药学学报

Herb	Active ingredient	Ref
Chaihu	Total saikosaponins	13, 14
Baishao	Total saikosaponins	15
Baihe	Total saikosaponins	16
Zhimu	Total saikosaponins	17
Dihuang	Catalpol	18
Suanzaoren	Total saikosaponins, total flavonoids	19, 20
Hehuanghua	Total flavonoids	21
Huanglian	Berberine	22
Wuzhuyu	Evodiamine	23
Baizhu	Atractylode Ⅰ, Ⅱ, Ⅲ	24
Ciwujia	Acanthopanax senticousus saponins	25
Dandouchi	Catherine genistein	26
Danggui	Ferulic acid	27
Foshou	Volatile	28
Fuling	Lysaccharides	29
Gancao	Flavonoids	30
Gouqizi	Polysaccharide	31
Heshouwu	Physcio	32
Houpo	Magnolol, honokiol	33
Huangqin	Baicalin, wogonoside, baicalein, wogonin	34
Renshen	Ginsenosides	35
Shichangpu	β-Asarone	36
Yuanzhi	Polygalaceae glycosides	37
Zhizi	Total crocin, iridoid glycoside	38
Jianyejia-	Bellidifolin, demethylbellidifolin,	39
longdan	swertianolin, norswertianolin

Herb	Active ingredient	Ref
Chaihu	Total saikosaponins	13, 14
Baishao	Total saikosaponins	15
Baihe	Total saikosaponins	16
Zhimu	Total saikosaponins	17
Dihuang	Catalpol	18
Suanzaoren	Total saikosaponins, total flavonoids	19, 20
Hehuanghua	Total flavonoids	21
Huanglian	Berberine	22
Wuzhuyu	Evodiamine	23
Baizhu	Atractylode Ⅰ, Ⅱ, Ⅲ	24
Ciwujia	Acanthopanax senticousus saponins	25
Dandouchi	Catherine genistein	26
Danggui	Ferulic acid	27
Foshou	Volatile	28
Fuling	Lysaccharides	29
Gancao	Flavonoids	30
Gouqizi	Polysaccharide	31
Heshouwu	Physcio	32
Houpo	Magnolol, honokiol	33
Huangqin	Baicalin, wogonoside, baicalein, wogonin	34
Renshen	Ginsenosides	35
Shichangpu	β-Asarone	36
Yuanzhi	Polygalaceae glycosides	37
Zhizi	Total crocin, iridoid glycoside	38
Jianyejia-	Bellidifolin, demethylbellidifolin,	39
longdan	swertianolin, norswertianolin

Herb pair	Object	Model	Text item	Biochemical indicator	Mechanism	Ref
Jianyejialongdan-Shichangpu	Male SD rat	CUMS	FST, OFT, body weight, SPT	5-HT, Glu, GABA, DA	Neuron protection, BDNF/Trkbsignal transduction pathway	54
Baihe-Zhimu	SD rat	Independent+CUMS	Morris water maze test, OFT, FST	CaM and CaMKⅡ proteins, CREB, mRNA	CaM signal transduction pathway	55
Wulinghunfen- Guyelianqiao	Male SD rat	CUMS	SPT	ACTH, CORT	HPA axis	56
Ciwujia-Zhizi	Male SD rat	Independent+CUMS		GSα, PKA, cAMP, IP₃ GIα, PKC	GSα-PKA-cAMP and PKC-IP3signal pathway	57 58
Chaihu-Baishao	Male SD rat	CUMS	Body weight, OFT, SPT	NE, 5-HT, 5-HIAA	Monoamine neurotransmitter system	59 60
Baihe-Zhimu	Male SD rat	CUMS	SPT, FST	NE, DA, 5-HT	Monoamine neurotransmitter system	61
Baihe-Dihuang	Male ICR mice	Behaviora despair, independent+CUMS	FST, TST, body weight	CORT, ACTH, DA 5-HT	HPA axis, monoamine neurotransmitter system	62
Baihe-Dihuabg	Male ICR mice	Behavioral despair, reserpine-induced	FST, OFT, TST, ptosis	NE, DA, 5-HIAA, 5-HT	Monoamine neurotransmitter system	63
Huanglian- Wuzhuyu	Male ICR mice	Behavioral despair, 5-HTP-induced, reserpine-induced	FST, TST, OFT, Ptosis, hypothermia	NE, DA, 5-HT	Monoamine neurotransmitter system	64
Sheng-Chao Suanzaoren	Male ICR mice	Behavioral despair, independent+CUMS, reserpine-induced, 5-HTP-induced, yohimbine-induced	SPT, TST Body weight, FST, OFT, head-twitch mortality rate, hypothermia ptosis	5-HT, 5-HIAA, DA	Monoamine neurotransmitter system	65
Banxia-Houpo	ICR mice	Behavioral despair	FST, TST			66
Suanzaoren- Hehuanhua	Clinical patient	Depression	HAMD, WCST, quality of life, cognitive function	5-HT, CRH, IL-6, BDNF	Nerve-endocrine-immune network, BDNF	67 68
Ciwujia-Zhizi	Clinical patient	Depression	HAMD, quality of life			69

Herb pair	Object	Model	Text item	Biochemical indicator	Mechanism	Ref
Jianyejialongdan-Shichangpu	Male SD rat	CUMS	FST, OFT, body weight, SPT	5-HT, Glu, GABA, DA	Neuron protection, BDNF/Trkbsignal transduction pathway	54
Baihe-Zhimu	SD rat	Independent+CUMS	Morris water maze test, OFT, FST	CaM and CaMKⅡ proteins, CREB, mRNA	CaM signal transduction pathway	55
Wulinghunfen- Guyelianqiao	Male SD rat	CUMS	SPT	ACTH, CORT	HPA axis	56
Ciwujia-Zhizi	Male SD rat	Independent+CUMS		GSα, PKA, cAMP, IP₃ GIα, PKC	GSα-PKA-cAMP and PKC-IP3signal pathway	57 58
Chaihu-Baishao	Male SD rat	CUMS	Body weight, OFT, SPT	NE, 5-HT, 5-HIAA	Monoamine neurotransmitter system	59 60
Baihe-Zhimu	Male SD rat	CUMS	SPT, FST	NE, DA, 5-HT	Monoamine neurotransmitter system	61
Baihe-Dihuang	Male ICR mice	Behaviora despair, independent+CUMS	FST, TST, body weight	CORT, ACTH, DA 5-HT	HPA axis, monoamine neurotransmitter system	62
Baihe-Dihuabg	Male ICR mice	Behavioral despair, reserpine-induced	FST, OFT, TST, ptosis	NE, DA, 5-HIAA, 5-HT	Monoamine neurotransmitter system	63
Huanglian- Wuzhuyu	Male ICR mice	Behavioral despair, 5-HTP-induced, reserpine-induced	FST, TST, OFT, Ptosis, hypothermia	NE, DA, 5-HT	Monoamine neurotransmitter system	64
Sheng-Chao Suanzaoren	Male ICR mice	Behavioral despair, independent+CUMS, reserpine-induced, 5-HTP-induced, yohimbine-induced	SPT, TST Body weight, FST, OFT, head-twitch mortality rate, hypothermia ptosis	5-HT, 5-HIAA, DA	Monoamine neurotransmitter system	65
Banxia-Houpo	ICR mice	Behavioral despair	FST, TST			66
Suanzaoren- Hehuanhua	Clinical patient	Depression	HAMD, WCST, quality of life, cognitive function	5-HT, CRH, IL-6, BDNF	Nerve-endocrine-immune network, BDNF	67 68
Ciwujia-Zhizi	Clinical patient	Depression	HAMD, quality of life			69

中药抗抑郁药对研究进展

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朱十伟 ¹^,² , 高晓霞 ¹ , 田俊生 ¹ , 秦雪梅 ¹ , 杜冠华 ¹^,³ , 周玉枝 ¹^,^*

药学学报 | 综述 2019,54(2): 235-244

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药学学报 | 综述 2019, 54(2): 235-244

中药抗抑郁药对研究进展

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朱十伟¹^,², 高晓霞¹, 田俊生¹, 秦雪梅¹, 杜冠华¹^,³, 周玉枝¹^,^*

作者信息

1.山西大学中医药现代研究中心, 山西太原 030006

2.山西大学化学化工学院, 山西太原 030006

3.中国医学科学院、北京协和医学院药物研究所, 北京 100050

通讯作者:

