Re: 자귀나무 합환피의 항우울 효과...

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Chin Herb Med. 2023 Apr; 15(2): 201–213.

Published online 2023 Mar 15. doi: 10.1016/j.chmed.2022.10.004

PMCID: PMC10230641

PMID: 37265761

Molecular basis and mechanism of action of Albizia julibrissin in depression treatment and clinical application of its formulae

Bishan Huang,a,1 Yingyao Wu,a,1 Chan Li,a Qingfa Tang,b and Yuanwei Zhanga,⁎

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Abstract

Albizzia julibrissin is empirically used as an antidepressant in clinical practice. Preclinical studies have indicated that its total extracts or bioactive constituents exerted antidepressant-like responses in animal models, providing the molecular basis to reveal its underlying mechanism of action. While attempts have been made to understand the antidepressant effect of A. julibrissin, many fundamental questions regarding its mechanism of action remain to be addressed at the molecular and systems levels. In this review, we conclusively discussed the mechanism of action of A. julibrissin and A. julibrissin formulae by reviewing recent preclinical and clinical studies conducted by using depressive animal models and depressive patients. Several representative bioactive constituents and formulae were highlighted as examples, and their mechanisms of action were discussed. In addition, some representative A. julibrissin formulae that have been shown to be compatible with conventional antidepressants in clinical practice were also reviewed. Furthermore, we discussed the future research directions to reveal the underlying mechanism of A. julibrissin at the molecular and systems levels in depression treatment. The integrated study using both the molecular and systematic approaches is required not only for improving our understanding of its molecular basis and mechanisms of action, but also for providing a way to discover novel agents or approaches for the effective and systematic treatment of depression.

알비지아 줄리브리신은

임상에서 항우울제로 경험적으로 사용되고 있습니다.

전임상 연구에 따르면

총 추출물 또는 생리 활성 성분이 동물 모델에서

항우울제와 유사한 반응을 나타내어

근본적인 작용 메커니즘을 밝힐 수 있는 분자적 근거를 제공했습니다.

A. 줄리브리신의 항우울 효과를 이해하려는 시도가 있었지만,

그 작용 메커니즘에 관한 많은 근본적인 의문은

분자 및 시스템 수준에서 해결해야 할 과제로 남아 있습니다.

이 리뷰에서는

우울증 동물 모델과 우울증 환자를 사용하여 수행된

최근의 전임상 및 임상 연구를 검토하여

A. 줄리브리신과 A. 줄리브리신 포뮬러의 작용 메커니즘에 대해

결론적으로 논의했습니다.

대표적인 생리활성 성분과 포뮬러 몇 가지를 예로 들어

그 작용 메커니즘에 대해 논의했습니다.

또한,

임상에서 기존 항우울제와의 호환성이 입증된

대표적인 A. 줄리브리신 포뮬러에 대해서도 검토했습니다.

또한, 우울증 치료에 있어

분자 및 시스템 수준에서

A. 줄리브리신의 근본적인 기전을 밝히기 위한

향후 연구 방향에 대해 논의했습니다.

분자적 접근과 시스템적 접근을 모두 활용한 통합적 연구는

분자적 기반과 작용 기전에 대한 이해를 높일 뿐만 아니라

효과적이고 체계적인 우울증 치료를 위한

새로운 약제나 접근법을 발굴할 수 있는 방법을 제공하기 위해서도 필요합니다.

Keywords: Albizia julibrissin Durazz., antidepressants, depression, mechanism of action, clinical application

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1. Introduction

Depression is a popular and all age-related mental illness, affecting approximate 10%–15% of the population worldwide (Hasin et al., 2018, WHO, 2017). According to the latest statistics, the lifetime preval‎ence rate of depression in China is 6.8%, that is, there are nearly 100 million depressive patients, but only 0.5% of the patients are fully treated (Huang et al., 2019, Lu et al., 2021). Depressive patients suffer greatly with poorly function at work, study, and social activities. Severe depression can lead to disability and suicide. The social and economic burdens caused by depression are gradually increasing, and depression has become a global public health problem.

Current medications in depression treatment have many shortcomings, such as slow onset, low efficacy, serious adverse effects, and high costs, all of which limit their use in clinical practice. On the other hand, the use of herbal medicine has been greatly increased as a complementary and alternative medicine in the past decades (WHO, 2019). Herbal medicine is a core part of traditional medicine that has been developed for a long history to maintain health as well as to prevent and treat physical and mental illness. The common reasons for using herbal medicine are that it is more affordable, more personalized health care, and less adverse effects than chemically synthesized drugs (Wachtel-Galor & Benzie, 2011). It should be noted that the use of herbal medicine increased when the synthesized medications are less effective in the treatment of complex diseases, such as depression.

Traditional Chinese medicine (TCM) is an important branch of traditional medicine, and it is broadly used to treat depression in East Asia today. In TCM practice, Chinese herbal medicine is usually used to exert its medicinal effects on depression by using a combination of multiple herbs, so-called formula, in which one herb at least is employed as an antidepressant drug to directly act against the main depressive symptoms, while others serve as modulators to strengthen the antidepressant efficacy or alleviate side effects (Zhang & Cheng, 2019). According to the Chinese Pharmacopoeia, more than 50 single Chinese herbs have empirically been used as antidepressants in clinical practice (Chinese Pharmacopoeia Commission, 2020). During the past two decades, studies have been extensively conducted to uncover the molecular basis and mechanism of action of these herbs in the treatment of depression. These studies have remarkably improved our understanding of Chinese herbal medicine for the effective treatment of depression (Li, Huang, Cheng, & Zhang, 2020).

Albizia julibrissin Durazz., a leguminous deciduous shrub, is one of the most common herbs used for depression treatment. In TCM practice, its dried flowers or bark are generally processed for medicinal purposes. The main ingredients in A. julibrissin include triterpenoids, lignans, flavonoids, saponins, sterols, etc. (Li, Tian, Luo, & Li, 2022). Preclinical studies have shown that these ingredients exhibited a broad array of pharmacological activities ranging from antidepressant and anxiolytic (Li, 2017, Li, Tian, Luo, & Li, 2022, Li, 2017, Wang et al., 2021, Yang & Li, 2019), anti-inflammation (Yang & Li, 2019), anti-oxidation (Sobeh et al., 2017, Shi et al., 2019), and antitumor (Qian et al., 2017, Yu et al., 2016) to enhance immunological function (Sobeh et al., 2017). This narrative review aims to conclusively discuss the mechanism of action as well as the latest progress in preclinical and clinical research of A. julibrissin in the treatment of depression. The literatures that demonstrated A. julibrissin constituents and formulae to produce antidepressant responses were selected for discussion. According to the mechanism of action and structural classification, several representative constituents that have been demonstrated to specifically act on the pathological systems in depression neurobiology are given. In addition, several representative A. julibrissin formulae traditionally used for depression treatment were discussed. Furthermore, we also discussed some A. julibrissin formulae that have been demonstrated to be compatible with conventional antidepressants. Finally, we discussed the future research directions to reveal the mechanism by which A. julibrissin exerts antidepressant-like activity in depression treatment. The comprehensive analysis could improve our understanding of the molecular basis and mechanism of action of A. julibrissin in the treatment of depression, which, in turn, will provide an opportunity to scientifically eval‎uate its benefits and risks in clinical practice.

1. 소개

우울증은 전 세계 인구의 약 10~15%에 영향을 미치는 흔한 전 연령 관련 정신 질환입니다(Hasin 등., 2018, WHO, 2017). 최신 통계에 따르면 중국의 우울증 평생 유병률은 6.8%, 즉 우울증 환자가 거의 1억 명에 달하지만 완전히 치료받은 환자는 0.5%에 불과합니다(Huang et al., 2019, Lu et al., 2021). 우울증 환자는 직장, 학업, 사회 활동에서 기능 저하로 큰 고통을 겪습니다. 심한 우울증은 장애와 자살로 이어질 수 있습니다. 우울증으로 인한 사회적, 경제적 부담은 점차 증가하고 있으며 우울증은 전 세계적인 공중 보건 문제가 되고 있습니다.

