Aconitum coreanum Rapaics: Botany, traditional uses, phytochemistry, pharmacology, and toxicology

Tian-Peng Yin; Yuan-Feng Yan; Jian-Min He

doi:10.1515/chem-2022-0235

Article Open Access

Aconitum coreanum Rapaics: Botany, traditional uses, phytochemistry, pharmacology, and toxicology

Tian-Peng Yin , Yuan-Feng Yan and Jian-Min He

Published/Copyright: November 21, 2022

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From the journal Open Chemistry Volume 20 Issue 1

Abstract

The present review summarizes the multifaceted uses and recent findings regarding the phytochemistry, traditional use, pharmacology, and toxicity of the extracts and compounds of Aconitum coreanum Rapaics (Ranunculaceae) for the first time to facilitate further research and exploitation of these types of compounds and the utilization of A. coreanum plants. A. coreanum is one of the most important medicinal Aconitum species and has been traditionally and popularly used in China and other Asian countries for the treatment of headaches and migraines, Bi syndrome induced by wind, cold and dampness, and facial paralysis. Phytochemical studies have led to the isolation of 55 distinct small molecule compounds from A. coreanum, most of which are diterpenoid alkaloids. Related pharmacological studies have focused primarily on the antiarrhythmic, anti-inflammatory, analgesic, and anticancer activities of A. coreanum and its derived drugs. Alkaloids have been demonstrated to be the main active ingredients in this plant. In particular, hetisine-type DAs, mainly Guan-fu base A and its analogues, which possess prominent antiarrhythmic effects, other effects, and hypotoxicity, could be regarded as the representative constituents of A. coreanum. Polysaccharides from A. coreanum also displayed broad bioactivities, demonstrating great potential for further research and exploitation. However, few of the current studies have examined the main active components in A. coreanum from different regions. In addition, most of the pharmacological studies on A. coreanum polysaccharides were carried out using crude or poorly characterized fractions. Finally, reliable analytical methods and deeper studies on the toxicity of the compounds from A. coreanum are needed to ensure the safe usage of these products.

Graphical abstract

Keywords: Aconitum coreanum Rapaics; Ranunculaceae; diterpenoid alkaloids; antiarrhythmic

1 Introduction

The genus Aconitum is an important member of the family Ranunculaceae, which comprises approximately 400 species that are widely distributed in the temperate regions of the Northern Hemisphere, including Asia, Europe, and North America. Among them, more than 200 species have been found in China [1,2]. Plants from this genus have been extensively utilized as medicines worldwide since ancient times. In China, the utilization of Aconitum plants in traditional Chinese medicine (TCM) has a particularly long history, which can be traced back to the Han dynasty, approximately two thousand years ago [3]. Currently, two Aconitum species, namely, A. carmichaelii Debeaux and A. kusnezoffii Reichb. are officially listed in the Chinese Pharmacopoeia (CP) [4]. In addition, there are at least 76 other Aconitum species that are used as herbal medicines in different regions of China [5], such as A. vilmorinianum Kom. and A. brachypodum Diels. in the Yunnan Province of China [6,7], A. pendulum Busch in Northwest China [8], and A. hemsleyanum Pritz. in Hubei Province [9]. Medicinal Aconitum species and their derived herbal drugs have received continuous strong interest due to their special and proven therapeutic effects on various diseases, such as fainting, rheumatic fever, painful joints, gastroenteritis, diarrhoea, oedema, bronchial asthma, various tumours, and some endocrine disorders, such as irregular menstruation [3,10].

A. coreanum Rapaics (Huanghua Wutou in Chinese) is one of the most important medicinal Aconitum species in China. This plant is mainly distributed in the Northeast Region of China, which, in ancient times, was outside Shanhaiguan Pass [1]. Hence, the commercial name for the processed roots of A. coreanum in TCM is Guan Baifu (GBF) after the area in which it was produced. It has also been called Bai Fuzi, Zhujie Baifu, Guanbai Fuzi [1], or Korean monkshood [11]. A. coreanum has been medicinally used for thousands of years and is well known for its observable curative effects on headaches and migraines, Bi syndrome induced by wind, cold and dampness, and facial paralysis [12]. This medicine has been documented in many classical pharmaceutical books, including the Tang Bencao (Tang dynasty), Haiyao Bencao (Tang dynasty), and Bencao Gangmu (Ming dynasty), and was recorded in the 2nd (1963) and 3rd (1977) editions of the CP (Radix Aconiti Coreani) [13].

Phytochemical and pharmacological research on A. coreanum has been carried out since the 1960s and has drawn lasting and strong attention from scientists for decades [14,15]. These explorations have revealed the presence of multiple active ingredients, mainly diterpenoid alkaloids (DAs) [14,15], along with phenolic acids [16], phytosterols [17], fatty acids [18], and polysaccharides [19]. The crude extracts and isolated compounds of A. coreanum have exhibited impressive biological activities, including antiarrhythmic [20], anti-inflammatory [21], analgesic, antitumour [22], anti-platelet aggregation [16], insecticidal [23,24], and antioxidant activities [25]. In particular, the major component of A. coreanum, the hetisine-type C₂₀-DA Guan-fu base A (acehytisine, 1), with prominent antiarrhythmic activity and high safety, was developed as the new drug acehytisine hydrochloride injection, which was approved by the China Food Drug Administration (CFDA) in 2005. However, to date, there has been no comprehensive review of this plant. Therefore, this review has been prepared to summarize the phytochemical and pharmacological advances in the study of A. coreanum for the first time. The aim of this review is to provide a complete overview of the existing knowledge of the chemical constituents and biological properties of A. coreanum, which will facilitate further research and exploitation of this plant.

2 Botanical characterization and distribution

A. coreanum is a perennial herb with erect or twining stems ranging from 0.3 to 1.0 m long (Figure 1) [1]. The simple or branched stems with crowded leaves are sparsely retrorse pubescent. Its roots are caudex obovate or fusiform with a length of approximately 2.8 cm. Its proximal cauline leaves are withered at anthesis. Its middle leaves are broadly rhombic-ovate, 4.2–6.4 cm long and 3.6–6.4 wide and are dissected as three segments with linear or linear-lanceolate ultimate lobes. The glabrous petiole with a length of 1.4–4.5 cm is narrowly sheathed. There is no hair on the petioles or either side of the blade. This plant flowers in August and September. Its terminal inflorescence is composed of 2–7 flowers. The rachis and pedicels are densely retrorse pubescent. The proximal bracts are pinnatifid, while the others are linear. The proximal pedicel ranging from 0.8 to 2 cm in length possesses two bracteoles with lengths of 1.5–2.6 mm in the middle, which are narrowly ovate to linear. The yellowish sepals are abaxially densely curved pubescent. The lower sepals are obliquely elliptical-ovate; the lateral sepals are obliquely broadly obovate; and the upper sepals are navicular-galeate or galeate, 1.5–2 cm high, shortly beaked, and with a lower margin of 1.4–1.7 cm. The petals are glabrous, claw smaller, limbs approximately 6.5 mm, spur capitate, and short. Stamens are sparsely pubescent, and filaments entire containing three densely appressed pubescent carpels. Follicles are approximately 1 cm in length, containing ovate seeds 2–2.5 mm in length.

Figure 1

Photographs of A. coreanum, created by Zhou Yao (http://www.iplant.cn/): (a) the whole plant of A. coreanum, (b) the young plant of A. coreanum, (c) the roots of A. coreanum, (d) the flowers of A. coreanum, and (e) the fruits of A. coreanum.

