A Review of the Traditional Uses,Botany,Phytochemistry,Pharmacology,Pharmacokinetics,and Toxicology of Corydalis yanhusuo

Abstract

Corydalis yanhusuo W. T. Wang (Papaveraceae) is a traditional Chinese herbal medicine that has long been used to treat several conditions and is widely distributed in Asian countries. This review focuses on the traditional uses, botany, phytochemistry, pharmacology, pharmacokinetics, and toxicology of C. yanhusuo. The literature on C. yanhusuo was reviewed using several resources, including classic books on Chinese herbal medicine and scientific databases, namely, PubMed, Springer, Web of Science, Science Direct, and China National Knowledge Infrastructure. Based on information from these databases regarding the chemical components of C. yanhusuo, we evaluated the underlying interaction network between chemical components, biological targets, and associated diseases using Cytoscape software. To date, more than 160 compounds have been isolated and identified from C. yanhusuo, including alkaloids, organic acids, volatile oils, amino acids, nucleosides, alcohols, and sugars. The crude extracts and purified compounds of this plant have analgesic, antiarrhythmic, and antipeptic ulcer properties, along with hypnotic effects. However, studies on the pharmacokinetics of C. yanhusuo extracts remain limited. C. yanhusuo has therapeutic potential in diseases such as cancer and depression, probably due to glaucine and corydaline. Our network pharmacology analysis revealed interactions between 20 compounds, 54 corresponding targets, and 4 health conditions. We found that leonticine, tetrahydroberberine, and corydalmine may regulate the expression of PTGS2, PTGS1, KCNH2, SCN5A, RXRA, CAMKK2, NCOA2, and ESR1, representing a potential treatment strategy against pain, gastric ulcers, inflammation, and cardiac arrhythmias. Additionally, this article discusses the future directions of research on C. yanhusuo.

Corydalis yanhusuo, also known as Yanhusuo or Xuanhu, is a perennial herb widely distributed in China, Japan, Korea, Russia, and other Asian countries. ^1,2 In China, C. yanhusuo is mainly distributed in the Zhejiang Province. Corydalis yanhusuo has been shown to improve blood circulation, alleviate pain caused by blood stasis, promote movement of Qi, and alleviate Qi stagnation-induced pain. ³

Details regarding the pharmacological efficacy of C. yanhusuo are reported in the Chinese Pharmacopoeia (2015 edition). To date, more than 160 compounds have been isolated and identified from C. yanhusuo, including alkaloids, organic acids, volatile oils, amino acids, nucleosides, alcohols, and sugars. ¹ This herb is often used to treat symptoms such as the chest, abdominal, and menstrual pain ⁴ and has been demonstrated to have several pharmacological effects: antinociceptive, antitumor, antibacterial, anti-inflammatory, and antidepressant effects, among others. ^5,6

Herein, we comprehensively reviewed available literature on C. yanhusuo, including its traditional uses and botany, as well as advances in phytochemistry, pharmacology, pharmacokinetics, and toxicology, from Chinese medicine books and scientific databases, namely, PubMed, Science Direct, Web of Science, Springer, Baidu Scholar, Elsevier, and China National Knowledge Infrastructure. Additionally, we present potential research pathways and new perspectives on C. yanhusuo.

Traditional Uses

Corydalis yanhusuo was first reported in Lei Gong Pao Zhi Lun (Northern and Southern Dynasties, 618‐907 AD) and has been used as an analgesic agent in traditional Chinese medicine for over 1100 years, ⁷ primarily for the treatment of chest pain. According to Hai Yao Ben Cao (Tang Dynasty, 907‐960 AD), C. yanhusuo was used to treat postpartum blood stasis, whereas Yi Xue Qi Yuan (Jin and Yuan Dynasties, 1115‐1368 AD) reported the use of this plant to treat spleen and stomach stasis and as an adjuvant to digestion. Ben Cao Gang Mu (Ming Dynasty, 1551‐1578 AD) also reported its use in improving blood circulation and Qi, relieving pain, and micturition. ⁸ In China, Japan, Korea, Russia, and other Asian countries, C. yanhusuo has been used to treat Qi stagnation, blood stasis, chest pain, abdominal pain, amenorrhea, dysmenorrhea, and postpartum stasis. ^2,5 Moreover, C. yanhusuo is commercially available in the United States as a dietary supplement. ⁹