현재 우울증 치료에 사용되는 약물은 느린 발병 속도, 낮은 효과, 심각한 부작용, 높은 비용 등 여러 단점이 있어 임상에서 사용이 제한되고 있습니다. 반면에 한약은 지난 수십 년 동안 보완 및 대체 의학으로서 그 사용이 크게 증가했습니다(WHO, 2019). 한약은 신체적, 정신적 질병을 예방하고 치료할 뿐만 아니라 건강을 유지하기 위해 오랜 역사 동안 개발되어 온 전통 의학의 핵심적인 부분입니다. 한약을 사용하는 일반적인 이유는 화학적으로 합성된 약물보다 저렴하고, 개인 맞춤형 건강 관리가 가능하며, 부작용이 적기 때문입니다(Wachtel-Galor & Benzie, 2011). 합성 의약품이 우울증과 같은 복잡한 질병의 치료에 효과가 떨어질 때 한약의 사용이 증가한다는 점에 주목해야 합니다.

한의학은 전통 의학의 중요한 분야로, 오늘날 동아시아에서 우울증 치료에 광범위하게 사용되고 있습니다. 한약은 일반적으로 여러 약초를 조합하여 우울증에 약효를 발휘하는 이른바 포뮬러를 사용하는데, 적어도 한 가지 약초는 주요 우울 증상에 직접 작용하는 항우울제로 사용되며 다른 약초는 항우울제 효능을 강화하거나 부작용을 완화하는 조절제 역할을 합니다(Zhang & Cheng, 2019). 중국 약전에 따르면 50개 이상의 단일 한약재가 임상에서 항우울제로 경험적으로 사용되었습니다(중국 약전 위원회, 2020). 지난 20년 동안 우울증 치료에서 이러한 허브의 분자적 근거와 작용 메커니즘을 밝히기 위한 연구가 광범위하게 진행되었습니다. 이러한 연구는 우울증의 효과적인 치료를 위한 한약에 대한 우리의 이해를 현저하게 향상시켰습니다(Li, Huang, Cheng, & Zhang, 2020).

콩과 낙엽 관목인 알비지아 줄리브리신은

우울증 치료에 가장 흔하게 사용되는

허브 중 하나입니다.

한의학에서는 일반적으로

말린 꽃이나 나무껍질을

약용으로 가공합니다.

A. 줄리브리신의 주요 성분으로는

트리테르페노이드, 리그난, 플라보노이드, 사포닌, 스테롤 등이 있습니다(Li, Tian, Luo, & Li, 2022).

전임상 연구에 따르면 이러한 성분은

항우울제 및 항불안제에 이르는 광범위한 약리 작용을 나타냈습니다(Li, 2017, Li, Tian, Luo, & Li, 2022, Li, 2017, Wang et al, 2021, 양 & 리, 2019), 항염증(양 & 리, 2019), 항산화(소베 외, 2017, 시 외, 2019), 항종양(치안 외, 2017, 유 외, 2016), 면역 기능 강화(소베 외, 2017)에 이르기까지 다양한 약리학적 활성이 보고되고 있습니다.

이 내러티브 리뷰는

우울증 치료에 대한 A. 줄리브리신의

전임상 및 임상 연구의 최신 진행 상황과 작용 메커니즘에 대해

결론적으로 논의하는 것을 목표로합니다.

A. 줄리브리신 성분과

항우울 반응을 일으키는 공식을 입증한 문헌이

논의 대상으로 선정되었습니다.

작용 기전 및 구조적 분류에 따라 우울증 신경 생물학에서 병리 시스템에 특이적으로 작용하는 것으로 입증 된 몇 가지 대표 성분을 제시합니다.

또한 전통적으로 우울증 치료에 사용되는 몇 가지 대표적인

A. 줄리브리신 제형에 대해 논의했습니다.

또한 기존 항우울제와의 호환성이 입증된 A. 줄리브리신 포뮬러에 대해서도 논의했습니다. 마지막으로, 우울증 치료에서 A. 줄리브리신이 항우울제와 유사한 작용을 하는 메커니즘을 밝히기 위한 향후 연구 방향에 대해 논의했습니다. 종합적인 분석을 통해 우울증 치료에서 A. 줄리브리신의 분자적 기반과 작용 메커니즘에 대한 이해를 높일 수 있으며, 이를 통해 임상에서 그 효능과 위험을 과학적으로 평가할 수 있는 기회를 제공할 수 있을 것입니다.

2. Mechanisms of antidepression

Tremendous progress in preclinical and clinical studies of depression has revealed many pathophysiological factors across divergent biological systems that are involved in the neurobiology of depression (Han & Yuan, 2021). Remarkably, many pharmacological targets in these biological systems have been employed to uncover the mechanism of action of antidepressants (Duman, Aghajanian, Sanacora, & Krystal, 2016, Gerhard & Duman, 2018). Studies showed that several total extracts or bioactive constituents of A. julibrissin exerted profound effects on the pathophysiological systems through multiple diverse underlying mechanisms of action. Herein, we discussed the mechanism by which A. julibrissin acts on the diverse pathophysiological systems and thereby possesses antidepressant activities (Fig. 1).

2. 항우울제의 기전

우울증에 대한 전임상 및 임상 연구의 엄청난 발전으로 우울증의 신경생물학에 관여하는 다양한 생물학적 시스템에 걸쳐 많은 병태생리학적 요인이 밝혀졌습니다(Han & Yuan, 2021). 놀랍게도 이러한 생물학적 시스템의 많은 약리학적 표적은 항우울제의 작용 메커니즘을 밝히는 데 사용되었습니다(Duman, Aghajanian, Sanacora, & Krystal, 2016, Gerhard & Duman, 2018).

연구에 따르면

A. 줄리브리신의 여러 총 추출물 또는 생리 활성 성분은

여러 가지 다양한 기본 작용 메커니즘을 통해

병리 생리 시스템에 깊은 영향을 미치는 것으로 나타났습니다.

여기에서는

A. 줄리브리신이 다양한 병리 생리 시스템에 작용하여

항우울제 활성을 갖는 메커니즘에 대해 논의했습니다 (그림 1).

Fig. 1

Proposed mechanisms of action by which A. julibrissin exerted antidepressant responses in animal models. A. julibrissin has been demonstrated to produce multiple antidepressant effects on various divergent pathological systems by modulating monoaminergic neurotransmission, the HPA axis, BDNF signaling cascade, or neuroimmune system.

동물 모델에서 A. 줄리브리신이 항우울 반응을 일으키는 작용 메커니즘이 제안되었습니다. A. 줄리브리신은 단일 아민성 신경전달, HPA 축, BDNF 신호 캐스케이드 또는 신경 면역계를 조절하여 여러 가지 다양한 병리학적 시스템에 대해 여러 가지 항우울 효과를 나타내는 것으로 입증되었습니다.

2.1. Monoamine neurotransmission

Impairment of monoamine neurotransmission is a major cause of depression. Most of the conventional antidepressants, such as fluoxetine and sertraline, selectively inhibit serotonin (5-HT) reuptake transporter, and subsequently enhance 5-HT transmission in the central nerve system (CNS). In addition, monoamine reuptake transporters for norepinephrine (NE) or dopamine (DA), monoamine metabolic enzymes, and postsynaptic monoamine receptors also play important roles in monoamine transmission. Therefore, these proteins are considered to be potential pharmacological targets in depression treatment (Murphy et al., 2021).