Generally, A. coreanum prefers warm and moist conditions compared to other Aconitum plants and often grows on grassy slopes and in forests at an altitude of 200–900 m. In China, it is mainly distributed in the Northeast Region, including the provinces of Liaoning, Jilin, and Heilongjiang. A few plants grow in the northern Hebei Province [26]. This plant can also be found in other Asian countries, such as Mongolia, Korea, and the Russian Far East [16,27].

3 Traditional and clinical uses

The utilization of A. coreanum (GBF) in TCM is often intertwined with another medicinal plant, Sauromatum giganteum (Engler) Cusimano & Hetterscheid (Typhonium giganteum Engl., Yu Baifu in Chinese) belonging to the family Araceae, as they have both been called Bai Fuzi for a long period of time [12]. Since the first record of Bai Fuzi as an inferior medicine in the Mingyi Bielu in the Han dynasty, this medicine has been widely used by many distinguished medical experts and has been recorded in a dozen classical pharmaceutical books in China. Although these records do not provide detailed morphological descriptions of the original plant, it can be inferred, mainly through the producing areas and the limited morphological descriptions, that A. coreanum was mainly used as Bai Fuzi from the Tang dynasty to the Ming dynasty. For example, the world’s earliest official pharmacopoeia Tang Bencao (compiled in 659 A.D. during the Tang dynasty) recorded, “Baifuzi looks like Tianxiong (processed products of A. carmichaelii), and was formerly produced in Goguryeo (Korean).” Haiyao Bencao, written at the beginning of the 10th century during the Five Dynasties, also said, “the young stems of Bai Fuzi are similar to Fuzi.” The most famous Chinese herbalism masterpiece, Compendium of Materia Medica written by Li Shenzhen in the Ming dynasty, recorded, “Bai Fuzi is named for its shape similarity to Fuzi. Its nodal roots are about an inch long, with wrinkled skin,” and almost identical descriptions were recorded in Bencao Congxin from the Qing dynasty. It is clear that during the Tang dynasty to the Ming dynasty, the Aconitum spices A. coreanum produced mainly from Northeast China and Korea is the main original plant for Bai Fuzi [13].

It is generally acknowledged that S. giganteum, mainly produced in Yuzhou City, Henan Province of China, has gradually gained the dominant position of serving as Bai Fuzi since the Ming dynasty. The illustrations in BenCao Yuanshi (Ming dynasty) show that Bai Fuzi has oblong or oval-shaped roots that are slightly constricted in the middle and look like cocoons with threads, which first presented the unambiguous assignment of S. giganteum as the original plant for Bai Fuzi [28]. This trend is also reflected in the CP. Initially, the 2nd edition of the CP (1963) acknowledged both A. coreanum (Guan Baifu) and S. giganteum (Yu Baifu) as the original plants of Bai Fuzi. Later, in 1977, the 3rd edition of the CP regarded S. giganteum (Yu Baifu) as the only original plant for Bai Fuzi, and it listed Guan Baifu separately as another drug. However, since 1985, the CP has listed only Yu Baifu, while Guan Baifu is no longer listed, which indicates that Yu Baifu has roughly replaced Guan Baifu to serve as Bai Fuzi [29].

Nevertheless, Guan Baifu remains a famous and important TCM in China. Currently, Guan Baifu produced in Northeast China is mainly sold to Eastern China, such as Zhejiang Province and Shanghai City, in which Guan Baifu is officially recorded in the provincial drug standards [30]. In addition, A. coreanum is almost the only raw material that is used for the extraction of Guan-fu base A in the pharmaceutical industry [31]. According to Zhonghua Bencao (Chinese Materia Medica) and the CP (the 1963 and 1977 editions), Guan Baifu is sweet and spicy in taste, warm in nature, and described as having activities related to such processes as dispelling wind phlegm, calming epilepsy, dissipating cold, and relieving pain. In TCM, it is usually used to treat stroke, cardialgia, facial distortion, epilepsies, migraine headaches, vertigo, tetanus, infantile convulsions, and rheumatic arthralgia. A multitude of classic prescriptions (e.g., Zhishang capsule, Chuangshang pulvis, Xiaoer Jingfeng pills) created by ancient doctors and pharmacists continue to be frequently used in the clinic (Table 1). For example, Guan Baifu serves as the monarch drug in the preparation of Zhishang capsule and Chuangshang pulvis (FTCM, Formulation of Traditional Chinese Medicine), which has been used for the treatment of pain and swelling caused by traumatic injury, pain in the neck, shoulders, waist and legs, internal chest injury, and rheumatic arthritis for thousands of years. Moreover, Guan Baifu has been developed to serve as antiarrhythmic, anti-inflammatory, antalgic, and antitumour components in TCM prescriptions [32,33].

Table 1

Traditional and clinical uses of A. coreanum in China

Preparations	Compositions	Traditional and clinical uses	Reference
Zhishang capsules	Radix Aconiti Coreani, Notopterygii Rhizoma et Radix, Angelicae Dahuricae Radix, Saposhnikoviae Radix, Arisaematis Rhizoma Preparatum	Pain and swell caused by traumatic injury, pain in neck, shoulder, waist and leg, internal injury of chest, and rheumatic arthritis	CP [4,34]
Chan Wu Ba Bu pastes	Radix Aconiti Coreani root, Toad, Aconiti Radix, Rhizoma Paridis, Zanthoxyli Radix, Folium Hibisci Mutabilis, Sparganii Rhizome, Curcumae Rhizoma, Carthami Flos, Asari Radix et Rhizoma, Caryophylli Flos, Cinnamomi Cortex, Rhododendron molle fruit, Fructus Piperis Longi, Nardostachyos Radix et Rhizoma, Galanga Resurrectionlily Rhizome, Olibanum, Myrrha, Donec, Borneolum syntheticum, Borneolum, Methyl salicylate	Pain caused by several kinds of tumour	National Standards Compilation for Chinese Patent Medicines [33,35]
Shen Gui Zaizao pills	Radix Aconiti Coreani, Ginseng Radix et Rhizoma Rubra, Cinnamomi Cortex, Ephedra Herba, Rehmanniae Radix Preparata, Glycyrrhizae Radix et Rhizoma, Rhei Radix et Rhizoma, Saposhnikoviae Radix, Wenyujin Rhizoma Concisum, Zaocys Dhumnade, Alpiniae Katsumadai Semen, Angelicae Pubescentis Radix, Scrophulariae Radix, Angelicae Pubescentis Radix, Citri Reticulatae Viride Pericarpium, Atractylodis Rhizoma, Bombyx batryticatus, Dioscoreae Hypoglaucae Rhizome, Olibanum, Linderae radix, Cyperi Rhizoma, Taxilli Herba, Myrrha Drynariae Rhizoma, Puerariae Lobatae Radix, Pangolin Scales, Borneolum Syntheticum	Arthralgia and myalgia, numbness of limbs, backache, and fatigue weakness	Formulation of Traditional Chinese Medicine (FTCM)
Chuangshang pulvis	Radix Aconiti Coreani, Typhonii Rhizoma, Aconiti Radix Cocta, Notoginseng Radix et Rhizome, Dioscoreae Rhizoma, Borneolum Syntheticum, Moschus, Angelicae dahuricae radix	Traumatic injury, traumatic or internal bleeding	FTCM
Yingning pulvis	Radix Aconiti Coreani Preparatum, Arisaema cum Bile, Cicadae Periostracum, Glycyrrhizae Radix et Rhizoma, Uncariae Ramulus cum Uncis, Mentha Haplocalyx Leaves, Bambusae Concretio Silicea, Scorpio, Angelicae Dahuricae Radix, Aucklandiae Radix, Trichosanthis Radix, Gastrodiae Rhizoma Preparatum, Gastrodiae Rhizoma, Bombyx Batryticatus, Calcined Micae Lapis Aureus, Rhizoma Acori Tatarinowii, Calculus Bovis Artifactus, Saposhnikoviae Radix, Moschus, Realgar, Borneolum Syntheticum, Polygalae Radix Preparatum, Margarita, Poria, Amber, Aquilariae Lignum Resinatum, Cinnabaris	Febrile convulsion, night cry and startle, abundant expectoration of babies	FTCM
Jinsu cinnabar	Radix Aconiti Coreani, Arisaema cum Bile, Bombyx Batryticatus, Scorpio, Calcined Haematitum, Moschus, Gastrodiae rhizoma, Borneolum syntheticum, Olibanum	Wind-phlegm syndrome, and cramp of babies	FTCM
Xiaoer Jingfeng tablets	Radix Aconiti Coreani Preparatum, Amber, Saposhnikoviae Radix, Bombyx Batryticatus, Gastrodiae Rhizoma, Bulbus Fritillariae Cirrhosae, Arisaema cum Bile, Bambusae Concretio Silicea	Thermal shock, infantile convulsions, hiding fever and flushing, irritation restless, convulsion of the limbs, abundant expectoration, coma	FTCM