Corydalis yanhusuo has been reported to have various pharmacological effects; over 20 different prescriptions of this plant are listed in the Chinese Pharmacopeia, Han Fang Bao Dian, Dong Yi Shi Shou Bao Yuan, Dong Yi Bao Jian, and Zhongyao chengfang zhiji. The forms of these prescriptions include tablets, granules, and powders, among which tablets are the most commonly used form (Table 1). However, owing to the poor analgesic effect of raw C. yanhusuo, vinegar-processed products are widely used in the clinical setting. Alkaloids present in the herb are insoluble in water; therefore, they are processed with acetic acid to enhance their activity. Briefly, the rhizoma of C. yanhusuo is soaked in vinegar (20 L of vinegar per 100 kg of C. yanhusuo), first, sealed infiltration for 30 minutes then 150-160°C temperature and at a frequency of 40 times per minute turn, fried for 6 minutes and then cooled. Vinegar-processed C. yanhusuo effectively promotes blood circulation and Qi and relieves pain. ¹⁰

Table 1

Traditional and Clinical Applications of Corydalis yanhusuo.

Preparation name	Main composition	Traditional and clinical applications	References
Yuan Hu Zhi Tong Pian	Rhizoma Corydalis, Radix Angelicae dahuricae	Treating stomachache, headache, and dysmenorrhea caused by qi stagnation and blood stasis	11
Qi Zhi Wei Tong Pian	Radix Bupleuri, Rhizoma Corydalis, Fructus Aurantii, Rhizoma Cyperi, Radix Glycyrrhizae, Radix Paeoniae Alba	Treating abdominal pain	4
An Zhong Pian	Ramulus Cinnamomi, Rhizoma Corydalis, Concha Ostreae, Fructus Foeniculi, Fructus Amomi, Rhizoma Alpinia officinarum, Radix Glycyrrhizae	Treating stomachache caused by yang deficiency	2,4
An Wei Pian	Rhizoma Corydalis, Alumen, Endoconcha Sepiae	Treating epigastric stabbing pain caused by Qi stagnation and blood stasis	4
Fu Le Ke Li	Caulis Lonicerae japonicae, Radix Glycyrrhizae, Folium Isatidis, Herba Taraxaci, Cortex Moutan, Radix Paeoniae rubra, Fructus toosendan, Rhizoma Corydalis, Radix Rehmanniae Prepared	Treating abdominal pain and pelvic inflammation	4
Kuai Wei Pian	Endoconcha Sepiae, Alumen, Rhizoma Corydalis, Rhizoma Bletillae, Radix Glycyrrhizae	Treating abdominal pain, vomiting, acid reflux, appetite loss, and gastritis	4
Shen Yang Hong Yao Jiao Nang	Radix and Rhizoma Notoginseng, Rhizoma Chuanxiong, Radix Angelicae Dahuricae, Radix Angelicae Sinensis, Eupolyphaga Steleophaga, Rhizoma Corydalis, Flos Carthami	Treating wind dampness caused by blood stasis	4
Jin Fo Zhi Tong Pills	Radix Paeoniae Alba, Rhizoma Corydalis, Radix and Rhizoma Notoginseng, Radix Curcumae, Fructus Citri sarcodactylis, Rhizoma Curcumae longae, Radix Glycyrrhizae	Treating abdominal pain, dysmenorrhea, peptic ulcer, and chronic gastritis caused by Qi stagnation and blood stasis	4
Gu You Ling Cha Ji	Flos Carthami, Radix Aconiti cocta, Radix Polygoni Multiflori Praeparata, Radix Dipsaci, Radix and Rhizoma Clematidis, Rhizoma Corydalis, Radix Saposhnikoviae, Caulis Spatholobi, Periostracum Cicadae	Treating osteoarthritis and joint swelling	4
Du Sheng Huo Xue Pian	Radix and Rhizoma Notoginseng, Rhizoma Cyperi, Radix Angelicae sinensis, Rhizoma Corydalis, Caulis Spatholobi, Radix and Rhizoma Rhei, Radix Glycyrrhizae	Promoting blood circulation, treating dysmenorrhea caused by blood stasis	4
Yang Xue Qing Nao Pills	Radix Angelicae Sinensis, Rhizoma Chuanxiong, Radix Paeoniae Alba, Radix Rehmanniae Prepared, Ramulus Uncariae Cum Uncis, Caulis Spatholobi, Spica Prunellae, Semen Cassiae, Concha Margaritifera, Rhizoma Corydalis, Herba Asari	Treating headache and insomnia	4
Jing Tong Ke Li	Radix and Rhizoma Notoginseng, Rhizoma Chuanxiong, Rhizoma Corydalis, Rhizoma and Radix Notopterygii, Radix Paeoniae Alba, Radix and Rhizoma Clematidis, Radix Puerariae	Treating neck, shoulder, and upper limb pain caused by Qi stagnation and blood stasis	4
Zhen Xin Tong Kou Fu Ye	Radix Codonopsis, Radix and Rhizoma Notoginseng, Rhizoma Corydalis, Pheretima, Bulbus Allii Macrostemonis, Semen Descurainiae, Cortex Cinnamomi, Borneolum Syntheticum, Mentholum	Treating chest pain caused by Qi and blood stasis	4
Xuan Hu Suo San	Rhizoma Corydalis, Radix Achyranthis Bidentatae, Radix Angelicae Sinensis, Fructus Psoraleae	Clearing postpartum blood stasis	12
Fu Nv Tong Jing Wan	Rhizoma Corydalis, Feces Trogopterorim, Radix and Rhizoma Salviae Miltiorrhizae, Pollen Typhae	Treating abdominal pain caused by Qi and blood stasis	12
Yan Bing Pian	Rhizoma Corydalis, Borneolum Syntheticum	Treating coronary heart disease and angina pectoris	12
Ba Wei Tong Jing Pian	Radix Cyathulae, Cortex Moutan, Radix Angelicae Sinensis, Radix Paeoniae Alba, Rhizoma Corydalis, Semen Persicae, Ramulus Cinnamomi, Radix Aucklandiae	Treating dysmenorrhea	13
Ru Shen Tang	Rhizoma Corydalis, Radix Angelicae Sinensis, Cortex Cinnamomi, Rhizoma Cyperi, Radix Aucklandiae	Treating pain caused by Qi and blood stasis	14
Fu Yuan Tong Qi San	Fructus Foeniculi, Squama Manis, Radix Aucklandiae, Rhizoma Corydalis, Semen Pharbitidis, Pericarpium Citri Reticulatae, Radix Glycyrrhizae	Treating pain caused by Qi stagnation	15
Xuan Hu Suo San	Radix Angelicae Sinensis, Radix Paeoniae Rubra, Rhizoma Corydalis, Pollen Typhae, Ramulus Cinnamomi, Frereana Boswellia, Commiphora myrrha	Clearing postpartum blood stasis	15