Zhang et al. reported that administration of an aqueous extract of Albiziae Flos alleviated chronic stress-induced growth abnormalities by regulating monoamine levels in rat brain (Zhang & Li, 2006). In addition, Kim et al. demonstrated that acute treatment with methylene chloride fraction of A. julibrissin (200 mg/kg, 30 min, p.o.) exerted antidepressant-like effects in mice, which could be specifically reversed by a 5-HT1A receptor antagonist, WAY-100635 (Kim, Kim, Lee, & Jang, 2007). This observation suggested that the A. julibrissin fraction produced antidepressant-like responses by modulating 5-HT transmission (Ji, Kim, Lee, & Jang, 2007). Furthermore, a recent report demonstrated that a 70% ethanol extract of Albiziae Cortex dramatically inhibited serotonin transporter (SERT), the principal target of the conventional antidepressant drugs (Huang et al., 2022). These studies suggested that some bioactive constituents in these A. julibrissin extracts specially act on monoaminergic signaling by modulating monoamine transporters or receptors in CNS, and thereby produce antidepressant-like responses in depressive animal models. However, further studies should be conducted to determine the nature of these constituents as well as the specific interactions with their target proteins.

2.2. Hypothalamic–pituitary–adrenal (HPA) axis

Hyperactivation of the HPA axis induced by stress impairs neuronal survival and neurogenesis, and thereby results in depressive symptoms. Studies have extensively been conducted to reveal pathophysiological factors in the HPA axis, and several pharmacological targets, such as corticotrophin releasing factor, corticotrophin releasing factor 1 receptor, and glucocorticoid receptors, have emerged for developing novel agents that suppress hyperactivation of the HPA axis (Ding et al., 2021, Juruena, Bocharova, Agustini, & Young, 2018, Menke, 2019).

Administration (6 g/kg, 21 d, p.o.) of an aqueous extract of A. julibrissin has been reported to reduce hyperactivation of the HPA axis in depressive rat models induced by chronic unpredictable mild stress (CUMS) (Li, 2017, Li, 2017). Behavioral tests showed that the aqueous extract improved spatial learning and memory in the stressed rats, which was comparable with the action of a conventional antidepressant, fluoxetine. Similarly, another study also indicated that an aqueous extract of A. julibrissin (3.6 g/kg, 28 d, p.o.) exerted an antidepressant-like activity by modulating the HPA axis, characterized by decreasing the release of serum corticotrophin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and corticosterone (CORT) in chronic restrain-stressed rats (Cui et al., 2019). A lignan glycoside isolated from A. julibrissin (3.6 mg/kg, 7 d, p.o.) has been demonstrated to exhibit an antidepressant-like activity by decreasing plasma concentrations of CRF (corticotropin releasing factor), ACTH, and CORT in the repeated acute restraint-stressed rats (Liu et al., 2017). However, these studies did not address if these extracts or constituents directly act on the pharmacological targets in the HPA axis. Only by understanding the specific drug-target interaction, we are able to uncover their mechanism of action at a molecular level.

It should be notable that several pharmacological targets to suppress stress-induced hyperactivation of the HPA axis have been proposed, however, attempts to develop novel agents directed toward the HPA axis in the treatment of depression have not been successful (Li, Huang, Cheng, & Zhang, 2020). The main reason is that the HPA axis and the neuroinflammatory system bidirectionally regulate through neural, immunological, and humoral intersystem interactions. The neuroendocrine-immune network poses difficulties associated with the development of antidepressant agents directed toward these biological systems for the effective treatment of depression (Li, Huang, & Zhang, 2021). On the other hand, multidrug and multitarget nature of Chinese herbal medicine has a great potential to assist in the development of novel medications for the systematic pharmacotherapy of depression. From this point of view, we expect that A. julibrissin could be an excellent example for the systematic treatment of depression by simultaneously acting multiple pharmacological targets in the diverse pathological systems of depression.

2.3. Neurotrophic signaling cascades

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, plays a key role in maintenance of neural plasticity. Deficiency of BDNF and other neurotrophins or dysfunction of their signaling cascades contributes the pathophysiology of depression (Duman, Deyama, & Fogaca, 2019, Masi and Brovedani, 2011, Voleti & Duman, 2012). The pharmacological targets in BDNF signaling cascade include cAMP response element binding protein (CREB), BDNF, BDNF receptor, TrkB, or its postreceptor signaling cascades such as Ras-Raf-ERK, PI3K-Akt, and PLCγ (Niciu, Ionescu, Mathews, Richards, & Zarate, 2013, Zhang, Yao, & Hashimoto, 2016).

An aqueous extract of A. julibrissin (6 g/kg, 21 d, p.o.) have been demonstrated to produce antidepressant-like effects on cAMP-CREB signaling cascade in the stressed rat models, and subsequently to attenuate behavioral abnormalities (Wang et al., 2015). In addition, total flavonoids isolated from Albiziae Flos (25 mg/kg, 21 d, p.o.) have been shown to increase the expression‎ levels of BDNF and its receptor, TrkB in the hippocampal CA1 and CA3 regions, suggesting that the flavonoids possess an antidepressant-like activity specifically through regulating BDNF signaling in the stressed rat models (Wang et al., 2012, Shi, 2014). It would be interesting to know if these herbal constituents directly act on BDNF signaling cascade and what targets they specifically interact with. Hence, more in-depth studies are required to address these questions, which are important for our understanding of their mechanistic details in order to further refine the use of these herbal antidepressants.

2.4. Inflammatory system

Studies have shown that the immune system bidirectionally communicates with the CNS at several levels through neural and immunological interactions (Jiang et al., 2019, Zunszain, Anacker, Cattaneo, Carvalho, & Pariante, 2011). Dysfunction of immune system has often been observed in many patients with depression and treatment of patients with proinflammatory cytokines can produce depressive symptoms (Chiu, Su, Su, & Chen, 2017, Ng et al., 2018). Therefore, proinflammatory cytokines and their signaling molecules have been suggested as contributing pathophysiological factors for depression (Kim, Na, Myint, & Leonard, 2016, Su et al., 2017, Zhang, Yao, & Hashimoto, 2016). Agents that act on the inflammatory systems, such as proinflammatory cytokines and their receptors, proinflammatory signaling pathways, and inflammasomes, could be effective to treat depressive symptoms (Tonhajzerova et al., 2020, Wohleb, Franklin, Iwata, & Duman, 2016).

Wei reported that an aqueous extract of Albizziae Flos (6 g/kg, 21 d, p.o.) reversed the increased levels of serum proinflammatory cytokines, such as IL-2 and IL-6, and proinflammatory signaling molecules, such as nitric oxide, induced by stress in rats, suggesting that the extract exerted an antidepressant-like activity by down-regulating inflammatory system (Wei, 2016). A earlier report to investigate the effect of an aqueous extract from Albiziae Cortex on immune function in mice showed that administration of the extract (0.5 g/kg, 6 d, p.o.) remarkably increased phagocytic rate of peritoneal macrophages and level of lymphocytic IL-2 in mice, suggesting the aqueous extract from Albiziae Cortex possesses an immune-improving property (Wang et al., 2000). While these studies demonstrated that A. julibrissin acted as a modulator in immune system, either by suppressing proinflammatory cytokines or improving immune function, the specific interaction between the herbal constituents and their acting targets in neuroimmune system as well as the molecular mechanism of action still remain to be addressed. It should be emphasized that agents targeting neuroimmune system alone would not be effective, and an additional medication that directly acts on the HPA axis is also required to achieve a better treatment, because of the intersystem crosstalk between the neuroimmune system and the HPA axis in the neuroendocrine system (Li, Huang, & Zhang, 2021). Hence, it is reasonable to parallelly investigate the effects of herbal bioactive constituents of A. julibrissin on both the pathological systems in depression treatment.