4 Phytochemistry

To date, phytochemical investigations on A. coreanum have led to the isolation and identification of approximately 55 distinct small molecule compounds, including 40 alkaloids and 15 other compounds. Table 2 lists the names, molecular formulas and weights, plant sources, along with the references of all the small molecule compounds isolated from A. coreanum. In addition, bioactive polysaccharides in A. coreanum have been investigated. Herein, the studied chemical constituents from A. coreanum are summarized and discussed by category.

Table 2

List of chemical compounds isolated from A. coreanum

No	Name	Molecular formula	Molecular weight	Part of plant	Ref.
Alkaloids (C ₂₀ -DAs)
1*	Guan-fu base A (acehytisine)	C₂₄H₃₁NO₆	429.50	Roots	[14,36,37]
2*	Guan-fu base F	C₂₆H₃₅NO₄	457.56	Roots	[38]
3*	Guan-fu base G	C₂₆H₃₃NO₇	471.54	Roots	[36,39]
4*	Guan-fu base N	C₂₂H₃₀NO₅	388.48	Roots	[40]
5*	Guan-fu base O	C₂₅H₃₃NO₆	443.53	Roots	[41]
6*	Guan-fu base P	C₂₈H₃₇NO₇	499.60	Roots	[38,42]
7*	Guan-fu base Q	C₂₂H₂₇NO₅	385.45	Stems, Leaves, Roots	[39,43]
8*	Guan-fu base R	C₂₇H₃₅NO₇	485.57	Roots	[42]
9*	Guan-fu base S	C₂₄H₂₉NO₅	411.49	Roots	[44]
10*	Guan-fu base T	C₂₀H₂₅NO₄	343.42	Roots	[45]
11*	Guan-fu base U	C₂₀H₂₅NO₄	343.42	Roots	[45]
12*	Guan-fu base V	C₂₀H₂₅NO₃	328.19	Roots	[46]
13*	Guan-fu base W	C₂₂H₂₉NO₅	387.47	Roots	[46]
14*	Guan-fu base Y(Guanfu base I, Guanfu base B, acorine)	C₂₂H₂₉NO₅	387.47	Epigeal parts	[27]
15*	Guan-fu base Z	C₂₈H₃₇NO₇	499.60	Roots	[39,47]
16*	Guan-fu base A1	C₂₄H₃₁NO₆	429.51	Roots	[39]
17	Hetisine	C₂₀H₂₇NO₃	329.43	Roots	[40]
18*	Acrodine	C₂₃H₃₁NO₅	401.50	Roots	[15,48]
19	Tangutisine(Guan-fu alcoholamine)	C₂₀H₂₇NO₄	345.43	Roots	[40,49]
20*	Trichodelphinine D	C₂₄H₃₁NO₅	413.51	Roots	[15]
21	2,11,13-Triacetylhetisine	C₂₆H₃₃NO₇	471.54	Roots	[15]
22*	Coreanine A	C₂₇H₃₇NO₆	471.59	Roots	[15]
23*	Coreanine B	C₂₅H₃₅NO₅	429.55	Roots	[15]
24*	Coreanine C	C₂₆H₃₅NO₆	457.56	Roots	[15]
25*	Coreanine D	C₃₁H₃₅NO₇	533.61	Roots	[15]
26	Hetisinone	C₂₀H₂₅NO₃	327.42	Roots	[50]
27*	Guan-fu base X	C 22 H 29 NO 6 −	403.47	Roots	[46]
28	14-Hydroxy-2-isobutyrylhetisine N-oxide	C 24 H 31 NO 6 −	431.52	Roots	[51]
29	Coryphine	C₃₁H₄₂N₂O₂	474.68	Roots	[52]
30*	Guan-fu base J	C₂₃H₃₁NO₅	401.50	Roots	[40]
31*	Guan-fu base K	C₂₀H₂₇NO₄	345.43	Roots	[53]
32	Dihydroatisine	C₂₁H₃₃NO₂	331.41	Roots	[40]
33	Guan-fu base H(Atisinium chloride)	C 21 H 32 N 2 O 2 +	330.48	Roots	[43]
34	Coryphidine	C₃₁H₄₄N₂O₃	492.69	Roots	[52]
35	Atisine	C₂₂H₃₃NO₂	343.50	Roots	[54]
36	Isoatisine	C₂₂H₃₃NO₂	343.50	Roots	[43]
Alkaloids (C ₁₉ -DAs)
37	Condelphine	C₂₅H₃₉NO₆	449.58	Roots	[44]
38	Talatisamine	C₂₄H₃₉NO₅	421.57	Roots	[40]
39	Mesaconitine	C₃₃H₄₅NO₁₁	631.71	Roots	[40]
40	Hypaconitine	C₃₃H₄₅NO₁₀	615.71	Roots	[14]
Others
41*	Guan-fu diterpenoid A	C₂₀H₃₄O₂	306.48	Roots	[44]
42	Caffeic acid	C₉H₈O₄	180.16	Roots	[11]
43	4,5-Dicaffeoylquinic acid	C₂₅H₂₄O₁₂	516.45	Roots	[11]
44	3,5-Dicaffeoylquinic acid	C₂₅H₂₄O₁₂	516.45	Roots	[11]
45	3,5-Dicaffeoylquinic acidmethyl ester	C₂₆H₂₆O₁₂	530.48	Roots	[11]
46	Trans-p-hydroxy cinnamic acid	C₉H₈O₃	164.16	Roots	[16]
47	Ferulic acid	C₁₀H₁₀O₄	194.19	Roots	[16]
48	3-(4′-β-d-Glucopyranosyl)-phenyl-2-propenoic acid	C₁₇H₂₂O₉	370.35	Roots	[16]
49	β-Sitosterol	C₂₉H₅₀O	414.71	Stems and leaves	[17]
50	Daucosterol	C₃₅H₆₀O₆	576.85	Stems and Leaves	[17]
51	Oleic acid	C₁₈H₃₄O₂	282.46	Roots	[18]
52	Linoleic acid	C₁₈H₃₂O₂	280.44	Roots	[18]
53	Palmitic acid	C₁₆H₃₂O₂	256.42	Roots	[18]
54	d-Mannitol	C₆H₁₄O₆	182.17	Stems and Leaves	[17]
55	Sucrose	C₁₂H₂₂O₁₁	342.30	Roots	[16]

The new compounds are labelled with ∗.

