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围绝经期综合征(climacteric syndrome, CMS)是绝经前后女性因其卵巢功能衰退、雌激素水平波动或下降，而出现的烦躁易怒、失眠多梦、潮热汗出等一系列症状。现代医学治疗CMS是以激素替代疗法(hormone replacement therapy, HRT)为主要手段，存在不良反应大、长期使用危害性大影响疗效等问题。中医以肝郁气滞为CMS的主要病因，而白芍养血柔肝、养阴润燥，具有疏肝解郁的功效，是近代中医临床上治疗CMS的高频用药。芍药苷(paeoniflorin, PF)是中药白芍的主要活性成分，已知具有抗抑郁、保肝、保护神经、镇静催眠等多种药理作用。对国内外相关文献进行梳理归纳，就PF在肝郁气滞所致CMS中情绪障碍、睡眠障碍、认知障碍、骨质疏松症、血管舒缩症状5个方面的药理作用及机制进行综述，发现PF通过调节下丘脑-垂体-肾上腺轴活性，保护海马神经、抑制海马炎症反应，调整肠道中的炎症因子表达发挥抗抑郁作用可改善CMS的情绪障碍；PF可通过调节海马脑源性神经营养因子(BDNF)/酪氨酸蛋白激酶受体B(TrkB)通路等途径来缓解睡眠障碍；PF能通过提高海马神经因子水平、缓解神经元损伤，激活腺苷A受体来起到改善CMS认知障碍的作用；PF可以促进成骨生成、抑制成骨细胞凋亡和破骨细胞的生成，从而改善骨质疏松症。此外，还讨论了PF药物动力学中生物利用度低及PF低毒性的特点。综上，PF的临床应用提供借鉴依据，促进对其进一步深入研究。
Abstract：Climacteric syndrome(CMS) is a group of symptoms that women suffer before and after menopause, including irritability, insomnia, excessive dreaming, hot flashes and sweating, due to the decline of ovarian function, fluctuations or decreases in estrogen levels. The modern medical treatment of CMS is hormone replacement therapy(HRT) and it has significant side effects and long-term harmful effects on the therapeutic effect. Traditional Chinese medicine believes that the main cause of CMS is liver depression and Qi stagnation, and Baishao(Paeonia lactiflora),commonly utilized in clinical practice for its capacity to nourish blood, soften liver, nourish Yin and moisten dryness, is a high-frequency drug used in modern Chinese medicine clinical practice to treat CMS. Paeoniflorin(PF),the major active component of Baishao(Paeonia lactiflora),has been shown to have antidepressant, hepatoprotective, neuroprotective, sedative and hypnotic activities. A review of relevant domestic and international literature was conducted in this study to summarize the pharmacological effects and mechanisms of PF in emotional disorders, sleep disorders, cognitive disorders, osteoporosis and vascular constriction symptoms caused by liver depression and Qi stagnation in CMS. It was discovered that PF can improve emotional disorders by regulating the activity of the hypothalamic-pituitary-adrenal axis, protecting hippocampal neurons, inhibiting hippocampal inflammation, while adjusting the expressions of inflammatory factors in the intestines. By influencing the hippocampus brain-derived neurotrophic factor(BDNF)/tyrosine protein kinase B(TrkB) pathway, PF can treat sleep problems. By raising hippocampus neurotrophic factor levels, alleviating neuronal damage and activating adenosine A receptors, PF can ameliorate cognitive problems in CMS. PF can improve osteoporosis by increasing bone production and inhibiting osteoblast death and osteoclastogenesis. Furthermore, this paper examined the properties of poor bioavailability in pharmacokinetics, and lower the toxicity of PF. Considering the aforementioned aspects, the objective of this scholarly paper was to establish a solid foundation for the practical implementation of PF within clinical settings and to encourage further comprehensive investigation in this particular area.
[1] 李婴，钱梅芳.综合治疗更年期综合征[J].现代中西医结合杂志，2007,16(32):4823.
[2] 王艳宏，张利那，赵曙宇，等.中药治疗围绝经期综合征的研究概述[J].中医药信息，2021,38(8):76-80.
[3] 晏子.调更汤治疗肝郁气滞型乳腺癌类更年期综合征患者病例观察[D].乌鲁木齐：新疆医科大学，2019.
[4] 付文静.治疗围绝经期综合征的中医近代文献研究[D].哈尔滨：黑龙江中医药大学，2021.