3. Bioactive constituents with antidepressant activities

As mentioned above, total extracts of A. julibrissin exerted antidepressant-like effects in animal models through multiple underlying mechanisms of action. These findings suggest that A. julibrissin must contain certain bioactive constituents that specifically act on these pharmacological targets to correct dysfunction of pathophysiological systems in neurobiology of depression. It is worth noting that depressive and anxious symptoms usually coexist in many patients and share common pathological factors and pharmacological targets for their treatment (Antypa, Vogelzangs, Meesters, Schoevers, & Penninx, 2016, Kaiser, Herzog, Voderholzer, & Brakemeier, 2021). Hence, several A. julibrissin constituents or formulae that have been shown to possess anxiolytic activity in preclinical or clinical studies are also included in our discussion. A. julibrissin is rich in flavonoids, lignan glucosides, and saponins, which have been demonstrated to exert pharmacological effects in animal models. Herein, we list several representative bioactive constituents that show antidepressant or anxiolytic-like effects, based on their chemically structural classification.

3.1. Flavonoids

Guo et al. reported that total flavonoids isolated from Albizziae Flos possessed antidepressant activities by antagonizing the hippocampal apoptosis of CA3 region in CUMS rats (Guo, Xia, Yin, & Shi, 2013, Kim, Kim, Lee, & Jang, 2007). Later, Li et al. demonstrated that the reduction in hippocampal apoptosis results from flavonoids-induced increases in 5-HT and NE levels and BDNF expression‎ as well as a decrease in the expression‎ of Bcl-2 associated X protein in CUMS rats (Li, Wang, & Gao, 2014). In addition, total flavonoids have also been investigated their effects on learning and memory in rat models. These studies indicated that flavonoids significantly alleviated stress-induced learning and memory impairment, probably through regulating monoamine levels in the brain (Ji-Hyun Kim, Kim, Lee, & Jang, 2007, Shi et al., 2013, Shi et al., 2013). Furthermore, anxiolytic effects of total flavonoids have been investigated using anxious animal models. Data showed that total flavonoids possessed an anxiolytic activity, but the molecular mechanism of action has not been fully uncovered (Liu et al., 2015).

While total flavonoids from A. julibrissin have been shown to exert antidepressant or anxiolytic effects in animal models, quercitrin (Fig. 2) is the only one flavonoid molecule that has been identified to be responsible for anxiolytic activity. In a study conducted by Li et al. (Li et al., 2016), administration of quercitrin (5.0 mg/kg, 7 d, p.o.) produced anxiolytic effects in animal models and its effects on animal behavior were blocked by WAY-100635 (3.0 mg/kg, i.p.), a 5-HT receptor 1A antagonist, but not a γ-aminobutyric acid (GABA) receptor A antagonist, flumazenil (0.5 mg/kg, i.p.). In addition, monoamine levels (5-HT and DA) and their metabolites in the brain were reduced after quercitrin treatment. These data suggest that the anxiolytic-like effects of quercitrin are mediated by 5-HT receptor 1A to enhance monoamine neurotransmission. However, the specific interaction between quercitrin and its molecular targets as well as the specificity for the monoamine signaling pathway still remain to be addressed in the future study.

3.1. 플라보노이드
Guo 등은 알비지애 플로스에서 분리한 총 플라보노이드가 CUMS 쥐에서 CA3 영역의 해마 세포 사멸을 길항하여 항우울 작용을 한다고 보고했습니다(Guo, Xia, Yin, & Shi, 2013, Kim, Kim, Lee, & Jang, 2007). 이후 Li 등은 플라보노이드에 의한 해마 세포사멸의 감소가 5-HT 및 NE 수준과 BDNF 발현의 증가와 CUMS 쥐에서 Bcl-2 관련 X 단백질의 발현 감소에 기인한다는 사실을 입증했습니다(Li, Wang, & Gao, 2014).

또한 총 플라보노이드가 쥐 모델에서 학습과 기억에 미치는 영향도 조사되었습니다. 이러한 연구에 따르면 플라보노이드는 뇌의 모노아민 수치를 조절함으로써 스트레스로 인한 학습 및 기억력 손상을 유의하게 완화하는 것으로 나타났습니다(김지현, 김, 이, & 장, 2007, Shi et al., 2013, Shi et al., 2013). 또한, 불안 동물 모델을 사용하여 총 플라보노이드의 불안 완화 효과를 조사했습니다. 데이터에 따르면 총 플라보노이드는 불안 완화 활성을 가지고 있지만 분자 작용 메커니즘은 완전히 밝혀지지 않았습니다(Liu et al., 2015).

Fig. 2

Several representative bioactive compounds shown to exert antidepressant activity, specifically by modulating monoaminergic system.

3.2. Saponins

Julibroside C1 (julibrogenin C 3-O-[β-D-xylopyranosyl1-(1,2)]-β-D-fucopyranosyl-(1,6)-[β-D-glucopyranosyl-(1,2)]-β-D-glucopyranoside) is a saponin-containing compound isolated from the stem bark of A. julibrissin (Fig. 2). Jung et al. performed a study to investigate the anxiolytic effects of julibroside C1 using behavioral and biochemical approaches (Jung et al., 2013). Administration of julibroside C1 (0.5 and 1 mg/kg, 1 h, p.o.) has been shown to increase the time spent in open arms and numbers of entries into the open arms in an elevated plus maze test. In addition, the anxiolytic-like effects of julibroside C1 were blocked by either a 5-HT1A receptor antagonist, WAY-100635, or a GABAA receptor antagonist, bicuculline or flumazenil. Furthermore, an antagonism study was conducted by using quantitative receptor autoradiography in the brain to confirm‎ the involvement of postsynaptic receptor systems in the anxiolytic-like effects of julibroside C1. Data showed that Julibroside C1 significantly decreased [3H]-8-OH-DPAT or [3H]-flunitrazepam binding, with little effect on [3H]-muscimol binding. Taken together, the study suggested that the anxiolytic-like effects of julibroside C1 were mediated by 5-HT1A and GABAA receptor systems (Jung et al., 2013). It is interesting to know the selectivity of julibroside C1 for the two receptor systems as well as the specific drug-receptor interaction for revealing its mechanism of action at the molecular level.

3.3. Lignan glucosides

A study was carried out to eval‎uate the anxiolytic-like effects of aqueous or several organic solvent extracts of Albiziae Cortex by using behavioral and biochemical approaches (Xiong et al., 2018). A n-butanol extract, which has been demonstrated to be rich in lignan glucosides, was observed to have the strongest anxiolytic-like activity among these extracts. (-)-Syringaresnol-4-O-D-apiofuranosyl-(1 → 2)-D-glucopyranoside (SAG) is one major bioactive constituent of A. julibrissin (Fig. 2). Liu et al. investigated the anxiolytic effects of SAG in acute restraint-stressed rats and subsequently analyzed its potential mechanism of action (Liu et al., 2017). Behavioral tests showed that administration of SAG (3.6 mg/kg, 7 d, p.o.) produced the anxiolytic-like responses in animal models. Moreover, SAG significantly attenuated the acute stress-induced increases in the plasma levels of CRH, ACTH, and CORT, as well as in the levels of neurotransmitters (NE, 5-HT, DA) and their metabolites (5-hydroxyindoleacetic acid, dihydroxyphenylacetic acid, and homovanillic acid) in the cerebral cortex and hippocampus of the rat brain.

Our laboratory has recently isolated and identified two lignan glycosides from A. julibrissin with antidepressant properties, one of which was SAG (Huang et al., 2022), another was a derivative of SAG, (-)-syringaresinol-4,4′-bis-O-β-D-glucopyranoside (SBG). Our results showed that these two lignan glycosides inhibited SERT noncompetitively by decreasing Vmax with little change in Km for its substrate. The two lignan glycosides decreased the accessibility of a cysteine residue placed in the extracellular substrate permeation pathway by inducing a conformational shift toward an outward-closed state of the transport protein. These results indicated that these herbal compounds from A. julibrissin acted on SERT by a novel underlying mechanism of action different from that of conventional antidepressant drugs (Huang et al., 2022). To our knowledge, it is the first example for one bioactive compound isolated from A. julibrissin that specifically targets SERT. However, both SAG and SBG have also been shown to weakly inhibit the transporters for DA and NE. The lack of selectivity for SERT increases our concerns about their addictive side effects caused by elevating synaptic concentrations of dopamine (Poisson, Engel, & Saunders, 2021).