4.1 Alkaloids

The alkaloidal components of A. coreanum have been investigated since the 1960s, and these investigations have lasted for decades. In 1966, Chinese scientists Gao et al. first reported the isolation of six DAs from the roots of A. coreanum, including five new alkaloids named Guan-fu bases A–E and the common C₁₉-DA component hapaconitine (40), although their structures were not clarified mainly due to the lack of sufficient spectral data [14]. Over the following decades, A. coreanum from different regions, including China, Korea, and Russia, was extensively investigated, which led to the isolation and identification of a total of 40 DAs (Figure 2). Most of these DAs were obtained from the roots, with the exception of a few compounds, such as alkaloids 7 and 14, which were isolated from the epigeal parts [27,43]. The isolated alkaloids include 36 C₂₀-DAs and 4 C₁₉-DAs, which cover five subtypes, namely, the C₂₀-hetisine type (1–28), C₂₀-hetidine type (29), C₂₀-kusnczoline type (30–31), C₂₀-atisine type (32–36), and C₁₉-aconitine type (37–40). Clearly, hetisine-type C₂₀-DAs are the most characteristic components of A. coreanum. Notably, of the 40 DAs isolated from A. coreanum, 25 were isolated as new compounds (labelled with *), which mainly vary in the variety, quantity, position, and orientation of the oxygenated groups substituted on the hetisine skeleton. The common oxygenated substituents found in these new DAs include hydroxyl (OH), carbonyl (═O), and various ester groups, such as acetyl (Ac), propionyl (Pr), isobutyl (iBu), 2-methylbutyryl (MeBu), and benzoyl (Bz). These new DAs found in A. coreanum demonstrated high chemical diversity and could serve as a vast resource for drug discovery.

Figure 2

Alkaloids isolated from A. coreanum.

Since the roots of A. coreanum are almost the only raw material that is used for the production of acehytisine-derived drugs in the pharmaceutical industry, the methods of extraction and separation of alkaloids from A. coreanum have been explored. Bai et al. optimized the extraction technology for acehytisine (1) from A. coreanum by the high-voltage pulsed electric field method and compared it with conventional extraction methods, including percolation, hot refluxing, and ultrasonic extraction [31]. The acehytisine content and extract yield from A. coreanum reached 0.391 and 39.92%, respectively, under the following optimal conditions using the high-voltage pulsed electric field method: a high voltage of 20 kV/cm, an impulsion frequency of 10, and a solid-to-solvent ratio of 1:14 with 90% ethanol as the extracting solvent; these conditions produced a higher content and extraction yield than the other three conventional methods listed previously. The results demonstrated that the high-voltage pulsed electric field method had the advantages of time savings, heat freedom, and high yields.

High-speed counter-current chromatography (HSCCC), a type of support-free liquid–liquid partition chromatography, could effectively eliminate the irreversible adsorption loss from samples and give higher recoveries and efficiencies than silica gel column chromatography, the most conventional separation method in phytochemical studies [55,56]. Several studies performed by Tang et al. revealed the superiority of HSCCC for the separation of DAs from A. coreanum. By optimizing two-phase solvent systems, up to eight DAs with highly similar structures could be simultaneously separated with purities over 90% each from approximately 1 g of crude extract of A. coreanum in a one-step HSCCC separation [49,54]. Several new compounds were also isolated by using the HSCCC method [42,45]. pH-Zone-refining counter-current chromatography (pH-zone-refining CCC) also has advantages, including a larger sample loading capacity, shorter separation time, high concentration of the fractions and concentration of the minor impurities, compared to conventional counter-current chromatography methods, and is an excellent technique for separating DAs. In a pH-zone-refining CCC separation, seven DAs were successfully purified from 3.5 g of a crude extract with an optimized two-phase solvent system of petroleum ether–EtOAc–MeOH–H₂O (5:5:1:9, v/v/v/v) [57].

4.2 Other small molecule compounds

In addition to the alkaloids described earlier, other types of natural products have been isolated from A. coreanum (Figure 3). Guan-fu diterpenoid A (41), which is an ent-kaurane-type diterpenoid, is the only non-alkaloidal diterpenoid found in A. coreanum [44]. This compound is of great interest due to its function in the biogenetic pathway of DAs. It has been supposed that a diterpenoid functions as a precursor of a C₂₀-hetisine diterpenoid alkaloid. However, diterpenoids are rarely found in Aconitum plants [2]. The discovery of guan-fu diterpenoid A (41) in A. coreanum could support the hypothesis of the biogenetic pathway of DAs involving a diterpenoid [58].

Figure 3

Other chemical compounds isolated from A. coreanum.

Several phenylpropionic acids have been found in A. coreanum. Caffeic acid (42) and its derivatives 4,5-dicaffeoylquinic acid (43), 3,5-dicaffeoylquinic acid (44), and 3,5-dicaffeoylquinic acid methyl ester (45) were isolated from Korean A. coreanum [11]. In addition, several widely distributed plant metabolites, including phytosterols, such as β-sitosterol (49) and daucosterol (50) [17], and long-chain unsaturated fatty acids, such as oleic acid (51), linoleic acid (52), and palmitic acid (53) [18], have also been isolated from this plant.

4.3 Polysaccharides

In addition to the small molecule compounds described earlier, the bioactive polysaccharides from A. coreanum have also been investigated, which has led to the isolation of a series of crude or homogeneous polysaccharides. Although crude polysaccharides are rarely clarified to determine their chemical structures, the structures of several homogeneous polysaccharides from A. coreanum have been reported by using high-resolution mass spectrometry (HR-MS) and extensive nuclear magnetic resonance (NMR) methods, including 1D (¹H and ¹³C NMR) and 2D (¹H–¹H COSY, HSQC, HMBC, and NOESY) NMR spectra. For example, the homogeneous polysaccharide KMPS-2A isolated by Li et al. was reported to consist of a [α-1,6-d-Glc]_n repeating structure with a molecular weight of 676,000 Da [19]. Another polysaccharide, KMPS-2E, consists of [→6)-β-d-Galp (1→3)-β-L-Rhap-(1→4)-β-d-GalpA-(1→3)-β-d-Galp-(1→] units with →5)-β-d-Arap(1→3,5)-β-d-Arap(1→ side chains attached to the backbone through O-4 of (1→3,4)-l-Rhap. T-β-d-Galp is attached to the backbone through O-6 of the (1→3,6)-β-d-Galp residues, and T-β-d-Ara is connected to the end group of each chain [59].