[5] 许琳娜，龚莉莉，杜雪寒，等.香芍颗粒治疗围绝经期妇女情绪障碍的随机双盲及安慰剂对照临床研究[J].中国妇幼保健，2021,7(21):5074-5077.
[6] MAKI P M,KORNSTEIN S G,JOFFE H,et al.Guidelines for the evaluation and treatment of perimenopausal depression:summary and recommendations[J].J Womens Health,2019,28(2):117-134.
[7] 王贵贤，常麦会，李庆丽，等.舒肝颗粒治疗围绝经期肝郁气滞型抑郁症的疗效观察[J].中国实验方剂学杂志，2019,25(6):114-119.
[8] HUANG H L,ZHAO J,JIANG L,et al.Paeoniflorin improves menopause depression in ovariectomized rats under chronic unpredictable mild stress[J].Int J Clin Exp Med,2015,8(4):5103-5111.
[9] MU D Z,XUE M,XU J J,et al.Antidepression and prokinetic effects of paeoniflorin on rats in the forced swimming test via polypharmacology[J].Evid Based Complement Alternat Med,2020,2020:2153571.
[10] CHEN X Q,CHEN S J,LIANG W N,et al.Saikosaponin A attenuates perimenopausal depression-like symptoms by chronic unpredictable mild stress[J].Neurosci Lett,2018,662:283-289.
[11] ZHANG S,JIANG M C,YAN S X,et al.Network pharmacology-based and experimental identification of the effects of paeoniflorin on major depressive disorder[J].Front Pharmacol,2021,12:793012.
[12] TAN X,DU Y P,LUO Q,et al.Network pharmacology and molecular docking analysis of the mechanism underlying yikunyin’s therapeutic effect on menopausal syndrome[J].Evid Based Complement Alternat Med,2022,2022:7302419.
[13] 杨琴，任昊阳，朱寒雨，等.白杨素通过抑制NLRP3炎性小体信号通路对围绝经期抑郁症模型大鼠产生保护作用[J].中国药理学通报，2020,36(7):1006-1011.
[14] TANG M L,CHEN M,LI Q.Paeoniflorin ameliorates chronic stress-induced depression-like behavior in mice model by affecting ERK1/2 pathway[J].Bioengineered,2021,12(2):11329-11341.
[15] 肖凯，罗艳敏，梁芯，等.抑郁症模型大鼠海马内小胶质细胞数量和炎症因子表达增加[J].第三军医大学学报，2021,43(5):367-375.
[16] 杨皓然，刘丽娜，葛飞，等.基于海马小胶质细胞M1型极化研究逍遥散对OVX联合CUS焦虑抑郁模型大鼠的影响[J].中国中药杂志，2020,45(20):4964-4970.
[17] CHEN J,WANG Z G,ZHENG Z M,et al.Neuron and microglia/macrophage-derived FGF10 activate neuronal FGFR2/PI3K/Akt signaling and inhibit microglia/macrophages TLR4/NF-κB-dependent neuroinflammation to improve functional recovery after spinal cord injury[J].Cell Death Dis,2017,8(10):e3090.
[18] BAI H L,CHEN S Z,YUAN T Z,et al.Paeoniflorin ameliorates neuropathic pain-induced depression-like behaviors in mice by inhibiting hippocampal neuroinflammation activated via TLR4/NF-κB pathway[J].Korean J Physiol Pharmacol,2021,25(3):217-225.
[19] CHENG J,CHEN M,WAN H Q,et al.Paeoniflorin exerts antidepressant-like effects through enhancing neuronal FGF-2 by microglial inactivation[J].J Ethnopharmacol,2021,274:114046.
[20] TIAN D D,WANG M,LIU A,et al.Antidepressant effect of paeoniflorin is through inhibiting pyroptosis CASP-11/GSDMD pathway[J].Mol Neurobiol,2021,58(2):761-776.
[21] ZHANG K,WANG Z Q,PAN X,et al.Antidepressant-like effects of Xiaochaihutang in perimenopausal mice[J].J Ethnopharmacol,2020,248:112318.
[22] 穆道周.芍药苷抗抑郁促动力作用的实验研究[D].南京：南京中医药大学，2016.
[23] 王成龙，覃裕旺，王林元，等.芍药苷、芍药内酯苷对血虚肝郁证大鼠行为学、HPA轴及单胺类神经递质的影响[C]//第二届临床中药学大会论文集，北京，2018.