*周玉枝, Tel:86-351-7019178, E-mail:zhouyuzhi@sxu.edu.cn

Research progress of traditional Chinese antidepressant herb-pair

Shi-wei ZHU¹^,², Xiao-xia GAO¹, Jun-sheng TIAN¹, Xue-mei QIN¹, Guan-hua DU¹^,³, Yu-zhi ZHOU¹^,^*

Affiliations

1. Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China

2. College of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China

3. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China

出版时间: 2019-02-12 doi: 10.16438/j.0513-4870.2018-0825

文章导航

摘要

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抑郁症是一种致病因素多样且严重影响人类身心健康的全球性疾病，在我国中医理论中属于“郁证”的范畴。目前，由于抗抑郁西药不良反应的日益凸显，抗抑郁中药大复方因其复杂性所致的在有效成分及配伍机制研究中存在的难题，使得抗抑郁中药药对成为抗抑郁药物研究领域的热点。药对是中药复方的核心，甚至有的方剂本身就是一个药对，对抗抑郁药对进行研究更有利于阐明抗抑郁中药之间配伍机制及药对共同对机体的作用机制。因此，本文从抗抑郁药对的物质基础研究、药物代谢动力学研究及功效作用研究方面，对抗抑郁中药药对展开系统的阐述，以期为抗抑郁药对配伍机制及抗抑郁中药新药的研究提供理论支持。

关键词

抗抑郁 / 中药 / 药对 / 配伍机制 / 抑郁模型 / 药代动力学

Abstract

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Depression, a global disease with various pathogenic factors, is seriously affecting human physical and mental health. In Chinese traditional medical theory, the disease belongs to the category of "Yu Zheng". At present, on the one hand, adverse reactions to antidepressant western medicine are becoming more and more prominent. On the other hand, the study of their antidepressant active ingredients and compatibility mechanisms has become a difficult field in the traditional Chinese medicine compounds due to their complexity. The Chinese antidepressant herb-pairs has become a hot topic in the field of antidepressant research. Herb-pair is the core of traditional Chinese medicine compound. In addition, the compound itself is a herb-pair. The study of traditional Chinese antidepressant herb-pairs is more conducive to clarify the compatibility mechanism of herb interaction and the mechanism of antidepressants on the body.Therefore, this paper systematically expounds antidepressant herb-pairs from the study of material, pharmacokinetics and efficacy, which aims at providing theoretical support for the compatibility mechanism of antidepressant herb-pairs and the research of new antidepressant drugs.

Key words

antidepressant / traditional Chinese medicine / herb-pair / compatibility mechanism / depression model / pharmacokinetics

引用本文

朱十伟, 高晓霞, 田俊生, 秦雪梅, 杜冠华, 周玉枝. 中药抗抑郁药对研究进展. 药学学报, 2019 , 54 (2) : 235 -244 . DOI: 10.16438/j.0513-4870.2018-0825

Shi-wei ZHU, Xiao-xia GAO, Jun-sheng TIAN, Xue-mei QIN, Guan-hua DU, Yu-zhi ZHOU. Research progress of traditional Chinese antidepressant herb-pair[J]. Acta Pharmaceutica Sinica, 2019 , 54 (2) : 235 -244 . DOI: 10.16438/j.0513-4870.2018-0825

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抑郁症是一种发病率逐年升高的严重情绪节律障碍性精神疾病, 以显著而持久的心境低落为主要的临床症状。现阶段以西药治疗为主, 在一定程度上改善了抑郁症患者的症状, 但药物起效慢、治愈率低, 与此同时产生心血管系统、内分泌系统和认知障碍及肝毒性等不良反应^[1-3]。中药方剂因其多成分、多效应、多环节、多通路、多靶点和毒副作用小的优势, 成为抗抑郁药物研究中的热点领域。然而, 其复杂性成了研究难点, 研究者们一直在试图寻找和探索中药方剂配伍规律的研究方法, 如整方研究、拆方研究和量效关系研究等, 但配伍规律的现代研究并无很大突破, 成为中医药研究领域的瓶颈。药对虽配伍简单但不同于单味药, 同时组成固定而又无大复方的复杂多样, 是单味药的深入发展又是对复方药研究的开端^[4]。中药药对相比于大复方同样具备复方在临床治疗上的优势, 并且药味简化更有利于阐明中药的配伍规律。药对的配伍使用在中医药领域已发挥并将持续发挥重要的作用^[5]。

药对是中药方剂的核心和重要组成部分。抗抑郁中药方剂中, 一些方剂本身就是药对, 如百合知母汤即百合-知母、百合地黄汤即百合-地黄、左金丸即黄连-吴茱萸、交泰丸即黄连-肉桂、杜仲丸即杜仲-续断、半夏秫米汤即半夏-秫米、双夏汤即半夏-夏枯草、补肝散即夏枯草-香附和栀子豉汤即栀子-淡豆豉等, 单一药对组成的方剂既符合中医药对配伍理论又能起到抗抑郁作用。如百合宁心安神, 润肺止咳; 知母清热泻火, 滋阴润燥; 生地清热凉血, 养阴生津。百合知母伍用, 一润一清, 共奏润肺清热, 宁心安神之效; 百合佐生地黄以凉血, 血凉则热毒解而蕴结自行。黄连苦寒清热, 清心除烦; 吴茱萸辛散温通, 开郁散结; 肉桂散寒止痛, 通温经脉。黄连吴茱萸配伍, 有辛开苦降, 反佐之妙用; 黄连肉桂伍用, 一寒一热, 清心除烦。杜仲甘温偏入肾经气分、长与补养。续断味苦而重, 偏入肾经血分、长于活血通络, 二者相续为用止血寓有行血。半夏性辛温能同阳, 燥湿化痰; 秫米性味甘能营养; 夏枯草性味辛苦, 清肝泻火, 散结消肿。半夏秫米相合, 有补虚泻实“决渎壅塞”之功; 半夏夏枯草合用, 能疏肝解郁, 化痰理气。香附性平, 能散能将, 善理肝经之气滞。夏枯草和香附组成的补肝散具有行气泻火、清肝明目的功效。栀子苦寒, 清热泻火, 通利三焦; 豆豉辛甘微寒宣郁清热达表。栀子豆豉合用, 一宣一泻, 能清热除烦, 宣发郁热。除此之外, 现在的研究报道大复方中含有的核心药对是发挥抗抑郁作用的基础药物, 且药对本身亦能发挥很好的抗抑郁效果。如柴胡-白芍是疏肝解郁、调畅情志最基础的配伍药对, 为多个抗抑郁疗效确切的复方, 如《太平惠民和剂局方》逍遥散^[6-8]、《景岳全书》柴胡疏肝散^[9-11]、《伤寒论》四逆散^[12]等的基础药物。为促进抗抑郁中药药对配伍机制和抗抑郁机制研究, 以及以中药药对为基础的新药开发, 现对抗抑郁中药药对研究性文献进行统计分析。

经查阅文献, 目前涉及抗抑郁药对的种类有31种, 文献数量如图 1所示。在抗抑郁药对研究中, 对于百合-知母、黄连-吴茱萸、黄连-肉桂、柴胡-白芍和百合-地黄药对的物质基础和抗抑郁作用研究较多, 约占文献总量的61.3%, 是当前研究的热点。而栀子-首乌、栀子-枸杞子、远志-茯苓、人参-当归、人参-炒酸枣仁、刺五加-山楂和柴胡-黄芩等仅有少数文献, 有待于进一步研究。

1 抗抑郁药对研究现状

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作者通过总结发现, 目前抗抑郁药对的研究可系统地分为3个层次:药对物质基础研究、药对代谢动力学研究及药对功效作用研究。

1.1 抗抑郁药对的物质基础研究

明确中药的化学成分是深入探讨其药效物质及作用的基础。中药药效物质基础是对中药发挥功效有贡献成分的通称, 可从本质上阐明方剂配伍的科学内涵。抗抑郁药对物质基础研究主要从药对中具有抗抑郁活性的成分研究、配伍前后化学成分的变化进行配伍规律研究。对抗抑郁药对所涉及中药的活性成分进行总结, 如表 1^[13-39]所示。