4. A. julibrissin formulae

Depression is a multigenetic and multifactorial syndrome with various underlying pathological mechanisms (Hammen, 2018). Conventional antidepressants with single targets are inadequate for the effective treatment of depression in clinical practice. Hence, agents that are simultaneously directed toward multiple pharmacological targets in the pathophysiology of depression are needed for a better treatment (Li, Huang, & Zhang, 2021). One typical TCM antidepressant formula generally contains multiple herbs, which are thought to act on diverse pathophysiological factors at the same time in the systemic treatment of depression.

There are many empirical A. julibrissin-containing herbal formulae, which have been broadly used for the treatment of depression with comparable efficacy to the conventional antidepressants in clinical practice (Shi et al., 2019, Shi et al., 2019, Shi et al., 2019, Shi et al., 2019; Shi et al., 2019c; Shi et al., 2019d; Shi, Zhang, & Jiang, 2016). As mentioned above, A. julibrissin contains various bioactive constituents that produce multiple antidepressant effects in animal models through diverse underlying mechanisms of action, indicating that A. julibrissin possibly plays a key role in these herbal formulae.

Numerous A. julibrissin formulae have been studied to reveal their mechanisms of action by using both behavioral and biochemical approaches. These preclinical studies demonstrated that an herbal composite formula had a greater efficacy than single herbs, possibly due to their synergistic interactions (Ou et al., 2019). On the other hand, clinical studies are also critical to improve our understanding of the underlying mechanisms of action as well as biological responses in human body. In this section, therefore, we discuss several representative A. julibrissin antidepressant formulae that have been preclinically or clinically studied and others are listed in Table 1, Table 2.

Table 1

A. julibrissin formulae traditionally used for depression treatment and their efficacy in clinical practice.

Herbal formulaeCompositionDaily human dosesTypes of depressionEval‎uation indexEfficacy eval‎uationReferences

Jieyu Granules	Bupleuri Radix, Toosendan Fructus, Citri Reticulatae Pericarpium, Paeoniae Radix Alba, Acori Tatarinowii Rhizoma, Albiziae Cortex, Ziziphi Spinosae Semen, Ambrum	Three times/day	Depression with chronic congestive heart failure	SDS	Relieves symptoms of depression without apparent side effects.	(Wang, Tang, Ji, Hu, & Lin, 2018)
Jieyu Granules	Bupleuri Radix, Toosendan Fructus, Citri Reticulatae Pericarpium, Acori Tatarinowii Rhizoma, Albiziae Cortex, Ziziphi Spinosae Semen	One time/day	Depression with permanent atrial fibrillation	HAMD	Alleviates symptoms of depression without adverse effects. The efficacy is better than that of Deanxit.	(Hu, Tang, Wang, & Reng, 2018)
Jieyu Granules	Bupleuri Radix, Hyperici Perforati Herba, Albiziae Cortex, Coptidis Rhizoma	Three times/day	Moderate or mild depression	HAMD SDS SAS	Relieves symptoms of depression and anxiety without apparent side effects. It is comparable with fluoxetine, but better than Xiaoyao Powder.	(Lin, Hui, Han, Li, & Rong, 2019)
Jieyu Shuxin Pills	Bupleuri Radix, Angelicae Sinensis Radix, Rehmanniae Radix, Aucklandiae Radix, Albizziae Flos, Codonopsis Radix, Glycyrrhizae Radix et Rhizoma	Three times/day	Postpartum depression	EPDS	Alleviates symptoms of postpartum depression without adverse effects.	(Sun & Zhang, 2016)
Hehuan Granules	Albizziae Flos, Fossilia, Platycladi Cacumen, Polygalae Radix, Valeriana Officinalis Herba, Citri Exocarpium Rubrum	Two times/day	Depression and insomnia	HAMD	Alleviates depressive symptoms and improves patients’ sleep quality.	(Lei, Zhang, & Chen, 2010)
Chaihu Shugan Pills	Bupleuri Radix, Curcumae Radix, Paeoniae Radix Alba, Chuanxiong Rhizoma, Citri Reticulatae Pericarpium, Cyperi Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Albiziae Cortex, Polygoni Multiflori Caulis, Coptidis Rhizoma, Scutellariae Radix, Citri Sarcodactylis Fructus, Citri Fructus, Glycyrrhizae Radix et Rhizoma	Two times/day	Post-stroke depression	HAMD	Alleviates symptoms of post-stroke depression, and better than paroxetine in clinical efficacy.	(Ha, 2020)
Yushu Granules	Bupleuri Radix, Gardeniae Fructus, Ziziphi Spinosae Semen, Albiziae Cortex, Fossilia, Ambrum	Three times/day	Depression	HAMD	Comparable with fluoxetine without apparent adverse effects.	(Mao, Lu, & Song, 2006)

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Note: HAMD, Hamilton depression scale; SDS, Self-rating depression scale; SAS, Self-rating anxiety scale; EPDS, Edinburgh postnatal depression scale; TESS, Treatment emergent symptom scale.

Table 2

A. julibrissin formulae combined with conventional antidepressants for clinical treatment of depression.

Herbal formulaeCompositionsConventionalantidepressantsTypes of depressionEval‎uationindexEfficacy eval‎uationReferences