5 Bioactivities

5.1 Antiarrhythmic effects

The antiarrhythmic effect is the most important function of A. coreanum, as documented in the Mingyi Bielu, “Bai Fuzi treats cardiodynia and blood arthralgia.” Pharmacological experiments performed by Ke et al. validated the antiarrhythmic effects of A. coreanum [60], which showed that unprocessed A. coreanum (raw product) and its steamed products could antagonize chloroform-induced ventricular fibrillation and aconitine-induced arrhythmia in mice and reduce the CaCl₂-induced incidence of ventricular fibrillation (VF) in rats and their death rate, while reduced efficacy was observed from products processed with tofu (bean curd) and ginger–alumen (KAl(SO₄)₂·12H₂O).

More extensive studies on the antiarrhythmic effects of A. coreanum have been devoted to its representative ingredient acehytisine (1), which was approved by the CFDA in 2005 to serve as a new antiarrhythmic drug to treat paroxysmal supraventricular tachycardia after a 30-year persistent effort by Chinese researchers, mainly Liu Jinghan and her co-workers. In pharmacological experiments, acehytisine (1) could effectively antagonize aconitine-induced arrhythmia in rats, significantly reduce the CaCl₂-induced incidence of VF in rats [61], markedly increase the ventricular fibrillation threshold to electrical stimulation in rabbits and cats [61], and notably increase the ouabain dose necessary to cause ventricular premature (VP) beats, VF, and cardiac arrest in anaesthetized guinea pigs [61]. The antiarrhythmic effects of acehytisine (1) could be attributed to its electrophysiological properties; it has been verified to be a multi-ion channel blocker, including sodium channels [62,63], calcium channels, potassium channels [64,65], and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels [66]. In clinical studies, acehytisine (1) showed unambiguous therapeutic efficacy on paroxysmal supraventricular tachycardia (PSVT), paroxysmal atrioventricular reentrant tachycardia, and ventricular tachycardia, along with reliable safety in humans [67,68]. Moreover, acehytisine (1) has the unique advantage of not affecting the function of the atrionector when it exerts other electrophysiological effects [20].

In addition to acehytisine (1), Guan-fu bases G (3) and I (14) also exhibit antiarrhythmic activity in the decreasing order of Guan-fu bases G (3) > A (1) > I (14) [69]. Structure–activity relationship (SAR) studies revealed that the propylene glycol amine group might be the key pharmacophore responsible for the antiarrhythmic activity of acehytisine (1) and its analogues [70], and additional ester groups could enhance the antiarrhythmic activity of acehytisine (1) [71], which provides a beneficial reference for the further discovery of additional effective antiarrhythmic agents.

In addition, five hetisine-type DAs found in A. coreanum showed significant blocking activities on sodium current as determined by a whole-cell patch voltage-clamp technique [40]. Among them, Guan-fu base S (9, IC₅₀ 3.48 μM) showed the strongest inhibitory effect. It suppressed the sodium current of guinea pig ventricular myocytes in a dose-dependent manner by binding to open channels and exhibited potential for further development as an antiarrhythmic agent. Guan-fu base Q (7, IC₅₀ 82.65 μM), hetisine (17, IC₅₀ 75.72 μM), acehytisine (1, IC₅₀ 41.17 μM), and Guan-fu base G (3, IC₅₀ 23.81 μM) showed moderate inhibitory effects and were more effective than the positive control acehytisine hydrochloride (the crude drug of acehytisine injection, IC₅₀ 78.26 μM). Sodium current plays a vital role in the early depolarization and duration of the cardiac action potential and is involved in the propagation of electrical impulses from one cell to another [72,73]; hence, sodium current blockers could be a useful candidate target for new potential therapeutic agents against arrhythmia.

5.2 Anti-inflammatory effects

In 1990, Wu et al. compared the anti-inflammatory effects and toxicities of A. coreanum and Yu Baifu. It was observed that both possess similar anti-inflammatory effects at the dose of 4.5 g/kg, which obviously restrain effusion and oedema in rat inflammation induced by egg whites and yeast and inhibit the growth of granulomas in mice [21]. A series of naturally occurring DAs have demonstrated prominent anti-inflammatory effects in vitro and in vivo, some of which exist in A. coreanum and might contribute to the anti-inflammatory action of drugs derived from A. coreanum. For example, mesaconitine (39) was reported to play a key role in the peripheral pathway for inflammatory pain relief [74], and hapaconitine (40) has also exhibited high antiexudative activity compared with that of sodium diclofenac in various models of acute inflammation [75]. In addition, in a primary study, it was found that acehytisine (98 mg/kg, ip) could restrain the inflammatory swelling of rats induced by egg whites and exhibits an effect equal to that of sodium salicylate (400 mg/kg) [76].

Caffeic acid (42) and its derivatives 43–45 from Korean A. coreanum inhibited NO production (IC₅₀ values of 2.07 ± 1.13, 1.20 ± 1.23, 0.76 ± 1.27 and 2.37 ± 1.13 μM, respectively) significantly more than the positive control L-NMMA (IC₅₀ = 7.83 ± 1.07 μM) and dose-dependently inhibited the expression of iNOS and COX-2 as well as their mRNA levels [11]. In addition, the homogeneous polysaccharide KMPS-2E showed significant anti-inflammatory effects in both lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and carrageenan-induced hind paw oedema models [59]. KMPS-2E could inhibit the expression of iNOS and inflammatory cytokines mediated by the NF-κB signalling pathways in macrophages. Also, in macrophages, KMPS-2E (50, 100 and 200 mg/mL) inhibited iNOS, TLR4, phospho-NF-κB-p65, phospho-IKK, and phospho-IκB-α expression as well as the degradation of IkB-α and the gene expression of inflammatory cytokines (TNF-α, IL-1β, iNOS, and IL-6) mediated by the NF-κB signalling pathways. KMPS-2E also inhibited LPS-induced activation of NF-κB as assayed by electrophoretic mobility shift assay (EMSA) in a dose-dependent manner and reduces NF-κB DNA binding affinity by 62.1% at 200 mg/mL. In rats, KMPS-2E (200 mg/kg) was shown to significantly inhibit carrageenan-induced paw oedema to the same extent as ibuprofen (200 mg/kg) within 3 h after a single oral dose. The results indicate that KMPS-2E is a promising herb-derived drug against acute inflammation [77,78].

These findings indicate that the anti-inflammatory action of A. coreanum might be a collective effort of the DAs, caffeic acid derivatives, and polysaccharides described earlier.

5.3 Analgesia activities

Analgesic effects are one of the most famous functions of Aconitum plants. In numerous TCM prescriptions, A. coreanum serves as the most important ingredient to exert analgesic effects, such as in Shen Gui Zaizao pills, Chuangshang pulvis, and Zhishang capsule. Mao et al. investigated the analgesic effects of A. coreanum and its processed products [79]. The raw product of A. coreanum and its steamed products could inhibit the pain induced by acetic acid and hot plates. The products processed with bean curd and ginger-alumen also alleviated the pain induced by acetic acid, but no remarkable effect was observed in mice on the pain induced by hot plates.

The analgesic effects of A. coreanum should be attributed to its DA components, which are fame for their remarkable analgesic effects [80]. It has been reported that diester DAs such as mesaconitine (39) and hypaconitine (40) could inhibit neuronal conduction by persistent depolarization to exert analgesic effects [81]. In addition, in a recent study, five DAs (1, 14–15, and 39–40) were evaluated for their analgesic effects using hot plate and acid-induced writhing tests. It was found that the C₁₉-DAs mesaconitine (39) and hypaconitine (40) exhibited a prominent analgesic effect similar to the positive control bulleyaconitine A, while Guan-fu bases A (1), Y (14), and Z (15) only possess weak analgesic effects in hot plate experiments (improvement in the pain threshold by approximately 30% at a dose of 10 mg/kg) [82].