1.1.1 药对中具有抗抑郁活性的成分研究

国内外对柴胡-白芍药对配伍前的化学组成、药效及质量控制等研究均较多, 认为柴胡皂苷、白芍总皂苷为抗抑郁有效成分^[13-15]。在百合-知母药对及百合-地黄药对配伍前的化学成分研究中, Wang等^[16]通过正交实验优化了百合总皂苷的提取, 并通过小鼠绝望模型和利血平诱导模型实验发现百合总皂苷具有确切的抗抑郁作用。Ren^[17]发现知母提取物知母总皂苷具有良好的抗抑郁活性, 且研究发现萨尔萨皂苷元是知母总皂苷中发挥抗抑郁作用的活性基团, 当其与糖基相联后可提高其抗抑郁活性。Wang等^[18]通过实验性研究发现地黄中主要化学成分梓醇可改善慢性温和不可预知抑郁模型(chronic unpredictable mild stress depression model, CUMS)大鼠的行为, 调节脑源性神经营养因子(brain derived neurotrophic factor, BDNF)、原肌球蛋白相关激酶、环氧化酶-2和前列腺素E2表达水平, 认为辛醇是地黄发挥抗抑郁作用的活性成分。生、炒酸枣仁药对和酸枣仁-合欢花药对的抗抑郁有效成分的研究中, Zhao等^{[19, 20]}通过小鼠行为绝望模型发现酸枣仁总皂苷和酸枣仁总黄酮为酸枣仁发挥抗抑郁作用的活性成分。Guo等^[21]应用孤养加CUMS建立抑郁症模型, 用旷场实验(open field test, OFT)测定各组大鼠行为变化, TUNEL原位杂交检测海马CA3区神经元细胞凋亡情况, 表明合欢花总黄酮具有抗抑郁作用。小檗碱作为一种抗炎药而被广泛应用, 对中枢神经系统疾病包括癫痫和阿尔茨海默病等具有药理学作用, 最近的研究发现小檗碱可能是黄连-肉桂药对抗抑郁作用的活性成分^[22]。Wang等^[23]通过CUMS模型实验观测大鼠体重、糖水偏好实验(sucroser prefrernce test, SPT)、行为学指标和大鼠海马单胺神经递质的影响, 发现吴茱萸碱具有明显的抗抑郁作用, 并通过利血平拮抗模型实验, 得到进一步证明。

1.1.2 药对配伍前后化学成分含量的变化

Geng等^[40]采用高效液相色谱法(HPLC)分析生、炒酸枣仁单煎液与二者合煎液的主要化学成分变化, 结果发现, 生、炒酸枣仁合煎液中斯皮诺素、酸枣仁皂苷A和酸枣仁皂苷B的含量均高于生、炒酸枣仁的单煎液, 表明生、炒酸枣仁相伍后其活性成分含量显著增加, 揭示促进抗抑郁有效成分的溶出量起到增效作用是药对配伍的机制之一。Zhu等^[41]通过LC-10ATvp HPLC考察白芍与柴胡配伍后对毒性成分苯甲酸煎出量的影响, 结果表明白芍与柴胡合煎后, 有害成分苯甲酸的煎出量明显下降。从另一方面揭示了降低毒性成分的溶出量起到减毒作用是药对配伍的另一机制。Hou等^[42]从盐炙与配伍角度对杜仲-续断药对及单品中3种药效部位进行含量分析, 发现杜仲、续断及杜仲丸盐炙品较三者生品中的总黄酮、总多糖含量有所增加, 总皂苷含量略有降低。用盐炙品合提, 总多糖含量低于两单味药之和, 总黄酮、总皂苷含量高于两单味药之和。通过对单味药泡制前后化学成分的对比进行配伍研究为药对研究提供了一条新思路。

1.1.3 药对配伍后新化学成分的发现

Wang等^[43]采用飞行时间质谱对知母-百合药对的成分进行了定性鉴别与结构解析。鉴定出4个新的知母皂苷类成分, 分别为知母皂苷I、知母皂苷AI、知母皂苷G和知母皂苷D, 阐述了加入百合后对知母物质基础的影响。Fang等^[44]从百合知母汤水煎液的二氯甲烷和醋酸乙酯萃取部分共分得9个化合物, 其中2, 3, 4'-三羟基-4-甲氧基二苯甲酮为首次公开报道的天然化合物, 对羟基桂皮酸首次在百合知母汤中发现, 可能为百合-知母共煎新产生的化学成分。Zhang等^[45]对柴胡-白芍药对的正丁醇萃取组份进行分离得到13个化合物, 其中邻苯二甲酸二丁酯、5-methyl-2-(1-methylethyl) phenyl β-D-glucopyranoside、马钱苷、3β, 1β, 29-三羟基齐墩果烷-12-烯-3-O-β-D-葡萄糖苷和旱莲苷Ⅰ均为首次从柴胡-白芍药对中分离得到。

综上, 根据目前文献报道在抗抑郁药对的物质基础研究中, 主要通过将从药物中分离出的化学成分进行抗抑郁作用研究来确定其活性成分, 进而通过化学方法研究抗抑郁药对中两种药物配伍后活性成分溶出量的增加或毒性的减少来确定其在体外的配伍机制。同时, 作者发现在药对配伍后的化学成分定性分析过程中, 研究者鉴定出一些新的化合物。但是这些新发现的化合物是否对药对的抗抑郁作用起到贡献有待进一步的证实。

1.2 抗抑郁药对的代谢动力学研究

中药的药物代谢动力学是借助于动力学原理, 研究中药发挥药效的有效部位、活性成分在生物体内吸收、分布、代谢和排泄的动态变化规律及在生物体内的时量-时效关系。运用药物代谢动力学方法研究药对, 定量表达药对中两种药物配伍后对彼此化学成分整体药代的相互影响, 可揭示药对在体内的协同增效配伍机制, 能够最大程度表征中药的整体处置规律, 反映整体效应物质在生物体内的存留特征。

1.2.1 抗抑郁药对配伍对药物吸收的影响

Zeng等^[46]研究黄连-吴茱萸不同配比在Caco-2单层细胞模型中的跨膜转运, 发现随着配比中黄连比例的增加, 小檗碱、巴马汀、药根碱和吴茱萸碱的渗透系数均随时间的推移呈线性增加趋势, 可以看出增加黄连的配伍比例, 有利于黄连和吴茱萸主要化学成分的吸收。Chen等^[47]研究了柴胡-白芍对肠吸收的影响, 结果显示, 在柴胡皂苷A、柴胡皂苷D的作用下, 芍药苷在回肠中的有效渗透率增加了2.11或1.90倍, 在结肠中的有效渗透率增加了2.42或2.18倍。Liu^[48]和Li^[49]等通过研究发现百合可使知母皂苷B-Ⅱ、知母皂苷B-Ⅲ和知母皂苷A-Ⅲ在动物体内的最大血药浓度(C_max)、血药浓度时间曲线下面积(AUC_0-t)、半衰期、平均滞留时间的药动学参数变大, 百合的加入促进了知母皂苷类成分的吸收。Zhu等^[50]考察了交泰丸在抑郁模型与空白大鼠体内的药代动力学行为, 结果表明巴马汀、黄连碱、小檗碱和药根碱在模型组与空白组大鼠体内相比, C_max分别为1.99、2.14、2.3和1.82倍, AUC_0-t分别为1.23、1.25、1.29和1.46倍, AUC_0-∞分别为1.21、1.25、1.30和1.43倍, 均具有极显著性差异。药物在发病和正常机体的吸收差异性为临床用药安全剂量提供了参考。

1.2.2 抗抑郁药对配伍对药物分布的影响

Zhang等^[51]探索黄连合用肉桂对小檗碱在大鼠体内分布的影响, 采用HPLC测定给药后大鼠心、肝、脾、肺和肾等脏器中小檗碱的浓度。发现多次给予黄连后, 小檗碱在组织中的浓度升高且在大鼠体内呈广泛分布, 但主要集中在肝组织中。配伍肉桂后, 大鼠心、肝、肾中小檗碱浓度明显增加, 而脾和肺中小檗碱浓度明显减少。说明肉桂明显影响着黄连中小檗碱在大鼠体内的分布趋向, 改变了小檗碱在大鼠各脏器中的分布比例, 使之分布趋向于心、肝和肾。