Jieyu Granules	Codonopsis Radix, Albiziae Cortex, Trichosanthis Radix, Curcumae Radix, Chuanxiong Rhizoma, Cyperi Rhizoma, Angelicae Sinensis Radix, Salviae Miltiorrhizae Radix et Rhizoma	Citalopram	Depression in elder people	HAMD	Combinative administration shows a better efficacy than citalopram alone.	(Yuan et al., 2010)
Xindanshu Capsules	Albiziae Cortex, Epimedii Folium, Juglandis Semen, Euphorbiae Humifusae Herba, Lilii Bulbus, Bupleuri Radix	Fluoxetine	Depression with lacking in self-confidence	HAMD	Combinative administration shows a better efficacy and less adverse effects than fluoxetine alone.	(Jin & Li, 2009)
Qingxin Anshen Granules	Pinelliae Rhizoma, Arisaema Cum Bile, Citri Exocarpium Rubrum, Coptidis Rhizoma, Gardeniae Fructus, Bambusae Caulis in Taenias, Polygalae Radix, Curcumae Radix,Poria, Atractylodis Macrocephalae Rhizoma, Aurantii Fructus, Ziziphi Spinosae Semen, Albiziae Cortex, Fossilia, Glycyrrhizae Radix et Rhizoma	Deanxit	Depression	HAMD TESS	Combinative administration shows a better efficacy than deanxit alone.	(Jiang & Zhang, 2009)
Baihe Anshen Decoction	Bupleuri Radix, Lilii Bulbus, Curcumae Radix, Albizziae Flos, Chuanxiong Rhizoma, Angelicae Sinensis Radix, Paeoniae Radix Alba	Deanxit	Anxiety and depression after coronary heart disease surgery	HAMD	Combinative administration shows a better efficacy than deanxit alone.	(Xu, Ren, & Li, 2020)
Baihe Anshen Decoction	Bupleuri Radix, Paeoniae Radix Alba, Chuanxiong Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Cyperi Rhizoma, Curcumae Radix, Albiziae Cortex, Ziziphi Spinosae Semen, Scutellariae Radix	Deanxit	Depression with chronic heart failure	HAMD	Combinative administration shows a better efficacy than deanxit alone.	(Wang & Liang, 2016)
Baihe Anshen Decoction	Bupleuri Radix, Lilii Bulbus, Curcumae Radix, Albizziae Flos, Chuanxiong Rhizoma, Angelicae Sinensis Radix, Paeoniae Radix Alba, Triticum, Anemarrhenae Rhizoma, Sojae Semen Praeparatum, Gardeniae Fructus, Fossilia, Ostreae Concha, Glycyrrhizae Radix et Rhizoma	Deanxit	Anxiety and depression	SAS SDS	Combinative administration shows a better efficacy than deanxit.	(Wen & Ji, 2015)
Jieyu Hehuan Decoction	Albizziae Flos, Paeoniae Radix Alba, Angelicae Sinensis Radix, Cinnabaris, Poria, Platycladi Semen,Polygalae Radix, Ziziphi Spinosae Semen, Ambrum, Salviae Miltiorrhizae Radix et Rhizoma, Fossilia, Sojae Semen Praeparatum, Nelumbinis Rhizomatis Nodus,Borneolum, Acori Tatarinowii Rhizoma, Ostreae Concha, Margarita, Ziziphi Spinosae Semen, Polygoni Multiflori Caulis, Triticum	Deanxit	Mild depression	HAMD	Combinative administration shows a better efficacy than Deanxit or Jieyu Hehuan decoction alone.	(Li, 2015)
Jieyu Hehuan Decoction	Moutan Cortex, Gardeniae Fructus, Angelicae Sinensis Radix, Cinnabaris, Poria, Polygalae Radix, Acori Tatarinowii Rhizoma, Paeoniae Radix Alba, Albizziae Flos, Ambrum, Polygoni Multiflori Caulis, Ziziphi Spinosae Semen, Triticum, Ostreae Concha, Fossilia, Glycyrrhizae Radix et Rhizoma	Paroxetine	Depression	HAMD	Combinative administration shows a better efficacy than paroxetine alone.	(Gong, 2016)
Baihe Ningshen Decoction	Lilii Bulbus, Polygoni Multiflori Caulis, Acori Tatarinowii Rhizoma, Angelicae Sinensis Radix, Glycyrrhizae Radix et Rhizoma,Curcumae Radix, Salviae Miltiorrhizae Radix et Rhizoma, Ziziphi Spinosae Semen, Albizziae Flos, Rosae Rugosae Flos, Scutellariae Radix, Ligustri Lucidi Fructus	Fluoxetine	Post-stroke depression	HAMD	Combinative administration shows better efficacy and fewer side effects than fluoxetine alone.	(Han, Liu, Ji, & Mi, 2010, Li, 2016)
Baihe Ningshen Decoction	Lilii Bulbus, Ziziphi Spinosae Semen, Albizziae Flos, Polygoni Multiflori Caulis, Salviae Miltiorrhizae Radix et Rhizoma, Angelicae Sinensis Radix, Glycyrrhizae Radix et Rhizoma	Clomipramine/ Amitriptyline	Depression	HAMD	Combinative administration shows a better efficacy than clomipramine/amitriptyline alone.	(Liu & Zhang, 2002)
Yangxin Docoction	Platycladi Cacumen, Schisandrae chinensis Fructus, Bupleuri Radix, Acori Tatarinowii Rhizoma, Glycyrrhizae Radix et Rhizoma, Codonopsis Radix, Curcumae Radix, Salviae Miltiorrhizae Radix et Rhizoma, Ziziphi Spinosae Semen, Polygalae Radix, Aurantii Fructus, Ophiopogonis Radix, Albiziae Cortex, Paeoniae Radix Alba, Citri Fructus	Sertraline	Depression	HAMD	Combinative administration shows better efficacy and fewer side effects than sertraline alone.	(Gao, 2018)
Baihe Ganmai Decoction	Lilii Bulbus, Anemarrhenae Rhizoma, Glycyrrhizae Radix et Rhizoma, Triticum, Albiziae Cortex, Ziziphi Spinosae Semen	Agomelatine	First-episode depression	HAMD	Combinative administration shows a better efficacy than agomelatine alone.	(Zhang, Cheng, Feng, Zhao, & Wang, 2021, Zhang et al., 2021, Zhang et al., 2015)
Jieyu Pills	Paeoniae Radix Alba, Bupleuri Radix, Angelicae Sinensis Radix, Curcumae Radix, Poria, Lilii Bulbus, Glycyrrhizae Radix et Rhizoma, Albiziae Cortex, Triticum, Ziziphi Spinosae Semen	Duloxetine	Depression with energy deficiency	SDS BDC HAMD	Better efficacy than Jieyu pills alone.	(Li, Ge, Wang, & Pan, 2020)
		Duloxetine	Post-stroke depression	HAMD CGI	Better efficacy than duloxetine alone without increased safety concerns.	(Bai, Guo, Ma, & Wang, 2020, Zhang, Liu, Zhang, Song, & Zhang, 2020)
		Deanxit	Post-stroke depression	HAMD HAMA	Better efficacy than deanxit alone without increased safety concerns.	(Wu & Yang, 2020)
		Mirtazapine	Depression	HAMD SDSS	Better efficacy and less adverse effects than mirtazapine alone.	(Ye, Fan, Chen, Li, & Cao, 2020)
		Paroxetine	Postpartum depression	HAMD	Better efficacy and less adverse effects than paroxetine alone.	(Yang & Zhong, 2020)
		Paroxetine	Post-stroke depression	NIHSS HAMD SDS	Better efficacy than paroxetine alone.	(Tang, Han, & Chen, 2019)
		Escitalopram	Post-stroke depression	HAMD NIHSS	Better efficacy than escitalopram alone without increased safety concerns.	(Tian, Bai, You, & Yao, 2020)
Jieyu Shuxin Pills	Bupleuri Radix, Angelicae Sinensis Radix, Rehmanniae Radix, Cyperi Rhizoma, Chuanxiong Rhizoma, Paeoniae Radix Alba, Acori Tatarinowii Rhizoma, Polygalae Radix, Polygoni Multiflori Caulis, Aucklandiae Radix, Albizziae Flos, Codonopsis Radix, Glycyrrhizae Radix et Rhizoma	Citalopram	Postpartum depression	EPDS HAMD SDS	Better efficacy than citalopram alone without increased safety concerns.	(Fang, Du, & Zheng, 2019, Sun, Li, & Wang, 2016)
Shenshuaining Pills	Acori Tatarinowii Rhizoma, Polygoni Multiflori Caulis, Platycladi Cacumen, Ziziphi Spinosae Semen, Albiziae Cortex, Schisandrae chinensis Fructus, Margarita, Cinnabaris, Rehmanniae Radix, Ecliptae Herba, Alpinae Oxyphyllae Fructus	Citalopram	Depression	HAMD TESS SDS	Better efficacy, faster onset, and fewer adverse effects than citalopram alone.	(Zhang, 2013)
Xingnao Jieyu Capsules	Acori Tatarinowii Rhizoma, Polygalae Radix, Curcumae Radix, Bupleuri Radix, Albiziae Cortex, Morindae Officinalis Radix, Salviae Miltiorrhizae Radix et Rhizoma	Deanxit	Post-stroke depression	HAMD SDS	Better efficacy and faster onset than deanxit alone.	(Yan, Yang, & Yang, 2011)
Baicaoxiang Jieyu Anshen Capsules	Prunellae Spica, Paeoniae Radix Alba, Albizziae Flos, Ziziphi Spinosae Semen, Bupleuri Radix, Cyperi Rhizoma, Rehmanniae Radix, Schisandrae chinensis Fructus, Polygoni Multiflori Caulis	Paroxetine	Depression	HAMD PSQI WHOQOL-BREF	Better efficacy and sleep quality than paroxetine alone.	(Liu, Cui, Li, & Yu, 2017)
Yushu Granules	Bupleuri Radix, Gardeniae Fructus, Ziziphi Spinosae Semen, Albiziae Cortex, Fossilia, Ambrum	Fluoxetine	Post-Stroke Depression	HAMD	Better efficacy than fluoxetine alone.	(Kan, 2012)
Jiawei Xiaoyao Powder	Bupleuri Radix, Angelicae Sinensis Radix, Paeoniae Radix Alba, Albiziae Cortex, Salviae Miltiorrhizae Radix et Rhizoma, Aurantii Fructus, Atractylodis Macrocephalae Rhizoma, Poria, Chuanxiong Rhizoma, Menthae Haplocalycis Herba, Glycyrrhizae Radix et Rhizoma, Zingiberis Rhizoma	Fluoxetine	Post-Stroke Depression	TESS	Better efficacy and less adverse effects than fluoxetine alone.	(Yan et al., 2015, Yang & Rong, 2009)
Anshen Dingzhi Decoction	Bupleuri Radix, Atractylodis Macrocephalae Rhizoma, Poria, Paeoniae Radix Alba, Curcumae Radix, Polygalae Radix, Lilii Bulbus, Acori Tatarinowii Rhizoma, Albiziae Cortex, Glycyrrhizae Radix et Rhizoma	Duloxetine	Depression	HAMD TESS	Better efficacy, faster onset, and fewer adverse effects than duloxetine alone.	(Gou et al., 2015)

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Note: CGI, clinical global impression; BDC, Burns depression checklist; HAMA, Hamilton anxiety scale; SDSS, social defect screening scale; NIHSS, National Institutes of Health stroke score; EPDS, Edinburgh postpartum depression scale; PSQI, Pittsburgh sleep quality index; WHOQOL-BREF, the world health organization quality of life-BREF.