[24] 李艳霞，张建军，王景霞，等.芍药苷对血虚肝郁证大鼠下丘脑-垂体-肾上腺轴和单胺类神经递质的影响[J].中华中医药杂志，2014,29(8):2591-2595.
[25] 张巧利，王妍，贾婵维，等.围绝经期抑郁大鼠肠道微生物菌群的研究[J].生殖医学杂志，2020,29(10):1344-1349.
[26] ZHANG Y,ZHU M Z,QIN X H,et al.The ghrelin/growth hormone secretagogue receptor system is involved in the rapid and sustained antidepressant-like effect of paeoniflorin[J].Front Neurosci,2021,15:631424.
[27] BAKER F C,ZAMBOTTI M D,COLRAIN I M,et al.Sleep problems during the menopausal transition:prevalence,impact,and management challenges[J].Nat Sci Sleep,2018,10:73-95.
[28] 柏新江.安神汤加减辨证治疗肝郁气滞型失眠的价值分析[J].医学食疗与健康，2022,20(10):17-20.
[29] 王永亮，贾坤平，袁珍，等.电针对慢性睡眠剥夺大鼠行为学及海马神经元形态学的影响[J].神经损伤与功能重建，2021,16(4):187-190.
[30] 石燕芳，张瑞娟，程惠，等.轻度认知功能障碍病人睡眠障碍与海马体积的相关性及中医证候分析[J].中西医结合心脑血管病杂志，2023,21(1):173-176.
[31] 曹华，冯美果，侯帅，等.电针三阴交对围绝经期失眠大鼠睡眠时相的影响及作用机制研究[J].针灸临床杂志，2019,35(8):80-83.
[32] 何军琴，尹晓丹，辛明蔚.补肾调肝清心方对围绝经期抑郁症睡眠障碍大鼠模型海马5-羟色胺1A受体、5-羟色胺2A受体的影响[J].环球中医药，2014(6):411-414.
[33] 司昕蕾，边甜甜，张育贵，等.基于BDNF/TrkB通路研究四逆散干预PTSD睡眠障碍大鼠的物质基础及其作用机制：中国睡眠研究会第十四届全国学术年会[C],中国，成都，2022.
[34] ALFINITO P D,CHEN X H,MASTROENI R,et al.Estradiol increases catecholamine levels in the hypothalamus of ovariectomized rats during the dark-phase[J].Eur J Pharmacol,2009,616(1-3):334-339.
[35] GUO W X,YAO X X,CUI R J,et al.Mechanisms of Paeoniaceae action as an antidepressant[J].Front Pharmacol,2022,13:934199.
[36] MONTI J M.Serotonin control of sleep-wake behavior[J].Sleep Med Rev,2011,15(4):269-281.
[37] 李越峰，张泽国，徐福菊，等.白芍改善睡眠作用的药效物质基础研究[J].中国实验方剂学杂志，2014,20(15):127-130.
[38] 李越峰，徐富菊，张泽国，等.芍药苷改善睡眠作用机制研究[J].中国临床药理学杂志，2015,31(1):56-58.
[39] 曾聪聪，谢泳泳，戴春秀，等.交泰丸治疗围绝经期心肾不交型失眠随机双盲对照临床研究[J].新中医，2022,54(8):41-44.
[40] CHEN C R,SUN Y,LUO Y J,et al.Paeoniflorin promotes non-rapid eye movement sleep via adenosine A1 receptors[J].J Pharmacol Exp Ther,2016,356(1):64-73.
[41] OISHI Y,HUANG Z L,FREDHOLM B B,et al.Adenosine in the tuberomammillary nucleus inhibits the histaminergic system via A1 receptors and promotes non-rapid eye movement sleep[J].Proc Natl Acad Sci U S A,2008,105(50):19992-19997.
[42] YIN D,LIU Y Y,WANG T X,et al.Paeoniflorin exerts analgesic and hypnotic effects via adenosine A1 receptors in a mouse neuropathic pain model[J].Psychopharmacology,2016,233(2):281-293.
[43] 胡佳佳.女性围绝经期抑郁症与雌激素受体基因多态性的相关性研究[D].广州：广州医学院，2011.
[44] 杨从，黄燕辉，莫友胜，等.当归芍药散通过调节ER/NF-ΚΚB/NLRP3缓解卵巢切除小鼠认知功能[J].中国药理学与毒理学杂志，2019,33(6):455.