1.2.3 抗抑郁药对配伍对药物代谢的影响

Huang等^[52]在研究配伍吴茱萸后, 对黄连中有效成分盐酸小檗碱对大鼠肝脏代谢及大鼠肝脏药物代谢酶活性的影响时, 通过采用Nash显色、分光光度法测定大鼠肝微粒体中红霉素N-脱甲基酶和氨基比林N-脱甲基酶的活性, 发现配伍吴茱萸能明显抑制盐酸小檗碱的肝脏代谢, 从而延长其在体内发挥药效的时长, 这可能是连萸配伍的重要机制。Wang等^[53]采用生化、逆转录和蛋白质印迹法等方法检测药对对肝脏微粒体CYP450亚型活性及其转录RNA(mRNA)和蛋白表达的影响, 发现半夏-厚朴配伍改善了半夏对肝脏Cyp2e1活性和表达的激活作用, 避免了肝脏过氧化和中毒等损伤以达到减毒目的, 同时它们逆转了单味半夏对肝脏Cyp3a11活性与表达的增加, 弥补了药物在肝脏代谢太快的不足, 表明厚朴具有缓解半夏毒性的作用, 提示两者相须配伍后使毒性减小、药效增加。

1.2.4 抗抑郁药对配伍对药物排泄的影响

Wang等^[53]发现单用半夏或厚朴使转运子表达增高则可能会加快其原形和代谢物的排泄, 从而降低药效。而半夏配伍厚朴使用能平衡半夏、厚朴单独使用所引起肾脏阴离子转运蛋白OAT1/3、OCT1/2 mRNA或蛋白的表达增加, 使其恢复至正常水平以达到减缓原形和代谢成分排泄的作用, 从而达到协同增效的目的。

综上, 抗抑郁药对配伍后对药代动力学的影响, 主要从以下途径增强抗抑郁效果: ①药对配伍能提高有效成分的吸收速率及最大血药浓度; ②药对配伍能促进有效成分在靶组织、器官的分布浓度; ③药对配伍能延长有效成分在体内的半衰期, 抑制原型成分的代谢速率; ④药对配伍能延缓有效原形及代谢成分的排泄速率。

1.3 抗抑郁药对的功效作用研究

临床实践是传统中医药理论体系形成的主要形式, 中药方剂的配伍应用符合中医整体观的特点, 而中药这种复杂性却成为了中药现代化和国际化的瓶颈问题。中药的药效物质基础及有效成分研究成为揭示中药发挥功效的关键。而抗抑郁药对功效研究从模型动物实验到临床抑郁症患者的治疗均有报道。评价指标主要集中在行为学评分、血清(浆)生化和对内源性代谢物调节等方面, 既有研究药对的整体抗抑郁效果, 又有药对配伍后与配伍前单味药的抗抑郁效果的对比研究。有关抗抑郁药对功效研究如表 2^[54-69]所示。

1.3.1 模型大鼠作为对象的研究

1.3.1.1 药对配伍的整体功效研究

Wu^[54]通过CUMS模型发现尖叶假龙胆-石菖蒲药对组与模型组相比, 在以下几个药效评价方法上均显示有良好的抗抑郁作用: ①行为学方面:能增加大鼠体重、提高糖水偏爱率、缩短强迫游泳实验(forced swimming test, FST)中的不动时间、增加在旷场实验中的活动总路程; ②神经递质含量方面:不同程度地提高大鼠海马和内侧前额叶皮质中5-羟色胺(5-HT)、多巴胺(DA)和γ-氨基丁酸(GABA)的浓度, 降低谷氨酸(Glu)的浓度; ③神经元形态方面:可有效保护大鼠海马CA3区和mPFC神经元和逆转其损伤, 可通过增强神经元结构的可塑性来保护CA3区和mPFC结构。同时测得大鼠海马CA3区和mPFC中Bax和caspase-3的蛋白表达明显降低, Bcl-2、p-CREB的蛋白、BDNF、cAMP反应元件结合蛋白(CREB)和TrkBmRNA表达均升高。尖叶假龙胆-石菖蒲药对可有效保护、逆转大鼠海马和mPFC神经元的损伤、预防和抑制神经元凋亡, 其抗抑郁机制可能与神经元保护和神经可塑性及激活BDNF/Trkb介导的信号通路有关。Yuan等^[55]发现百合-知母药对能使抑郁模型大鼠海马组织CaM信号转导通路中的CaM、钙调蛋白激酶Ⅱ (CaMKⅡ)和CREB的mRNA表达水平明显升高。认为其发挥抗抑郁作用的机制与大鼠海马组织CaM信号转导通路中的CaM、CaMKⅡ和CREB等关键分子有关联。Liu等^[56]发现乌灵菌粉-贯叶连翘配伍可显著降低CUMS模型大鼠血清中促肾上腺皮质激素(ACTH)、皮质醇(CORT)和促肾上腺皮质激素释放激素(CRH)的含量, 升高海马组织中5-HT、NE和DA含量。其机制可能与增加海马组织中5-HT、DA和NE含量、改善应激刺激导致的下丘脑-垂体-肾上腺轴(hypothalamic- pituitary-adrenal axis, HPA)功能紊乱状态有关。Xu等^{[57, 58]}在对刺五加-栀子抗抑郁机制研究中发现药对组能通过增强CUMS模型大鼠海马、前额叶皮层中GSα蛋白表达和蛋白激酶A (PKA)活性及增加环磷酸腺苷(cAMP)含量; 亦可降低大鼠海马和额叶皮层中鸟嘌呤核苷酸偶联蛋白(GIα)、蛋白激酶C (PKC)和三磷酸肌醇(IP₃)含量, 认为刺五加-栀子药对可能通过调节GSα-PKA-cAMP信号通路和PKC-IP3信号通路发挥抗抑郁作用。

1.3.1.2 药对配伍前后的功效对比研究

Yu^[59]和Lu^[60]等通过CUMS模型大鼠实验, 发现柴胡-白芍药对在行为学上能使大鼠的体质量、糖水消耗量及旷场实验中穿越横格数及直立次数均显著增加; 在神经递质上能够对大鼠海马组织、皮质组织、下丘脑组织中NE和5-HT水平明显升高, 5-羟吲哚乙酸(5-HIAA)水平均明显降低; 单用柴胡和单用白芍各剂量组可以不同程度地逆转NE和5-HT减少, 降低5-HIAA水平, 柴胡白芍配伍使用抗抑郁效果优于单用柴胡和白芍。Du等^[61]发现百合-知母药对具有改善CUMS模型大鼠强迫游泳及糖水偏爱率的效果; 通过高效液相色谱-电化学检测法发现, 能提高5-HT和NE水平; 基于超高效液相质谱联用的代谢组学技术发现, 能使抑郁模型大鼠海马代谢谱中32种差异代谢物中的18种有明显的回升。与单味药相比, 24种差异代谢物有较好的回升, 说明知母-百合药对比单用知母、百合能发挥更好的抗抑郁作用。

1.3.2 模型小鼠作为对象的研究

1.3.2.1 药对配伍后的整体功效研究

Sun^[62]在百合地黄汤的实验研究中发现, 百合地黄汤能增加孤养加CUMS模型小鼠的体质量, 缩短强迫游泳和悬尾实验(tail suspension test, TST)中小鼠的不动时间, 显著降低小鼠血浆CORT和ACTH的浓度, 增加脑组织内单胺类神经递质DA和5-HT含量。提示百合地黄汤有很好的抗抑郁作用, 其机制可能是通过增加脑内单胺类递质含量来实现或可能与调节HPA轴功能紊乱有关。Chen等^[63]发现百合-地黄药对能够明显缩短行为绝望模型小鼠在强迫游泳和悬尾实验中的不动时间, 拮抗利血平拮抗模型中的小鼠眼睑下垂次数, 提高小鼠脑内NA、NE和5-HT水平同时降低5-HT/5-HIAA的比值。Wang等^[64]发现黄连-吴茱萸药对的醇提物显著减少了小鼠在强迫游泳和悬尾实验中的不动时间, 增强了在5-HTP诱导甩头模型中引起的小鼠甩头次数, 拮抗了利血平拮抗模型中的眼睑下垂和体温下降, 提高小鼠海马组织中NE、5-HT含量及纹状体中NE、DA和5-HT含量, 具有显著的抗抑郁效果。