4.1. Suanzaoren Hehuan Decoction

Suanzaoren Hehuan Decoction is an aqueous extract of an herbal pair comprising Ziziphi Spinosae Semen and A. julibrissin. It has been generally used for the treatment of depression or anxiety in TCM practice. Preclinical studies were conducted to reveal its mechanism of action using behavioral and neurochemical approaches (Li et al., 2019, Shi et al., 2019, Shi et al., 2016, Shi et al., 2018, Shi, Xia, Feng, Zhang, & Jiang, 2016). From these studies, its mechanism of action was proposed to include enhancement of monoaminergic transmission, elevation of neurotrophic factor expression‎, dehyperactivation of the HPA axis, suppression of inflammation, and attenuation of hippocampal apoptosis. A study was also performed to investigate the synergy and compatibility of the herb pair (Ou et al., 2019). While single herbs showed a potent action in stress-induced depressive animal models, a combination of the herb pair has a greater efficacy. However, this study neither addressed the synergistic interactions between two herbs at the molecular level, nor defined the optimized herb pair ratio that produced the greatest efficacy in the animal models. It would be interesting to know the role of A. julibrissin playing in this herb pair.

Clinical studies indicated that the decoction possessed a comparable efficacy with a conventional antidepressant, venlafaxine, but fewer adverse effects (Shi et al., 2013, Shi et al., 2016). We are encouraged by these clinical studies to explore the mechanism of action of the herb pair as an effective antidepressant in the systematic treatment of depression.

4.2. Jieyu Hehuan Decoction

Jieyu Hehuan Decoction, a combination of 13 herbs, including Albizziae Flos, Curcumae Longae Rhizoma, Aquilariae Lignum Resinatu, Angelicae Sinensis Radix, Paeoniae Radix Alba, Salviae Miltiorrhizae Radix et Rhizoma, Platycladi Cacumen, Gardeniae Fructus, Bupleuri Radix, Menthae Haplocalycis Herba, Poria, Ziziphi Spinaosea Semen, and Citri Exocarpium Rubrum, is an empirical formula for depression treatment (Zhang, 2018). The composition and dosage of Jieyu Hehuan decoction depend on the symptoms of individual patients and can be modified to fit specific individuals more accurately. A preclinical study showed that administration of the decoction (6.8 g/kg, 14 d, p.o.) shortened the immobility time in both the tail suspension and forced swimming tests and increased expression‎ of hippocampal p-GSK3β in mice, suggesting its antidepressant activity is partially mediated by BDNF signaling (Jia et al., 2017). It is extremely difficult to clearly interpret a complicated herbal formula at the molecular level, the system-wide mechanism of action as well as the role of each herb including A. julibrissin, however, should be uncovered in future studies.

Several clinical studies have been performed to investigate the system-wide responses associated with Jieyu Hehuan decoction administration (Chen & Zhang, 2007, Jia et al., 2017, Liang et al., 2018, Tian and Zhang, 2016, Zhang, 2018, Zhang et al., 2009). These studies showed that the decoction produced a better treatment efficacy than conventional antidepressants, such as fluoxetine and paroxetine, with fewer side effects. These clinical results support the idea that the holistic, multidrug, and multitarget nature of one herbal formula is more effective for the treatment of depression.

4.3. Jiawei Wendan Decoction

Jiawei Wendan Decoction, a mixture of eight herbs (Pinellia Rhizoma, Citri Reticulatae Pericarpium, Bambusae Caulis in Taenias, Aurantii Fructus, Albizziae Flos, Acori Tatarinawii Rhizoma, Magnoliae Officinalis Cortex, Poria), has been historically used for the treatment of mood disorders, loss of appetite, and sleep disturbances (Nie and Fang, 2019, Shi et al., 2007, Wu, Tang, Zhang, & Song, 2015). Zhang et al. reported that the decoction exerted both antidepressant and anxiolytic activities in rat models through enhancing 5-HT transmission (Zhang et al., 2021). In addition, studies conducted by Wu et al. (Wu, Tang, Zhang, & Song, 2015) and Wang et al. (Wang et al., 2016) showed that the antidepressant-like effects of Jiawei Wendan decoction were possibly mediated by modulating the levels of hippocampal neuropeptides, neuroendocrine hormone CRH, and Ras protein. Furthermore, studies also indicated that administration of the formula attenuated ultrastructural damage of hypothalamic neurons and gastrointestinal tissues in chronic stress-induced depressive models (Song et al., 2018, Xu, Zhang, Song, & Chen, 2019).

A clinical study demonstrated that Jiawei Wendan decoction had a comparable efficacy with fluoxetine (76.7% vs 80.0%), but fewer adverse effects (2.5% vs 5.5%), assessed by the Hamilton Depression Scale (HAMD) and Treatment Emergent Symptom Scale (TESS), respectively (Shi, Liu, Tang, & Zhang, 2007).

4.4. Jieyu Qingxin Anshen Decoction

Jieyu Qingxin Anshen Decoction is an aqueous extract from an herbal mixture composed of 12 herbs (Bupleuri Radix, Aurantii Fructus, Curcumae Radix, Cyperi Rhizoma, Citri Reticulatae Semen, Citri Reticulatae Pericarpium, Gardeniae Fructus, Sojae Semen Praeparatum, Ziziphi Spinosae Semen, Polysoni Multiflori Caulis, Albiziae Cortex, Margarita), and it has been clinically used for the treatment of depression with “vital energy” deficiency and arrhythmia symptoms (Zhang & Cao, 2013). Clinical studies showed that the herbal decoction is more effective in depression treatment than either conventional antidepressants, such as citalopram and paroxetine or one TCM antidepressant formula, Xiaoyao Powder (Gong, 2020, Guo and Gao, 2019, Sun et al., 2018, Tian, 2017). However, preclinical study to reveal the mechanism by which Jieyu Qingxin Anshen decoction produces antidepressant responses in depressive animal models has not been performed.

5. Clinical studies on combinative use of conventional antidepressants with herbal formulae

Although conventional antidepressants with single targets have been broadly used for the treatment of depression, additional agents that show synergistic activity are needed to act on diverse pathophysiological factors for a better therapeutic efficacy. An herbal formula is usually prescribed to activate blood circulation, eliminate phlegm and dampness, correct digestive and gastrointestinal dysfunction, or improve immune function, all of which are pharmacological targets in systems pharmacology in depression treatment (Wang et al., 2017). In this context, herbal formulae could serve as adjuvants to the conventional medications in the effective treatment of depression. Indeed, clinical studies indicated that treatment with a combination of a conventional antidepressant with an herbal formula showed a better therapeutic efficacy without increased safety concerns (Fu et al., 2021, Lin et al., 2021).

