory phenotype and its physiological and pathological implications[J]. Nat Rev Mol Cell Biol, 2024, 25(12): 958-78. doi：10.1038/s41580-024-00727-x
[32]	Theleritis C, Siarkos K, Politis A, et al. A systematic review of pharmacological interventions for apathy in aging neurocognitive disorders[J]. Brain Sci, 2023, 13(7): 1061. doi：10.3390/brainsci13071061
[33]	Rao YL, Ganaraja B, Murlimanju BV, et al. Hippocampus and its involvement in Alzheimer's disease: a review[J]. 3 Biotech, 2022, 12(2): 55. doi：10.1007/s13205-022-03123-4
[34]	Chidambaram SB, Anand N, Varma SR, et al. Superoxide dismutase and neurological disorders[J]. IBRO Neurosci Rep, 2024, 16: 373-94. doi：10.1016/j.ibneur.2023.11.007
[35]	Militello R, Luti S, Gamberi T, et al. Physical activity and oxidative stress in aging[J]. Antioxidants (Basel), 2024, 13(5): 557. doi：10.3390/antiox13050557
[36]	Fan AP, An HY, Moradi F, et al. Quantification of brain oxygen extraction and metabolism with [¹⁵O]-gas PET: a technical review in the era of PET/MRI[J]. Neuroimage, 2020, 220: 117136. doi：10.1016/j.neuroimage.2020.117136
[37]	Li YY, Li F, Qin DD, et al. The role of brain derived neurotrophic factor in central nervous system[J]. Front Aging Neurosci, 2022, 14: 986443. doi：10.3389/fnagi.2022.986443
[38]	Johnstone A, Mobley W. Local TrkB signaling: themes in development and neural plasticity[J]. Cell Tissue Res, 2020, 382(1): 101-11. doi：10.1007/s00441-020-03278-7
[39]	Arévalo JC, Deogracias R. Mechanisms controlling the expression and secretion of BDNF[J]. Biomolecules, 2023, 13(5): 789. doi：10.3390/biom13050789
[40]	Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: From synaptic regulation to psychiatric disorders[J]. Cell, 2022, 185(1): 62-76. doi：10.1016/j.cell.2021.12.003
[41]	Guo CP, Liu Y, Fang MS, et al. ω-3PUFAs improve cognitive impairments through Ser133 phosphorylation of CREB upregulating BDNF/TrkB signal in schizophrenia[J]. Neurotherapeutics, 2020, 17(3): 1271-86. doi：10.1007/s13311-020-00859-w
[42]	Cai CY, Wang LF, Li SX, et al. Ras inhibitor lonafarnib rescues structural and functional impairments of synapses of Aβ_1-42 mice via α7nAChR-dependent BDNF upregulation[J]. J Neurosci, 2022, 42(31): 6090-107. doi：10.1523/jneurosci.1989-21.2022
[43]	Mirza FJ, Zahid S. The role of synapsins in neurological disorders[J]. Neurosci Bull, 2018, 34(2): 349-58. doi：10.1007/s12264-017-0201-7
[44]	Schmitt U, Tanimoto N, Seeliger M, et al. Detection of behavioral alterations and learning deficits in mice lacking synaptophysin[J]. Neuroscience, 2009, 162(2): 234-43. doi：10.1016/j.neuroscience.2009.04.046
[45]	Mardones MD, Jorquera PV, Herrera-Soto A, et al. PSD95 regulates morphological development of adult-born granule neurons in the mouse hippocampus[J]. J Chem Neuroanat, 2019, 98: 117-23. doi：10.1016/j.jchemneu.2019.04.009
[46]	VanGuilder HD, Farley JA, Yan H, et al. Hippocampal dysregulation of synaptic plasticity-associated proteins with age-related cognitive decline[J]. Neurobiol Dis, 2011, 43(1): 201-12. doi：10.1016/j.nbd.2011.03.012
[47]	Li B, Wang ZJ, Yu M, et al. miR-22-3p enhances the intrinsic regenerative abilities of primary sensory neurons via the CBL/p-EGFR/p-STAT3/GAP43/p-GAP43 axis[J]. J Cell Physiol, 2020, 235(5): 4605-17. doi：10.1002/jcp.29338

芪芎左归颗粒通过上调BDNF/TrkB通路提高衰老大鼠突触可塑性

Qixiong Zuogui Granules enhance synaptic plasticity in aging rats by regulating the BDNF/TrkB signaling pathway

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

图/表 6

参考文献 47

相关文章 10

编辑推荐

Metrics

本文评价

[1]	李明明, 何梁超, 李天雨, 鲍岩, 徐祥, 陈光. 小鼠顶叶皮层反复轻度创伤性脑损伤抑制延髓NLG-1和PSD-95的表达[J]. 南方医科大学学报, 2024, 44(5): 960-966.
[2]	林如辉, 夏金言, 马小涵, 李钻芳. 电针通过促进突触再生改善脑缺血再灌注损伤大鼠的学习记忆功能[J]. 南方医科大学学报, 2024, 44(12): 2317-2326.
[3]	李帆, 朱艳艳, 孙晓明, 胡慧娟, 周苗苗, 白怡雪, 胡浩. 邻苯二甲酸二乙基己酯可能通过损伤血脑屏障诱导小鼠焦虑样行为和学习记忆障碍[J]. 南方医科大学学报, 2022, 42(8): 1237-1243.
[4]	葛鑫宇, 郭芳, 范俊, 陈宝田, 于林, 任静, 李纪强, 卢成林, 莫嘉文, 李树基, 袁乐欣, 胡号应, 刘赟, 周晓, 崔娟, 朱志敏, 曹雄. 柴胡桂枝汤通过sirt1-p53信号通路产生抗抑郁作用[J]. 南方医科大学学报, 2021, 41(3): 399-405.
[5]	张泰然，张威，孙远远，霍强. 氟西汀增强小鼠的联合式学习记忆能力[J]. 南方医科大学学报, 2020, 40(03): 413-417.
[6]	柴继侠，李徽徽，王元元，柴强，贺文欣，周艳梅，胡小冬，王震寰. 二烯丙基二硫对AD模型小鼠学习记忆能力和海马突触的影响[J]. 南方医科大学学报, 2016, 36(10): 1417-.
[7]	秦启忠，赵奇，陈纯海，周舟，余争平. 芦丁对三甲基锡损害学习记忆功能的保护作用与拮抗突触囊泡蛋白表达下调有关[J]. 南方医科大学学报, 2015, 35(01): 113-.
[8]	朱汉祎，宾娟，王闯，林焕冰，周恒，徐江平. 椒苯酮胺对脑缺血再灌注大鼠认知障碍的影响[J]. 南方医科大学学报, 2011, 31(11): 1858-.
[9]	曹新生, 吴兴裕, 孙喜庆, 刘挺松. 低G预适应对高G暴露致大鼠学习记忆功能受损的影响[J]. 南方医科大学学报, 2005, 25(02): 212-215.
[10]	巴恩平¹, 欧阳石², 李琳², 徐江平². 中药益智胶囊对大鼠全脑缺血后海马CA1区神经元迟发性死亡的影响[J]. 南方医科大学学报, 2004, 24(07): 749-751.