1.3.2.2 药对配伍前后的功效对比研究

Wang^[65]在生、炒酸枣仁配伍抗抑郁作用研究中, 通过行为绝望模型发现, 生、炒酸枣仁相伍明显缩短小鼠强迫游泳和悬尾实验中不动时间。通过孤养加CUMS模型发现与模型组相比, 小鼠体质量增加、糖水消耗百分比和旷场行为学参数均有显著改善, 能够逆转小鼠中枢5-HT水平下降。通过药物诱导模型发现, 生、炒酸枣仁相伍可对抗利血平引起的体温下降和运动不能, 对睁眼不能没有明显的对抗作用; 能明显增加5-羟基色氨酸(5-HTP)诱导的甩头行为; 且没有增加育宾亨的毒性作用, 说明该药对发挥抗抑郁作用与5-HT能系统有关, 与NE能系统无关。且生、炒酸枣仁相伍组抗抑郁作用优于生、炒酸枣仁单用。通过对小鼠的基因表达研究发现生、炒酸枣仁配伍可下调慢性应激抑郁模型小鼠海马部位DA转运体编码基因Slc6a3和5-HT转运体编码基因Slc6a4的表达, 上调5-HT1A受体编码基因Htrla的表达, 通过基因的表达来调节神经递质的释放和再摄取, 认为该药对通过抑制神经递质再摄取来发挥抗抑郁作用。Zhang等^[66]通过小鼠绝望抑郁模型实验得出结论:半夏、厚朴单独使用时能够缩短小鼠在强迫游泳和悬尾实验中的不动时间, 但是效果并不明显, 组间比较无统计学意义。但是两者复配后, 呈现明显的促进作用, 差异有统计学意义。证明半夏厚朴汤的物质基础不仅依靠厚朴的成分而实现, 还需半夏的辅助才能得到更好地发挥, 即半夏-厚朴药对发挥抗抑郁作用的物质基础是两种药物共同作用的结果。

1.3.3 临床患者作为对象的研究

Shi等^{[67, 68]}在抑郁症患者的临床治疗中发现, 服用酸枣仁-合欢花药对后, 抑郁症患者血清中5-HT、CRH含量上升, BDNF含量明显上升, 白介素-6 (IL-6)含量下降, 抑郁症患者的汉密顿抑郁量表(HAMD量表)评分和威斯康星卡片分类(WCST)评分得到提高, 总体生活质量提升。酸枣仁-合欢花发挥抗抑郁功效的同时改善抑郁患者的认识功能。Wang等^[69]在对老年抑郁障碍患者的治疗中发现, 刺五加-桅子药对可有效降低患者的抑郁评分, 提高治疗效果, 改善患者认知功能、活动状态及生活质量, 提示刺五加-栀子药对在临床上同样发挥显著的抗抑郁作用。

综上, 抗抑郁药对不但在以模型动物为研究对象的实验中, 而且在临床抑郁症患者的治疗中同样发挥良好的抗抑郁作用。抗抑郁药对不仅作为一个整体能够发挥抗抑郁作用, 而且药对配伍后较单味药使用能够发挥更好的效果, 充分说明药对配伍后使用的可行性和必要性。

2 结语

收起

药对相比于大复方, 由于药味简化, 更有利于阐明药物之间的相互作用机制及药物共同对机体的作用机制, 同时, 药对作为中药配伍应用的最为常见形式, 本身即为小方剂, 可反映复方配伍的特殊规律与内在联系。以药对为切入点, 开展方剂配伍规律研究, 对于揭示方剂配伍的科学内涵拥有十分重要的意义。相比于单用其中一味药, 药对配伍使用能够发挥更好的抗抑郁作用。抗抑郁药对配合在一起使用的过程中伴随复杂的物理和化学变化, 通过这些化学物质间的相互作用, 使得药对溶出的功效物质发生量变或质变, 以及降低毒性成分含量, 从而影响药对整体功效的变化。当药对进入机体后, 不同的化学物质在体内的吸收、分布、代谢与排泄也能产生各种相互作用, 即抗抑郁药对配伍后使得药效物质基础在体内、外发生了变化, 可能是抗抑郁药对使用的配伍机制。而药对发挥抗抑郁的作用机制研究, 目前主要集中在验证药对对所调节差异性代谢物相关蛋白的差异性表达, 或验证相关转录或基因组差异性表达, 所验证的药对发挥抗抑郁效果的信号通路可能是相应药对发挥抗抑郁作用的机制。

抗抑郁中药药对研究在配伍机制和抗抑郁作用方面取得了一定的进展, 然而仍然存在一些亟待解决的问题: ①中药药对抗抑郁的活性成分研究尚不全面, 且中药毒理学相关研究鲜有报道, 安全性评价机制尚不成熟; ②目前药对配伍主要以某类药效成分为基础进行研究, 有效成分间的配比研究鲜有文献报道, 另外药对配伍所引起的新化学成分的变化是否贡献于抗抑郁作用的药效有待进一步验证; ③抑郁症的致病因素和机制研究尚无一致定论, 从生化指标方面评价药对发挥抗抑郁药效的评价机制尚不完善; ④目前抗抑郁作用机制还停留在假说阶段, 尚无完整的将代谢组学、蛋白组学与基因组学相结合的方法研究药对抗抑郁作用机制。当然, 随着科技技术的发展, 多种技术联合应用将有助于抗抑郁中药药对的研究。联合应用药对有效成分群、高通量筛选技术和网络药理学可在体外寻找对特定靶点具有生物活性的化合物, 将有利于抗抑郁药对活性物质的研究, 进而为中药抗抑郁新药研发奠定基础。实现定量代谢组学、多重反应检测、高通量测序技术和实时荧光定量PCR技术对小分子代谢物、蛋白质、转录组和基因的定量测定, 将更加客观地揭示药对经过体内过程对机体所产生的影响, 整合代谢组学、蛋白组学、转录组学和基因组学, 形成一条以“代谢物-蛋白(酶)-转录组-基因组”为模式的研究途径进行综合分析, 将是揭示抗抑郁药对调控发病机体作用机制的有效途径。

基金

收起

国家自然科学基金资助项目(81673572)
山西省应用基础研究项目(201601D021164)
山西省高校科技创新项目(2016120)

参考文献

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文献

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参考文献引证文献

排序方式：

[1]

Yang

, Zhu

, Pan

. The efficacy and safety of the commonly used antidepressant drugs[J]. China Licensed Pharm (中国执业药师), 2012, 9: 20-25. http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZYYS201204010.htm

[2]

Kennedy

. A review of antidepressant treatments today[J]. Eur Neuropsychopharmacol, 2006, 16: S619-S623.

https://doi.org/10.1016/S0924-977X(06)70007-4

[3]

, Gu

. Adverse reactions and treatment of antidepressants[J]. Chin J Clin Pharm (中国临床药学杂志), 2002, 11: 311-315. http://d.old.wanfangdata.com.cn/OAPaper/oai_doaj-articles_d7ca85ef05afd43c24d4da850f4e47e2

[4]

Pan LS. Material Basis Research of Three Traditional Chinese Herb-pairs (三种中药药对的物质基础研究)[D]. Hangzhou: Zhejiang University, 2004.

[5]

Wang

, Hu

, Tan

et al . Compatibility art of traditional Chinese medicine:from the perspective of herb pairs[J]. J Ethnopharmacol, 2012, 143: 412-423.

https://doi.org/10.1016/j.jep.2012.07.033

[6]

Dai

, Li

, Xue

et al . Metabolomics study on the anti-depression effect of xiaoyaosan on rat model of chronic unpredictable mild stress[J]. J Ethnopharmacol, 2010, 128: 482-489.

https://doi.org/10.1016/j.jep.2010.01.016

[7]

Zhou

, Lu

, Li

et al . Antidepressant-like effects of the fractions of Xiaoyaosan on rat model of chronic unpredictable mild stress[J]. J Ethnopharmacol, 2011, 137: 236-244.

https://doi.org/10.1016/j.jep.2011.05.016

[8]

Zhang

, Han

, Liu

et al . Chinese herbal formula Xiao Yao San for treatment of depression:a systematic review of randomized controlled trials[J]. Evid-Based Complement Alternat Med, 2012, 2012: 931636 http://d.old.wanfangdata.com.cn/OAPaper/oai_pubmedcentral.nih.gov_3159992

[9]

Kim

, Han

, Seog

et al . Antidepressant effect of Chaihu-Shugan-San extract and its constituents in rat models of depression[J]. Life Sci, 2005, 76: 1297-1306.

https://doi.org/10.1016/j.lfs.2004.10.022

[10]

Wang

, Fan

, Huang

. Meta-analysis of the clinical effectiveness of traditional Chinese medicine formula Chaihu-Shugan-San in depression[J]. J Ethnopharmacol, 2012, 141: 571-577.

https://doi.org/10.1016/j.jep.2011.08.079

[11]

Zhang

, Huang

, Wang

et al . Ferulic acid-induced anti-depression and prokinetics similar to Chaihu-Shugan-San via polypharmacology[J]. Brain Res Bull, 2011, 86: 222-228.