5.4 Antitumour activities

Several polysaccharide fractions from A. coreanum have shown antiproliferative activity against certain cell lines in vitro and in vivo, which could support the application of this herbal medicine in the treatment of corresponding tumours. Liang et al. obtained the crude polysaccharide CACP from the stems of A. coreanum by hot water extraction and ethanol precipitation [22], which specifically inhibited the growth of hepatoma 22 (H22) tumour cells both in vivo and in vitro via the induction of apoptosis and exhibited significantly lower cytotoxicity to nontumorous cell lines. Moreover, CACP treatment greatly prolonged the survival period in H22 ascites tumour-bearing mice. A subsequent pharmacological study revealed that the inhibitory effects of CACP on the growth of H22 cells may occur through repression of PTTG1 (pituitary tumour transforming gene 1) followed by inactivation of the P13K/Akt signalling pathway and activation of the p38 MARK (mitogen-activated protein kinase) signalling pathway [83].

Zhang et al. reported that a polysaccharide from A. coreanum (ACP1) and its sulphated derivative (ACP1-s) caused significant inhibition of human breast cancer MDA-MB-435S cell migration in vitro. ACP1 and ACP1-s significantly impaired the migratory behaviour of MDA-MB-435S cells and markedly reduced their cumulative distance and average velocity, which may be associated with their abilities to affect dynamic remodelling of the actin cytoskeleton and suppress phosphorylation and activation of signalling molecules [84]. Moreover, these two polysaccharides were also found to induce apoptosis in U87MG human brain glioblastoma cells via the NF‑κB/Bcl‑2 cell apoptotic signalling pathway [85].

These findings suggest the potential value of polysaccharides from A. coreanum as novel therapeutic agents for the treatment of malignant tumours. However, their structures have not been thoroughly clarified; thus, their SARs are still not clear, which hinders their application and use. It is necessary to carry out further, deeper studies to clarify the detailed structural information to facilitate additional research and exploitation of the antitumour polysaccharides from A. coreanum (Figure 4).

Figure 4

Biological activities of A. coreanum and their mechanisms.

5.5 Anti-platelet aggregation activity

Zhou et al. screened the anti-platelet aggregation effects of eight compounds from A. coreanum using ADP-induced method in rat blood [16]. Five compounds (14, 33, and 46–48) showed strong inhibitory effects on ADP-induced blood platelet aggregation (with inhibition rates ranging from 44.2 to 66.7% at 5 μM), which indicated that they may be responsible for the blood-activating effects of Guan Baifu [86].

5.6 Insecticidal activities

The aqueous extracts of A. coreanum roots are used as natural pesticides for the prevention and cure of wheat stem rust in the Northeast Region of China [1], which might be attributed to the DA components with insecticidal activities. In a screen of the insect-repellent activities of natural DA components against Tribolium casteneum, hetisine (17) was found to possess the highest activity among all 29 tested alkaloids, as hetisine exerted a repellence of 59.12% at 3 mg/mL [87]. Condelphine (37) also showed a class III repellent effect with a repellency value of 40.62% at 3 mg/mL, while hetisinone (26) and talatisamine (38) showed only a low-class II repellent effect with repellency values of 37.50 and 34.37% at 3 mg/mL, respectively. In addition, hetisinone (26) showed certain insect antifeedant activity against Leptinotarsa decemlineata with an EC₅₀ value of 13.1 μg/cm² [23,24].

Other compounds were also evaluated for their insecticidal activities. Gu et al. compared the contact activity of the steam distillation from three Aconitum species found on Changbai Mountain against the borers of three crops, namely, Sesamia inferens, Ostrinia nubilalis, and Etiella zinckenella [88]. The steam distillation of A. coreanum showed strong contact activity against S. inferens (lethality rate of approximately 85% at 24 h) but was ineffective against O. nubilalis and E. zinckenella. However, in another screen of the acaricidal and insecticidal activities of 20 plant-derived oils against Sitotroga cerealella, Sitophilus oryzae, Sitophilus zeamais, and Tyrophagus putrescentiae adults, A. coreanum oils did not exhibit significant acaricidal or insecticidal activity [89].

5.7 Antioxidant activities

Crude polysaccharides from A. coreanum have exhibited antioxidant activities in in vitro antioxidant assays. Three polysaccharide fractions (ACPSA-1, ACPSB-2, and ACPSB-3) obtained from A. coreanum roots by DEAE-cellulose and Sepharose CL-6B chromatography were evaluated for their antioxidant potential. The experimental results showed that ACPSB-2 and ACPSB-3 exhibited significant antioxidant activity in a concentration-dependent manner and could effectively scavenge 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide, and hydroxyl radicals as well as chelate ferrous ions [25]. Another two investigations reported that crude polysaccharides from A. coreanum possess a powerful ability to suppress the production of O₂ ⁻ and OH^- in the self-oxidation method of pyrogallol and the Fenton system and inhibit Fe²⁺–H₂O₂-induced liver lipid peroxidation in rats [90,91].

In addition, caffeic acid (42) and its three derivatives 43–45 showed significantly more potent DPPH radical scavenging activity than the positive control L-ascorbic acid. The IC₅₀ values of caffeic acid and its derivatives were 11.09, 10.09, 9.95, and 9.53 μM, respectively, whereas that of L-ascorbic acid was 14.1 μM [17]. These potent antioxidative activities might be due to the ortho-dihydroxy-phenolic moiety and the presence of a CH═CH–COOR group, both of which enable a hydrogen atom to be donated to an active free radical [92] (Table 3).