[45] 沈建英，梁文娜，张凌媛，等.肝郁对围绝经期综合征大鼠认知功能及脑组织氧化应激的影响[J].福建中医药，2023,54(1):20-24.
[46] 李健，刘春娜，刘新宇，等.芍药苷对认知功能障碍小鼠学习记忆功能和海马神经因子的影响[J].江苏医药，2014,40(12):1365-1367.
[47] HE Z Q,HUAN P F,WANG L,et al.Paeoniflorin ameliorates cognitive impairment in Parkinson’s disease via JNK/p53 signaling[J].Metab Brain Dis,2022,37(4):1057-1070.
[48] 罗先钦.芍药苷激活CB2R对血管性痴呆大鼠的神经保护作用及机制研究[D].重庆：重庆医科大学，2018.
[49] KONG Y Y,PENG Q J,LV N,et al.Paeoniflorin exerts neuroprotective effects in a transgenic mouse model of Alzheimer’s disease via activation of adenosine A1 receptor[J].Neurosci Lett,2020,730:135016.
[50] 宋微，郭鑫，巴音桑，等.基于网络药理学和分子对接的关黄母颗粒治疗围绝经期综合征的作用机制研究[J].现代药物与临床，2023,38(1):48-57.
[51] ZHONG M,SONG W L,XU Y C,et al.Paeoniflorin ameliorates ischemic neuronal damage in vitro via adenosine A1 receptor-mediated transactivation of epidermal growth factor receptor[J].Acta Pharmacol Sin,2015,36(3):298-310.
[52] Management of osteoporosis in postmenopausal women:the 2021 position statement of The North American Menopause Society[J].Menopause,2021,28(9):973-997.
[53] 袁翰.补肾通络方激活HIF/VEGF信号通路促进骨质疏松大鼠模型的血管生成与抑制骨量流失[D].南京：南京中医药大学，2017.
[54] GONG R,XIAO H M,ZHANG Y H,et al.Identification and functional characterization of metabolites for bone mass in peri- and postmenopausal Chinese women[J].J Clin Endocrinol Metab,2021,106(8):e3159-e3177.
[55] 杨立宇，郭然，牟帅，等.芍药苷促进小鼠成骨分化抗骨质疏松作用的实验研究[J].中国骨质疏松杂志，2020,26(12):1742-1748,1759.
[56] 林紫微，杨菲，黄天一，等.芍药苷干预成骨细胞凋亡抗骨质疏松作用研究[J].南京中医药大学学报，2019,35(4):426-431.
[57] 王雨辰，芮立宁，贾川，等.强骨合剂通过Wnt3a/β-catenin/VEGF信号通路促进血管生成改善围绝经期大鼠骨质疏松的研究[J].南京中医药大学学报，2022,38(9):819-826.
[58] GUO W,YANG X G,SHI Y L,et al.The effects and mechanism of paeoniflorin in promoting osteogenic differentiation of MC3T3-E1[J].J Orthop Surg Res,2022,17(1):90.
[59] 郭紫缪，罗阳，王翠雪.围绝经期妇女血管舒缩症状测量及应用进展[J].护理学杂志，2016,31(24):99-102.
[60] 陈治梅.曲秀芬教授治疗围绝经期血管舒缩症状的用药规律研究[D].哈尔滨：黑龙江中医药大学，2022.
[61] 李连香，陈亚琼，吕葆真，等.GnRH受体和5-HT受体与更年期大鼠潮热的关系[J].解剖学杂志，2004,27(4):380-382.
[62] 乐娜，赵丹萍，张睿，等.白芍柔肝解郁有效成分芍药苷抗应激作用机制[J].中华中医药杂志，2021,36(12):7020-7028.
[63] 杨永录，昝旺，卜舒，等.5-HT1A受体阻断剂对乙醇引起大鼠低体温和行为性体温调节反应的影响[J].中国应用生理学杂志，2017,33(1):26-30.
[64] 金树梅，苏文华，崔广智.芍药苷在药物诱发抑郁模型中的抗抑郁作用观察[J].山东医药，2013,53(19):28-29.
[65] 靳贺超.血管性痴呆肾虚血瘀证病证结合动物模型的建立[D].石家庄：河北中医学院，2019.
[66] 陈继明.黑升麻制剂治疗GnRh-a所致围绝经期症状的临床评估与机制研究[D].南京：南京医科大学，2015.
[67] 王俊苹.芍药苷对抑郁模型大鼠生物节律的影响及机制研究[D].哈尔滨：黑龙江中医药大学，2015.