https://doi.org/10.1016/j.brainresbull.2011.07.002

[12]

Wang

, Tan

, Sun

et al . Possible therapeutic effect of a traditional Chinese medicine, Sinisan, on chronic restraint stress related disorders[J]. Neurosci Lett, 2009, 449: 215-219.

https://doi.org/10.1016/j.neulet.2008.10.100

[13]

, Guo

, Liu

et al . Neuroprotective effects of total Saikosaponins of Bupleurum yinchowense on corticosterone-induced apoptosis in PC12 cells[J]. J Ethnopharmacol, 2013, 148: 794-803.

https://doi.org/10.1016/j.jep.2013.04.057

[14]

, Jing

, Liu

et al . Saikosaponin D acts against corticosterone-induced apoptosis via regulation of mitochondrial GR translocation and a GR-dependent pathway[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2014, 53: 80-89.

https://doi.org/10.1016/j.pnpbp.2014.02.010

[15]

Mao

, Ip

, Ko

et al . Peony glycosides produce antidepressant-like action in mice exposed to chronic unpredictable mild stress:effects on hypothalamic-pituitary-adrenal function and brain-derived neurotrophic factor[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2009, 33: 1211-1216.

https://doi.org/10.1016/j.pnpbp.2009.07.002

[16]

Wang

. Extraction technology and anti-depression activity of Saponins from Liliumbrownii[J]. China Pharm (中国药房), 2014, 25: 602-604. http://www.cabdirect.org/abstracts/20153302060.html;jsessionid=ED37A898CDFE8B9A1E178089BCC77319

[17]

Ren LX. Studies on the Antidepressant Effect and Mechanisms of Total Timosaponin and Sarsasapogenin (知母总皂苷及萨尔萨皂苷元的抗抑郁作用及其机制研究)[D]. Shenyang: Shenyang Pharmaceutical University, 2007.

[18]

Wang

, Yang

, Zhang

et al . BDNF and COX-2 participate in anti-depressive mechanisms of catalpol in rats undergoing chronic unpredictable mild stress[J]. Physiol Behav, 2015, 151: 360-368.

https://doi.org/10.1016/j.physbeh.2015.08.008

[19]

Zhao

, Shu

, Wang

et al . Experimental study on antidepressant effect of total flavonoids from Semen Ziziphi Spinosae[J]. Tianjin J Tradit Chin Med (天津中医药), 2011, 28: 335-337. https://www.sciencedirect.com/science/article/pii/S0378874110001856

[20]

Zhao

, Shu

, Wang

et al . Antidepressant effect of total saponins from Semen Ziziphi Spinosae[J]. Cent South Pharm (中南药学), 2011, 9: 489-491. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=znyx201107003

[21]

Guo

, Xia

, Yin

et al . Antidepressant effect by Albizzia Julibrissin Flower total flavonoids and its mechanism[J]. Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2013, 19: 225-228. http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201313067.htm

[22]

Zhao J. Berberine Elicits Antidepressant-Like Effect in the Ovariectomized Mice (小檗碱对卵巢摘除小鼠的抗抑郁作用及其机制研究)[D]. Changchun: Northeast Normal University, 2015.

[23]

Wang YW, Chen X, Jiang ML. Use of evodiamine for antidepressant. CN 103340872A[P]. 2013.

[24]

Guo YH. Studies on Chemical Composition of Effective Fractions from Rhizoma Atractylodis Macrocephalae of Xiaoyaosan (白术对逍遥散抗抑郁有效部位贡献成分研究)[D]. Taiyuan: Shanxi University, 2014.

[25]

Chen

, Gu

, Wu

et al . Protective effect of Acanthopanax Senticousus Saponins on glutamate-induced cortical neuron damage[J]. J Brain Nerv Dis (脑与神经疾病杂志), 2004, 12: 84-87. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=nysjjbzz200402002

[26]

Han Y. Pharmacodynamic Material Basic of Zhizi Chi Decoction (栀子豉汤的药效物质基础研究)[D]. Fuzhou: Fujian University of Traditional Chinese Medicine, 2015.

[27]

Yan

, Wu

, Xu

et al . Antidepression-like effect and mechanism of ferulic acid[J]. Chin J Pharm Toxicol (中国药理学与毒理学杂志), 2014, 28: 645.

[28]

, Wu

, Yang

et al . Antidepressant effects of Citrus medica L. var. sarcodactylis swingle from Sichuan province[J]. J Zhengzhou Univ(郑州大学学报), 2011, 46: 220-222. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=henanykdx201102018

[29]

Zhang

, Chen

, Duan

. Study on the antidepressant activities of polysaccharides from three herbs and their mechanism[J]. J Shanxi Agirc Univ (山西农业大学学报), 2017, 37: 905-912. http://d.old.wanfangdata.com.cn/Periodical/sxnydxxb201712012

[30]

Fan

, Zhao

, Guo

et al . Antidepressant activities of flavonoids from Glycyrrhiza uralensis and its neurogenesis protective effect in rats[J]. Acta Pharm Sin (药学学报), 2012, 47: 1612-1617. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=QK201205758869

[31]

Huang

. Application and research of Wolfberry Fruit in treatment of depression[J]. Chin Arch Tradit Chin Med (中华中医药学刊), 2014, 32: 1841-1843. http://en.cnki.com.cn/Article_en/CJFDTotal-ZYHS201408014.htm

[32]

Tong

, Wu

. Experimental study on antidepressant effect of physcion[J]. Pharmacol Clin Chin Mater Med (中药药理与临床), 2013, 29: 60-62. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=QKC20132013050700056086

[33]

, YangYF , Zhang

et al . Different extraction methods of Zhi-Zi-Hou-Pu decoction and the antidepressant profile-effect[J]. Chin J Pharm (中国医药工业杂志), 2014, 45: 424-428. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=zgyygy201405008

[34]

, Shen

, Liu

et al . Screening of antidepressant effects of four main flavonoids compounds from Scutellaria baicalensis[J]. Chin J Exp Tradit Med Form (中国实验方剂学杂志), 2012, 18: 166-169. http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZSFX201211052.htm

[35]

Zhang

, Li

, Zhou

et al . Antidepressant-like effects of ginsenosides:a comparison of ginsenoside Rb 3, and its four deglycosylated derivatives, Rg 3, Rh 2, compound K, and 20(S)-protopanaxadiol in mice models of despair[J]. Pharmacol Biochem Behav, 2015, 140: 17-26. http://europepmc.org/abstract/MED/26528894

[36]

Dong

, Gao

, Rong

et al . β-Asarone reverses chronic unpredictable mild stress-induced depression-like behavior and promotes hippocampal neurogenesis in rats[J]. Molecules, 2014, 19: 5634-5649.

https://doi.org/10.3390/molecules19055634

[37]

, Lin

, Qin

et al . Senegenin exerts anti-depression effect in mice induced by chronic un-predictable mild stress via inhibition of NF-kappa B regulating NLRP3 signal pathway[J]. Int Immunopharmacol, 2017, 53: 24-32.

https://doi.org/10.1016/j.intimp.2017.10.001

[38]

Tao WW, Chen G. The refined part of Gardenia total crocin with antidepressant effect and its preparation method and application. CN 104491075A[P]. 2015.

[39]

, Ren

, Na

et al . Bioassay-guided separation of effective components from Gentianella acuta and their protective effect on oxidative damage in PC12 cells induced by H₂O₂[J]. Chin Tradit Herb Drugs (中草药), 2017, 48: 1957-1963. http://d.old.wanfangdata.com.cn/Periodical/zcy201710005

[40]

Geng

, Li

. Content changes of main chemical constituents in raw semen Zizyphi Spinosae and fried semen Zizyphi Spinosae before and after compatibility[J]. J Liaoning Univ Tradit Chin Med (辽宁中医药大学学报), 2017, 19: 64-67. http://www.en.cnki.com.cn/Article_en/CJFDTotal-LZXB201701021.htm

[41]

Zhu

, Chen

, Zhang

et al . Comparison of water decocted quantity of total glycosides of Radix Paeoniae Alba and benzoic acid with different compatibility of Radix Paeoniae Alba and Radix Bupleuri[J]. Tianjin J Tradit Chin Medi (天津中医药), 2011, 28: 78-79. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=tjzy201101033

[42]

Hou

, Lu

, Zhao

et al . Comparative analysis of 3 kinds of active parts in Eucommia ulmoides pill by salt-baking and compatibility[J]. Chin Tradit Pat Med (中成药), 2010, 32: 1442-1444.