Table 3

Pharmacological bioactivities of A. coreanum

Crude drug/compounds	Models	Dose/concentration	Results	Ref.
Antiarrhythmic
Raw and processed products	Chloroform-induced ventricular fibrillation in mice	6.25, 12.5 g/kg	VF↓; Effect: raw, steamed products > products decocted with alum, or tofu	[60]
	Aconitine-induced arrhythmia in mice	6.25, 12.5 g/kg	arrhythmia↓; Effect: raw, steamed products > products decocted with alum, or tofu.
	CaCl₂-induced arrhythmia in mice	6.25, 12.5 g/kg	VF↓, VT+VP↓; Effect: raw, steamed products > products decocted with alum, or tofu.
Compound 1	Aconitine-induced arrhythmia in rats	10, 25 mg/kg	Dose of aconitine to cause VF↑	[61]
	Ouabain-induced arrhythmia in dogs	11.25 mg/kg	VT↓
	Electrical stimulation ventricular fibrillation in rabbits	12.5, 15 mg/kg	VF↓, inhibiting rate: 60% at 12.5 mg/kg, 100% at 15 mg/kg
	Cats	5, 10, 15 mg/kg	heart rate↓, blood pressure↓, P Q interval↑, Q T interval↑, ST interval↑, Electrocardiogram resting period↑
Compounds 1, 3 and 14	Chloroform-induced ventricular fibrillation in mice	ED₅₀ (mg/kg): 9.53 (3), 81.87 (1), and 189.9 (14)	Antiarrhythmic effect: 3 > 1 > 14	[69]
	Aconitine-induced arrhythmia in mice	2.5, 5.0 mg/kg for 3, 10 mg/kg for 1	VP↓, VT↓, VF↓; antiarrhythmic effect: 3 > 1
	Langendorff mode of isolated guinea-pig heart	29.5 μM of 3	VF↓
Compounds 1 and 3	Human embryonic kidney 293 cells transiently transfected with HERG complementary DNA using a whole-cell patch clamp technique	IC₅₀ (μM): 1.64 mM (1), 17.9 μM (3)	HERG channel current inhibiting effect: 3 > 1	[65]
Compounds 1, 3, 7, 9, and 17	Blocking activities on sodium current	IC₅₀ (μM): 3.48 (9), 82.65 (7), 41.17 (1), 23.81 (3), and 75.72 (17)	Sodium current inhibitory effect: 9 > 3 > 1 > 17 > 7	[40]
Anti-inflammatory
Powder	Egg whites and yeast induced inflammation in rat	4.5 g/kg	Restrain effusion↓, oedema↓	[21]
Compound 1	Egg whites induced inflammation in rat	98 mg/kg	Swelling↓; equal to sodium salicylate (400 mg/kg).	[76]
Homogeneous polysaccharide KMPS-2E	LPS-stimulated RAW 264.7 macrophages	50, 100 and 200 mg/mL	iNOS↓, TLR4↓, phospho-NF-κB–p65↓, phosphor-IKK↓, phosphor-IκB-α↓, NF-κB activity↓, TNF-α↓, IL-1β↓, iNOS↓, IL-6↓	[59]
Homogeneous polysaccharide KMPS-2E	Carrageenan-induced hind paw oedema	200, 400, and 800 mg/kg	Paw oedema↓	[59]
7Compound 42–45	LPS-stimulated RAW 264.7 macrophages	IC₅₀: 0.76–2.37 μM	NO production inhibiting effect: 42–45 > L-NMMA (IC₅₀, 7.83 μM)	[11]
7Compound 42–45	LPS-stimulated HaCaT cell	10, 100 μM	iNOS↓, COX-2↓	[11]
Analgesia
Raw and processed products	Acetic acid-induced writhing tests	Analgesic rate: 52.23% (at 50 g/kg), 71.38% (at 25 g/kg), and 41.98% (at 12.5 g/kg) for 50% EtOH extracts of raw product;	Raw, steamed products > products decocted with alum, or tofu	[79]
		Analgesic rate for 50% EtOH extracts (at 25 g/kg): 54.75% for raw product extracts, 39.15 for steamed product, 37.18% for alum decocted product, and 34.34% for tofu decocted product;
		Analgesic rate for 95% EtOH extracts (at 25 g/kg): 56.8% for raw product extracts, 43.6% for steamed product, 31.5% for alum decocted product, and 19.5% for tofu decocted product
	Hot plates tests	12.5, 25 g/kg	Pain threshold↑ after 1.5 h; Effect: raw, steamed products > products decocted with alum, or tofu
Compounds 39–40, 46–47 and 49	Hot plate experiment	Improvement rate (30 min): 77.34% for 39, 105.46% for 40 (0.1 mg/kg), about 30% for 49, 46, and 47 (10 mg/kg), and 73.90% for bulleyaconitine A (0.1 mg/kg)	Alkaloids 39 and 40 exerted an analgesic activity similar to bulleyaconitine A, while 49, 46, and 47 showed only weak analgesic effects in hot plate experiments	[82]
Compounds 39–40, 46–47 and 49	Acetic acid-induced writhing tests	ED₅₀ (mg/kg): 0.054 (39), 0.051 (40), and 0.048 (bulleyaconitine A)		[82]
Antitumour
Crude polysaccharides	Hepatoma 22 (H22) tumour cells	IC₅₀: 25.3 μg/mL	Cell growth↓, cell arrested in G0/G1 phage	[22]
	H22 tumour-bearing mice	25, 50, and 100 mg/kg	Tumour growth↓ (inhibiting ratio: 27.2–55.6%), median survival time↑ (30.1 days at 100 mg/kg, negative control: 17.9 days), life span↑ (68.2%)	[22]
	Hepatocellular carcinoma cells	10–40 μg/mL	Cell growth↓, PTTG1↓, p-Akt↓, p-p38MARK↑	[83]
	H22-tumour-bearing mice	100 mg/kg	Tumour growth↓, p-Akt↓, p-p38MARK ↑	[83]
Polysaccharide (ACP1) and its sulphated derivative (ACP1-s)	Human breast cancer MDA-MB-435S cells	800 and 1,600 μg/mL	Cell growth↓, cell migration↓, F-actin↓, Vav2↓, Rac1↓;	[85]
Polysaccharide (ACP1) and its sulphated derivative (ACP1-s)	Human breast cancer MDA-MB-435S cells	800 and 1,600 μg/mL	ACP1-s exhibited stronger cytotoxic effect than ACP-1	[85]
ACP1-s	Human brain glioblastoma U87MG cells	400, 800, and 1,600 μg/mL	Cell growth↓, cell apoptosis↑, IκB↑, NF‑κB↓, Bcl‑2/Bax↓, caspase‑3↑, p65↑	[84]
Anti-platelet aggregation
Compounds 14, 33, and 46–48	ADP-induced blood platelet aggregation in rat	Inhibition rate at 5 μM: 44.2–66.7%	These compounds be responsible for the blood-activating effects of A. coreanum	[16]
Insecticidal
Compounds 17, 26, and 37–38	Repellent activity against Tribolium casteneum	Repellence rete at 3 mg/mL: 59.12% (17), 37.50% (26), 40.62% (37), 34.37% (38)	Hetisine exhibited the highest activity among 29 tested alkaloids	[87]
Compound 26	Antifeedant activity against Leptinotarsa decemlineata	EC₅₀: 13.1 μg/cm²	Hetisinone exhibited moderate antifeedant activity against L. decemlineata	[23,24]
Steam distillation	Contact activity against Sesamia inferens, Ostrinia nubilalis and Etiella zinckenella	Lethality rate against S. inferens: approximately 85% at 24 h	The steam distillation showed strong contact activity against S. inferens, but invalid to O. nubilalis and E. zinckenella	[88]
Antioxidant Activity
Polysaccharide fractions (ACPSA-1, -2, and -3)	DPPH assay, superoxide radical scavenging assay, hydroxyl radical scavenging assay, and Fe²⁺ chelating assay	IC₅₀ (mg/mL): 2.8–6.6 (DPPH), 3.0–11.5 (superoxide radical), 3.5–16.2 (hydroxyl radical); Fe²⁺ chelating rete of 49.5–68.7% at 8.0 mg/mL		[25]
Crude polysaccharide	Pyrogallol self-oxidation method, Fenton method, Fe²⁺–H₂O₂-induced liver lipid peroxidation in rats	Inhibition rate: 51.8% at 0.4 μg/mL (O²⁻), 90.9% at 0.6 μg/mL (OH^–), and 100% at 0.6 μg/mL (liver lipid peroxidation)		[90,91]
Compounds 42–45	DPPH assay	IC₅₀ (μM): 9.53 (42), 9.95 (43), 10.09 (44), and 11.09 (45)	Better than L-ascorbic acid (IC₅₀, 14.1 μM)	[11]

The bold numbers refer to compounds mentioned in the text. All of the mentioned compounds in text have been numbered and are presented as bold number across this manuscript.