[68] ZEIDABADI A,YAZDANPANAHI Z,DABBAGHMANESH M H,et al.The effect of Salvia officinalis extract on symptoms of flushing,night sweat,sleep disorders,and score of forgetfulness in postmenopausal women[J].J Family Med Prim Care,2020,9(2):1086-1092.
[69] WANG S W,WU F H,ZHANG Y B,et al.Ameliorating effect of Erxian decoction combined with Fructus Schisandrae chinensis (Wu Wei Zi) on menopausal sweating and serum hormone profiles in a rat model[J].Chin Med,2016,11:47.
[70] XU Y,HE H,LI P,et al.Paeoniflorin inhibits proliferation and promotes autophagy and apoptosis of sweat gland cells[J].Exp Ther Med,2022,23(1):53.
[71] 霍晓光，胡欣彤，陈丽霞，等.芍药苷稳定性研究[J].中国科技论文，2017,12(18):2092-2097.
[72] 于双慧，毕开顺，佟玲.LC-MS/MS同时检测大鼠血浆中芍药苷和芍药内酯苷的浓度及其药代动力学研究[J].中华中医药学刊，2015,33(3):539-542.
[73] BAO B,ZHAO Y L,GONG H,et al.Quantification of paeoniflorin by fully validated LC-MS/MS method:its application to pharmacokinetic interaction between paeoniflorin and verapamil[J].Molecules,2022,27(23):8337.
[74] 刘丽丽，陈谢谢，殷玉婷，等.芍药苷对正常及毒性剂量下士的宁经皮给药大鼠体内药代动力学行为及脑组织分布影响研究[J].中国中药杂志，2022,47(4):1064-1072.
[75] WU C,LI B,ZHANG Y,et al.Intranasal delivery of paeoniflorin nanocrystals for brain targeting[J].Asian J Pharm Sci,2020,15(3):326-335.
[76] 徐唯哲，赵妍，秦一，等.低氧与常氧状态下芍药苷在大鼠体内的药代动力学比较[J].国际药学研究杂志，2016,43(2):336-340.
[77] 韩嘉艺，高飞，陈立江，等.单剂量口服芍药苷微乳在大鼠体内的药动学研究[J].中国药剂学杂志(网络版),2019,5(3):44-49.
[78] ZHAO M Y,ZHOU P,YU J,et al.The tissue distribution and excretion study of paeoniflorin-6'-O-benzene sulfonate (CP-25) in rats[J].Inflammopharmacology,2019,27(5):969-974.
[79] 李俊，李延凤，周爱武，等.白芍总甙的毒性研究[J].中国药理学通报，1991(1):53-55.
[80] 严伟伟，李国辉，赵佳骏，等.芍药苷抑制醋酸铅诱导大鼠海马神经元凋亡的机制[J].中华劳动卫生职业病杂志，2022,40(3):170-176.
[81] 赵迪，董浩然，刘学芳，等.芍药苷对缺氧人脐静脉血管内皮细胞的保护作用与摄取机制研究[J].中药药理与临床，2021,37(3):56-60.
[82] ZHANG X X,WANG Y G,LIANG Q D,et al.The Correlation between Chemical Composition,as Determined by UPLC-TOF-MS,and Acute Toxicity of Veratrum nigrum L.and Radix paeoniae alba[J].Evid Based Complement Alternat Med,2014,2014:892797.
[83] 张晗，罗清琼，朱丽萍，等.芍药苷抑制骨髓源性树突状细胞的成熟及功能[J].国际检验医学杂志，2018,39(24):3015-3018.
[84] 朱聪，贾秀红，刘迎雪.芍药苷对慢性髓系白血病耐阿霉素细胞株K562/ADR多药耐药性的逆转作用及机制[J].山东医药，2018,58(47):24-27.
[85] 宋柳.明水凝控巨噬细胞促糖尿病伤口愈合的研究[D].长春：吉林大学，2022.
基本信息:
DOI：10.13193/j.issn.1673-7717.2024.11.034
中图分类号:R271.116
引用信息:
[1]申琦,史磊,孙亚等.芍药苷针对围绝经期综合征的作用机制研究进展[J].中华中医药学刊,2024,42(11):177-184+293.DOI:10.13193/j.issn.1673-7717.2024.11.034.
基金信息:
国家科技部科技重大新药创制专项(2017ZX091064); 山东省自然科学基金面上项目(ZR2020ZD17)