[43]

Wang KR. Chemical Composition Analysis and Pharmacokinetic Study of Zhimu-Baihe Herb-pair (知母百合药对的化学成分分析及药动学研究)[D]. Shanghai: The Second Military Medical University, 2011.

[44]

Fang

, Qin

, Pan

et al . Chemical constituents of Baihe Zhimu decoction (I)[J]. Chin Tradit Herb Drugs (中草药), 2010, 41: 517-520. http://d.old.wanfangdata.com.cn/Periodical/zcy201004004

[45]

Zhang

, Wang

, Cheng

. Study on chemical constituents of Radix Bupleuri and Radix Paeoniae Alba[J]. J Liaoning Univ Tradit Chin Med (辽宁中医药大学学报), 2018, 20: 52-55. http://en.cnki.com.cn/Article_en/CJFDTotal-LZXB201802017.htm

[46]

Zeng

, Tu

, Sun

et al . Membrane transport of couple of Coptis and Evodia in Caco-2 cell monolayer model[J]. Pharmacol Clin Chin Mater Med (中药药理与临床), 2012, 28: 9-11. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=QK201200251973

[47]

Chen

, Wang

, Yuan

et al . Interaction of the main components from the traditional Chinese drug pair Chaihu-Shaoyao based on rat intestinal absorption[J]. Molecules, 2011, 16: 9600-9610.

https://doi.org/10.3390/molecules16119600

[48]

Liu

, Dong

, Ding

et al . Comparative pharmacokinetics of timosaponin B-Ⅱ and timosaponin A-Ⅲ after oral administration of Zhimu-Baihe herb-pair, Zhimu extract, free timosaponin B-Ⅱ and free timosaponin A-Ⅲ to rats[J]. J Chromatogr B, 2013, 926: 28-35.

https://doi.org/10.1016/j.jchromb.2013.03.003

[49]

, Tang

, Yang

et al . Simultaneous determination of five components in rat plasma by UPLC-MS/MS and its application to a comparative pharmacokinetic study in Baihe Zhimu Tang and Zhimu extract[J]. Molecules, 2015, 20: 6700-6714.

https://doi.org/10.3390/molecules20046700

[50]

Zhu

, Bai

, Zhang

et al . Pharmacokinetic of Jiaotai pill in normal and depressed rats[J]. Acta Pharm Sin (药学学报), 2018, 53: 425-431. http://www.cnki.com.cn/Article/CJFDTotal-CHME201802014.htm

[51]

Zhang

, Li

, Yang

et al . Effect of Rhizoma Coptidisco administration with Cortex Cinnamomi on tissue distribution of berberine in rats[J]. China J Chin Mater Med (中国中药杂志), 2010, 35: 2180-2183. http://europepmc.org/abstract/MED/21046757

[52]

Huang

, Li

, Yang

et al . In vitro liver metabolism study of rats with Huanglian and Wujing[J]. China J Chin Mater Med (中国中药杂志), 2010, 35: 651-653.

[53]

Wang

, Lu

, Kong

. Compatibility of Banxia Houpo decoction on hepatic CYP450 and renal organicion transporters in mice[J]. China J Chin Mater Med (中国中药杂志), 2011, 36: 60-65. http://d.old.wanfangdata.com.cn/Periodical/zgzyzz201101013

[54]

Wu QE. Study on the Effect and Mechanism of Gentianella acuta Combined with Acorus tatarinowii Compatibility in a Rat Model of Depression (尖叶假龙胆配伍石菖蒲对抑郁模型大鼠的作用及机制研究)[D]. Harbin: Heilongjiang University of Chinese Medicine, 2016.

[55]

Yuan

, Liu

, Fan

et al . Influence of Baihe Zhimu decoction in levels of key factors of CaM signaling pathway in hippocampus tissue of rats with depression and its antidepressant mechanism[J]. J Jilin Univ (吉林大学学报), 2016, 42: 704-710. http://www.en.cnki.com.cn/Article_en/CJFDTotal-BQEB201604014.htm

[56]

Liu

, Zhang

, Dong

et al . Effects of mixture of Wuling powder and Hypericum per-foratum L. on depressed model rats induced by chronic unpredictable stress[J]. Chin J Comp Med (中国比较医学杂志), 2016, 26: 81-86.

[57]

, Sun

, Xu

et al . Influence of couplet medicines with Ciwujia[Acanthopanax senticosus (Rupr. Maxim.) Harms] and Zhizi[Gardenia jasminoides Ellis] on GSα-PKA-cAMP signaling pathway in chronic stress depression model rats[J]. Chin J Gerontol (中国老年学杂志), 2016, 36: 6063-6065.

[58]

, Xu

, Song

et al . Influence of couplet medicines with Ciwujia[Acanthopanax senticosus (Rupr. Maxim.) Harms] and Zhizi[Gardenia jasminoides Ellis] on PKC-IP3 signaling pathway in chronic stress depression model rats[J]. J Tradit Chin Med (中医杂志), 2017, 58: 414-417. http://d.old.wanfangdata.com.cn/Periodical/zyzz201705015

[59]

, Lu

, Zhou

et al . Effect of herb pair of Bupleuri Radix and Paeoniae Alba Radix on single amine neurotransmitter in brain of CUMS depression model of rats[J]. Chin Tradit Herb Drugs (中草药), 2016, 47: 2887-2892. http://d.old.wanfangdata.com.cn/Periodical/zcy201616019

[60]

, Yu

, Yao

et al . Behaviour on effect of herb pair of Bupleuri Radix and Paeoniae Alba Radix in chronic unpredictable mild stress depression model of rats[J]. Chin Tradit Herb Drugs (中草药), 2016, 47: 2137-2141. http://d.old.wanfangdata.com.cn/Periodical/zcy201612020

[61]

, Wang

, Su

et al . Metabonomic identification of the effects of the Zhimu-Baihe saponins on a chronic unpredictable mild stress-induced rat model of depression[J]. J Pharmaceut Biomed, 2016, 128: 469-479.

https://doi.org/10.1016/j.jpba.2016.06.019

[62]

Sun Y. Empirical Study on Anti-depression of Baihe Dihuang Decoction (百合地黄汤抗抑郁作用的实验研究)[D]. Hangzhou: Zhejiang Chinese Medical University, 2009.

[63]

Chen

, Gao

, He

et al . Involvement of the cerebral monoamine neurotransmitters system in antidepressant-like effects of a Chinese herbal decoction, Baihe Dihuang Tang in mice model[J]. Evid-Based Complement Alternat Med, 2012, 2012: 419257 http://europepmc.org/abstract/MED/22956973

[64]

Wang

, Ding

, Mao

et al . Antidepressant-like effect of ethanol extract from Zuojin pill, containing two herbal drugs of Rhizoma Coptidis and Fructus Evodiae, is explained by modulating the monoaminergic neurotransmitter system in mice[J]. J Ethnopharmacol, 2013, 148: 603-609.

https://doi.org/10.1016/j.jep.2013.05.011

[65]

Wang WK. The Study on the Antidepressant Mechanisms of Compatibility of SZS with its Processing Product and the Changes of Chemical Composition after the Compatibility (生、炒酸枣仁相伍抗抑郁作用机制及相伍后化学成分变化研究)[D]. Harbin: Heilongjiang University of Chinese Medicine, 2014.

[66]

Zhang

, Ni

. Alleviation effect of Pinellia Ternata and Magnolia Bark extract on mouse depression model[J]. Chin J Mod Drug Appl (中国现代药物应用), 2013, 7: 245-246.

[67]

Shi

, Xia

, Feng

et al . Effects of herb pair of Semen Ziziphi Spinosae (SZS) and Albizia julibrissin flower (AJF) on the life quality and NEI of patients with depression[J]. Lishizhen Med Mater Med Res (时珍国医国药), 2016, 27: 2348-2350.