6 Toxicity and processing methods

Plants from the genus Aconitum are generally considered to be poisonous due to their highly toxic DA components, especially aconitine-type C₁₉-DAs with diester substituents at both C-8 and C-15 (e.g., aconitine, hapaconitine, yunaconitine, and indaconitine), which have been reported to possess acute neurotoxicity and cardiotoxicity in humans [93,94]. Since diester C₁₉-DAs, such as hypaconitine (40) and mesaconitine (39), have been reported to exist in A. coreanum, it can be easily concluded that A. coreanum and its derived drugs have a certain toxicity, as documented in the Chinese Materia Medica. However, several studies performed by Wu et al. revealed a relatively low toxicity for A. coreanum. In 1991, Wu et al. compared the acute and subacute toxicities of the crude drugs of A. coreanum and Yu Baifu [21]. No deaths or toxic reactions were observed in mice after three days of intragastric administration at the doses of 15 g/kg (once daily) and 10 g/kg (twice daily) for crude A. coreanum and Yu Baifu, respectively. In addition, in the subacute toxicity test, these two drugs did not show obvious influence on the body weights and characteristics of the peripheral haemogram (contents of erythrocytes, leukocytes, and haemoglobin) of mice after 28 days of intragastric administration of 5, 10, and 15 g/kg A. coreanum and Yu Baifu. Later, in 1995, Wu et al. prepared an apozem, a suspension, hot and cold aqueous extracts, and a 95% EtOH extract of A. coreanum from Liaoning Province in China and compared their acute toxicities to mice at doses of 120, 36, 60, 30, and 75 g/kg/day [95]. No deaths or toxic reactions were observed in the mice after oral administration of the aforementioned samples. However, approximately 93–100% of the tested mice died a few minutes after abdominal administration of 7.5 g/kg cold aqueous extract (equal to 83 times the human oral dose) or 10 g/kg hot aqueous extract (equal to 83 times the human oral dose) of A. coreanum, which suggests certain toxicity for A. coreanum.

The relatively low toxicity of A. coreanum is probably due to the low content of toxic DAs in the plant, e.g., hypaconitine and mesaconitine. It has been reported that the toxicity of the main constituents of A. coreanum, namely the hetisine-type DAs, is much lower than that of diester-type C₁₉-DAs [76,96]. Nevertheless, high toxicological risks remain due to the inescapable improper or overdosed usage of related drugs. Hence, similar to other medicinal Aconitum species, processing (Paozhi in Chinese) is also necessary for A. coreanum, which could reduce toxicity but retain pharmacological activity [97]. There are various A. coreanum processing methods that have been recorded in medicine books in all of the previous dynasties, and some of these methods are still widely employed today [30], such as decocting with adjuvants, e.g., alum, ginger juice, calclime, or tofu, as documented in the CP (1963 and 1977 editions) and several provincial drug standards [98]. Among them, decocting with tofu is the most commonly used method in pharmaceutical enterprises. Generally, 100 kg of A. coreanum is decocted with 25 kg of tofu for 2–9 h until the mixture is thoroughly boiled and produces slightly numb feelings on the tongue. In addition, steaming has also been utilized in the processing of A. coreanum. In this method, A. coreanum is dip bleached with three washes of water for two days (the water is changed twice a day), then steamed in a steamer for 2–4 h, cut into slices, and dried before use. It has been reported that the toxicity introduced by abdominal administration of A. coreanum could be reduced significantly by these processing methods, and their pharmacological effects, such as analgesic effects, are preserved [79]. The detoxification effects of these processing methods are mainly due to the promotion of hydrolysis of highly toxic diester-type DAs (e.g., hypaconitine) into low toxicity monoester- and amine-type DAs [99], leaving the active ingredients such as acehytisine (1) unaffected.

7 Conclusion

The present review summarizes the multifaceted uses and recent findings regarding the phytochemistry, traditional use, pharmacology, and toxicity of the extracts and compounds of A. coreanum (Figure 5). A. coreanum is one of the most important medicinal Aconitum species and has been traditionally and popularly used in China and other Asian countries. The related pharmacological studies have focused primarily on the antiarrhythmic, anti-inflammatory, analgesic, and anticancer activities of A. coreanum and its derived drugs. In particular, more substantial effort has been devoted to the antiarrhythmic effects of A. coreanum and its isolated compounds. Alkaloids have been demonstrated to be the main active ingredients in this plant. In particular, hetisine-type DAs, mainly acehytisine (1) and its analogues, which possess prominent antiarrhythmic effects, other effects and hypotoxicity, could be regarded as the representative constituents of A. coreanum. Polysaccharides from A. coreanum have also displayed broad bioactivities, demonstrating great potential for further research and exploitation.

Figure 5

Traditional use, phytochemistry, and pharmacology of A. coreanum.

Although phytochemical and pharmacological studies on A. coreanum have received considerable research interest, some deficiencies remain. First, during the last four decades, most of the work on the chemical constituents of A. coreanum from different regions were focused on obtaining compounds with new structures, and few studies paid attention to the contents of these known compositions, especially the active compositions. The contents of the main active components, such as acehytisine, are important indices for the assessment of the quality of the herbal medicine; thus, further determination of the main active components of A. coreanum from different regions is needed. Second, A. coreanum polysaccharides have been evaluated and exhibit various pharmacological activities. However, some of these polysaccharides have been extracted as crude polysaccharides, and their structures are undetermined, which hinders follow-up studies. Further purification of the crude polysaccharides to obtain homogeneous polysaccharides for pharmacological studies is encouraged, and extensive structural investigations on them are necessary. Finally, because A. coreanum contains potentially toxic compounds, reliable analytical methods are required for proper quality control to ensure that the toxic components are kept below the tolerance levels in A. coreanum products. It is necessary to perform more toxicology research on extracts or isolated compounds from A. coreanum to ensure the safety of its products.

Abbreviations

CFDA: China Food Drug Administration
CP: Chinese Pharmacopoeia
DA: diterpenoid alkaloid
GBF: Guan Baifu
HCN: hyperpolarization-activated cyclic nucleotide-gated
HSCCC: high-speed counter-current chromatography
LPS: lipopolysaccharide
MARK: mitogen-activated protein kinase
PSVT: paroxysmal supraventricular tachycardia
PTTG1: pituitary tumour transforming gene 1
SAR: structure–activity relationship
TCM: traditional Chinese medicine
VF: ventricular fibrillation
VP: ventricular premature

Funding information: This research was funded by grants from the National Natural Science Foundation of China (No. 31860095), the Basic Research Joint Special Project of Local Universities in Yunnan Province (No. 2018FH001-126), the University Undergraduate Education and Teaching Reform Research Project of Yunnan Province (No. JG2018225). The First Construction Project of Baoshan University in 2018 for the Demonstration College of School Level Application Talents Training (No. ZXZ201801).
Author contributions: Tian-Peng Yin – resources, supervision, writing – original draft, writing – review and editing. Yuan-Feng Yan – visualization, writing – review and editing. Jian-Min He – supervision, writing – review and editing, funding acquisition.
Conflict of interest: The authors state no conflict of interest is associated with this article.
Ethical approval: The conducted research is not related to either human or animal use.
Data availability statement: All data generated or analysed during this study are included in this published article.

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Received: 2022-05-03

Revised: 2022-10-05

Accepted: 2022-10-22

Published Online: 2022-11-21

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/chem-2022-0235

Keywords for this article

Aconitum coreanum Rapaics; Ranunculaceae; diterpenoid alkaloids; antiarrhythmic

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