Several clinical attempts using a combination of an A. julibrissin formula with a conventional antidepressant have been conducted to treat patients with depressive symptoms. Conventional antidepressants commonly used with A. julibrissin formulae include fluoxetine, citalopram, paroxetine, flupentixol, clomipramine, etc., all of which exert antidepressant responses through enhancement of monoamine neurotransmission in the brain (Lv et al., 2018, Zhang et al., 2018, Casarotto et al., 2021, MahmoudianDehkordi et al., 2021). Clinical studies demonstrated that A. julibrissin formulae were compatible with these conventional antidepressants, showing a faster onset, shorter course of treatment, lower rate of relapse, and better therapeutic efficacy without increased adverse effects (Table 2). Experimental evidence for the combinative use of conventional antidepressants with herbal formulae have been obtained exclusively from clinical studies. Preclinical study using animal models is required for our understanding of the synergistic mechanism by which the combinative administration exerts a better efficacy.

6. Perspective

SERT is a well-established molecular target for the antidepressant drugs, such as selective serotonin reuptake inhibitors including fluoxetine and citalopram. The high-resolution structures of SERT in several conformational states have been resolved (Coleman et al., 2019, Coleman, Green, & Gouaux, 2016, Coleman & Gouaux, 2018, Yang and Gouaux, 2021), providing structural insight into antidepressant action on the transporter protein. In these structures, conventional antidepressant molecules occupy the central binding cavity and thus competitively inhibit the conformational conversion required for serotonin transport (Fig. 3). In addition, we previously demonstrated that a natural alkaloid, ibogaine, noncompetitively inhibited SERT by stabilizing an inward-facing conformation of the transporter (Bulling et al., 2012, Jacobs, Zhang, Campbell, & Rudnick, 2007). The cryo-electron microscopy structures of SERT-ibogaine complexes uncovered the ibogaine binding site and mechanism of ibogaine inhibition (Coleman et al., 2019). Furthermore, the recently resolved cryo-electron microscopy structures of SERT revealed an allosteric site formed by an aromatic pocket positioned in the scaffold domain in the extracellular vestibule (Yang & Gouaux, 2021). These structural analyses, thus, shifted our efforts in exploring the molecular mechanism of action toward the herbal compounds that target different conformation or the allosteric site of SERT. Experimental evidence has been recently shown that the lignan glycosides isolated from A. julibrissin, SAG and SBG, directly bind to SERT, presumably to the allosteric site, thus noncompetitively inhibit SERT activity (Huang et al., 2022). Taken together, these works have provided an excellent paradigm to explore the mechanism of action of the herbal compound as an antidepressant agent at the molecular level.

Fig. 3

High-resolution structures of SERT bound with paroxetine (PDB accession code, 5I6X, paroxetine in the central site, (A) in an outward open conformation, with ibogaine (PDB accession code, 6DZZ, ibogaine in the central site, (B) in an inward open conformation, and with two molecules of 5-HT in the central and allosteric sites (PDB accession code, 7LIA, two molecules of 5-HT in the central and allosteric sites, (C) in an outward open conformation. Cartoon views of the structures are shown from the membrane plane with the extracellular side above and the cytoplasm below the structure. The bundle domain (TMs 1, 2, 6, and 7) and other part of the protein are colored yellow and gray, respectively. The purple and green spheres in the center of the structures represent Na+ and Cl-, respectively. SERT structures in this figure were made by PyMOL.

While several other herbal molecules isolated from A. julibrissin have also been demonstrated to specifically modulate one of the pathological systems in the neurobiology of depression, their targeting proteins have not been fully understood. Identification of bioactive constituents and their specific interactions with pharmacological targets is essential to reveal the molecular mechanism of action by which A. julibrissin exerts antidepressant-like effects. These efforts could also significantly improve our understanding of its benefits and risks at the molecular level. Several advanced identification techniques, such as DNA or RNA microarray (Panossian et al., 2013, Panossian et al., 2014, Panossian, Seo, & Efferth, 2018, Panossian, Seo, Wikman, & Efferth, 2015, Woo, Lim, Myung, Kim, & Lee, 2018) and quantitative proteomics (Wang et al., 2020), have been recently used for identifying potential targeting proteins that are associated with an herb or herbal formula. We expect that these high-throughput technologies can be used for analyzing the acting targets of bioactive constituents isolated from A. julibrissin.

Meanwhile, molecular approaches also play an important role in the identification of specific interactions of herbal molecules with their targeting proteins. The results from high-throughput screening technologies need to be validated by these molecular approaches. Three complementary molecular approaches, including biochemical analysis, genetic interaction, and computational inference, have been extensively used for identifying pharmacological targets (Schenone, Dancik, Wagner, & Clemons, 2013). Biochemical analysis is directly to detect the binding affinity of a bioactive molecule by using a binding assay (Burdine & Kodadek, 2004). Profiling the herbal molecule activity with an available panel of presumed proteins can be used to directly detect its targets. Genetic interaction is used to identify targets by genetic manipulation of putative targets in cells, by changing small molecule sensitivity (Zheng, Chan, & Zhou, 2004). Gene knockout and RNAi can be used to change the action of presumed targets, revealing the dependencies of herbal molecules on biological activity. Computational inference is to compare the responses of small molecules with those of known target molecules by pattern recognition (Daniel et al., 2008). In general, databases can be used to provide useful information about the targets of an herbal molecule by comparing the similarity to compounds with known targets. In practice, a combination of these three methods should be used for defining the pharmacological targets. Using a combinative method of high-throughput screening and molecular approaches will undoubtedly promote to reveal the molecular mechanism of action of A. julibrissin, which, in turn, will improve our understanding of its on-target or off-target effects in the treatment of depression.

As discussed above, A. julibrissin exerts antidepressant-like effects through various underlying mechanisms by acting on multiple pathological factors across divergent biological systems. It is evident that the interaction between a single herbal molecule and its target revealed by the molecular approaches cannot exactly reflect the actions of an herb or an entire herbal formula, which contains numerous bioactive constituents that are proposed to act on multiple systems or targets. Hence, it is necessary to investigate the mechanism of action at the systems level for our understanding of A. julibrissin formulae in the systemic treatment of depression.

It is a challenge to uncover the mechanism of action of an herb or herbal formula at the systems level because we are not clear about all bioactive constituents and their pharmacological profiles. The synergistic interactions (Chatterjee, Verma, Maurya, & Palit, 2011) and compatibility between bioactive constituents or herbs in an herbal formula are fundamental questions to be addressed in systems pharmacology. The synergistic interactions between herb pairs in several herbal formulae have been successfully studied by several laboratories (Adams, Seeram, Hardy, Carpenter, & Heber, 2006, Wang et al., 2012, Yi & Wetzstein, 2011). In addition, a study has been conducted to optimize the compatibility of herb pairs in Kaixin Powder by examining the activation of neurofilament expression‎ in PC12 cells (Lu et al., 2015). Furthermore, Dong et al. have recently used a quantitation-based proteomics approach to identify proteins in response to Kaixin Powder administration (0.6 g/kg, 14 d) across biological systems (Dong et al., 2020). Knowledge obtained from these studies can be employed for the study of A. julibrissin formulae, such as Suanzaoren Hehuan decoction, a simplest herbal formula comprising only two herbs.

In summary, the identification of bioactive constituents and their interactions with pharmacological targets will offer the molecular basis for our understanding of the antidepressant effects of A. julibrissin. Moreover, it is vital to integrate the molecular and systematic approaches into the study of A. julibrissin or formulae for revealing its mechanism of action in its entirety. We expect that the comprehensive study would provide a way to discover novel agents or approaches in the effective and systematic treatment of depression.

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Author’s contributions

BH, YW, QT, and YZ wrote the manuscript. YW and CL prepared the figures and tables and assisted in the collection of references. YZ revised and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

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Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Acknowledgements

This research was funded by the Innovation Research of the Postgraduates of Guangzhou University (2020GDJC-M28); This research was also funded by the Guangdong Basic and Applied Basic Research Foundation (2019A1515011569 and 2021A1515012067) and National Natural Science Foundation of China (32071233).

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References