[68]

Shi

, Guo

, Fan

et al . Effects of herbal pair of Semen Ziziphi Spinosae and Albizia Julibrissin Flower on quality of life among elderly patients with depression[J]. World Sci Technol-Mod Tradit Chin Med Mater Med (世界科学技术:中医药现代化), 2013, 15: 1933-1936. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=sjkxjs-zyxdh201309014

[69]

Wang

, Ren

, Xu

. Randomized, double-blinded controlled study of Eleutherococcus Senticosus extract compatible with Gardenia in the treatment of geriatric depressive disorder[J]. China Med Her (中国医药导报), 2013, 10: 11-12. http://www.wanfangdata.com.cn/details/detail.do?_type=perio&id=yycyzx201308005

2019年第54卷第2期

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doi: 10.16438/j.0513-4870.2018-0825

接收时间：2018-09-08
首发时间：2026-01-26
出版时间：2019-02-12

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收稿日期：2018-09-08
修回日期：2018-10-18

基金

国家自然科学基金资助项目(81673572)

山西省应用基础研究项目(201601D021164)

山西省高校科技创新项目(2016120)

作者信息

1.山西大学中医药现代研究中心, 山西太原 030006

2.山西大学化学化工学院, 山西太原 030006

3.中国医学科学院、北京协和医学院药物研究所, 北京 100050

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*周玉枝, Tel:86-351-7019178, E-mail:zhouyuzhi@sxu.edu.cn

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https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2018-0825

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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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Herb	Active ingredient	Ref
Chaihu	Total saikosaponins	13, 14
Baishao	Total saikosaponins	15
Baihe	Total saikosaponins	16
Zhimu	Total saikosaponins	17
Dihuang	Catalpol	18
Suanzaoren	Total saikosaponins, total flavonoids	19, 20
Hehuanghua	Total flavonoids	21
Huanglian	Berberine	22
Wuzhuyu	Evodiamine	23
Baizhu	Atractylode Ⅰ, Ⅱ, Ⅲ	24
Ciwujia	Acanthopanax senticousus saponins	25
Dandouchi	Catherine genistein	26
Danggui	Ferulic acid	27
Foshou	Volatile	28
Fuling	Lysaccharides	29
Gancao	Flavonoids	30
Gouqizi	Polysaccharide	31
Heshouwu	Physcio	32
Houpo	Magnolol, honokiol	33
Huangqin	Baicalin, wogonoside, baicalein, wogonin	34
Renshen	Ginsenosides	35
Shichangpu	β-Asarone	36
Yuanzhi	Polygalaceae glycosides	37
Zhizi	Total crocin, iridoid glycoside	38
Jianyejia-	Bellidifolin, demethylbellidifolin,	39
longdan	swertianolin, norswertianolin

Herb

Active ingredient

Ref

Chaihu

Total saikosaponins

13, 14

Baishao

Total saikosaponins

Baihe

Total saikosaponins

Zhimu

Total saikosaponins

Dihuang

Catalpol

Suanzaoren

Total saikosaponins, total flavonoids

19, 20

Hehuanghua

Total flavonoids

Huanglian

Berberine

Wuzhuyu

Evodiamine

Baizhu

Atractylode Ⅰ, Ⅱ, Ⅲ

Ciwujia

Acanthopanax senticousus saponins

Dandouchi

Catherine genistein

Danggui

Ferulic acid

Foshou

Volatile

Fuling

Lysaccharides

Gancao

Flavonoids

Gouqizi

Polysaccharide

Heshouwu

Physcio

Houpo

Magnolol, honokiol

Huangqin

Baicalin, wogonoside, baicalein, wogonin

Renshen

Ginsenosides

Shichangpu

β-Asarone

Yuanzhi

Polygalaceae glycosides

Zhizi

Total crocin, iridoid glycoside

Jianyejia-

Bellidifolin, demethylbellidifolin,

longdan

swertianolin, norswertianolin

Herb pair	Object	Model	Text item	Biochemical indicator	Mechanism	Ref
Jianyejialongdan-Shichangpu	Male SD rat	CUMS	FST, OFT, body weight, SPT	5-HT, Glu, GABA, DA	Neuron protection, BDNF/Trkbsignal transduction pathway	54
Baihe-Zhimu	SD rat	Independent+CUMS	Morris water maze test, OFT, FST	CaM and CaMKⅡ proteins, CREB, mRNA	CaM signal transduction pathway	55
Wulinghunfen- Guyelianqiao	Male SD rat	CUMS	SPT	ACTH, CORT	HPA axis	56
Ciwujia-Zhizi	Male SD rat	Independent+CUMS		GSα, PKA, cAMP, IP₃ GIα, PKC	GSα-PKA-cAMP and PKC-IP3signal pathway	57 58
Chaihu-Baishao	Male SD rat	CUMS	Body weight, OFT, SPT	NE, 5-HT, 5-HIAA	Monoamine neurotransmitter system	59 60
Baihe-Zhimu	Male SD rat	CUMS	SPT, FST	NE, DA, 5-HT	Monoamine neurotransmitter system	61
Baihe-Dihuang	Male ICR mice	Behaviora despair, independent+CUMS	FST, TST, body weight	CORT, ACTH, DA 5-HT	HPA axis, monoamine neurotransmitter system	62
Baihe-Dihuabg	Male ICR mice	Behavioral despair, reserpine-induced	FST, OFT, TST, ptosis	NE, DA, 5-HIAA, 5-HT	Monoamine neurotransmitter system	63
Huanglian- Wuzhuyu	Male ICR mice	Behavioral despair, 5-HTP-induced, reserpine-induced	FST, TST, OFT, Ptosis, hypothermia	NE, DA, 5-HT	Monoamine neurotransmitter system	64
Sheng-Chao Suanzaoren	Male ICR mice	Behavioral despair, independent+CUMS, reserpine-induced, 5-HTP-induced, yohimbine-induced	SPT, TST Body weight, FST, OFT, head-twitch mortality rate, hypothermia ptosis	5-HT, 5-HIAA, DA	Monoamine neurotransmitter system	65
Banxia-Houpo	ICR mice	Behavioral despair	FST, TST			66
Suanzaoren- Hehuanhua	Clinical patient	Depression	HAMD, WCST, quality of life, cognitive function	5-HT, CRH, IL-6, BDNF	Nerve-endocrine-immune network, BDNF	67 68
Ciwujia-Zhizi	Clinical patient	Depression	HAMD, quality of life			69

Herb pair

Object

Model

Text item

Biochemical indicator

Mechanism

Ref

Jianyejialongdan-Shichangpu

Male SD rat

CUMS

FST, OFT, body weight, SPT

5-HT, Glu, GABA, DA

Neuron protection, BDNF/Trkbsignal transduction pathway

Baihe-Zhimu

SD rat

Independent+CUMS

Morris water maze test, OFT, FST

CaM and CaMKⅡ proteins, CREB, mRNA

CaM signal transduction pathway

Wulinghunfen- Guyelianqiao

Male SD rat

CUMS

SPT

ACTH, CORT

HPA axis

Ciwujia-Zhizi

Male SD rat

Independent+CUMS

GSα, PKA, cAMP, IP₃ GIα, PKC

GSα-PKA-cAMP and PKC-IP3signal pathway

57 58

Chaihu-Baishao

Male SD rat

CUMS

Body weight, OFT, SPT

NE, 5-HT, 5-HIAA

Monoamine neurotransmitter system

59 60

Baihe-Zhimu

Male SD rat

CUMS

SPT, FST

NE, DA, 5-HT

Monoamine neurotransmitter system

Baihe-Dihuang

Male ICR mice

Behaviora despair, independent+CUMS

FST, TST, body weight

CORT, ACTH, DA 5-HT

HPA axis, monoamine neurotransmitter system

Baihe-Dihuabg

Male ICR mice

Behavioral despair, reserpine-induced

FST, OFT, TST, ptosis

NE, DA, 5-HIAA, 5-HT

Monoamine neurotransmitter system

Huanglian- Wuzhuyu

Male ICR mice

Behavioral despair, 5-HTP-induced, reserpine-induced

FST, TST, OFT, Ptosis, hypothermia

NE, DA, 5-HT

Monoamine neurotransmitter system

Sheng-Chao Suanzaoren

Male ICR mice

Behavioral despair, independent+CUMS, reserpine-induced, 5-HTP-induced, yohimbine-induced

SPT, TST Body weight, FST, OFT, head-twitch mortality rate, hypothermia ptosis

5-HT, 5-HIAA, DA

Monoamine neurotransmitter system

Banxia-Houpo

ICR mice

Behavioral despair

FST, TST

Suanzaoren- Hehuanhua

Clinical patient

Depression

HAMD, WCST, quality of life, cognitive function

5-HT, CRH, IL-6, BDNF

Nerve-endocrine-immune network, BDNF

67 68

Ciwujia-Zhizi

Clinical patient

Depression

HAMD, quality of life