Botany

Corydalis yanhusuo belongs to the genus Corydalis of the Papaveraceae family. It is a glabrous perennial herb, approximately 10‐20 cm in height, with spherical or oblate spheroid-shaped tubers (0.5-2.5 cm in diameter) and a yellowish interior. Its leaves are either 2-lobed or 3-lobed, with lanceolate segments that are often 2-3 parted, and its racemes contain 5‐15 sparse flowers. The sepals are small and caducous with a symmetrical corolla. It has 4 petals, which are either purple or red; the upper part of the outer wheel is the largest, with a length of 1.5‐2 cm; its top is dimpled, and its tail extends cylindrically having a length of 1.1‐1.3 cm. Male flowers have 6 stamens bundled into 2 filaments, whereas female flowers have an oblate-columnar ovary, a subcircular stigma, and a linear capsule. Flowering occurs during April, while fruiting occurs from May to June(Figure 1). ¹⁶

Figure 1

Corydalis yanhusuo plant (A), C. yanhusuo rhizoma (B), vinegar-fried C. yanhusuo (C).

Corydalis yanhusuo is distributed in China, Japan, Korea, Russia, and other Asian countries, with a wide ecological niche. ² In China, it is primarily distributed in Anhui, Jiangsu, Zhejiang, Hubei, Henan, and Shaanxi provinces. ¹⁷ The Zhejiang province is famous for its high production and quality of C. yanhusuo, as it has the largest areas for cultivation. ¹

Phytochemistry

To date, more than 160 constituents of C. yanhusuo have been isolated and identified. ¹⁸ Alkaloids and terpenoids were identified as the characteristic components of this species. The following section details phytochemical studies conducted on C. yanhusuo. The compounds identified from this plant are listed in the relevant tables, and their structures are also presented.

Alkaloids

The earliest known study of Corydalis alkaloids was published in 1928. ¹⁸ Alkaloids are the primary constituents of C. yanhusuo and play an important role in pain relief. To date, 64 alkaloids have been isolated from the plant; they are primarily categorized as isoquinoline alkaloids based on their structure. Other alkaloids include berberine, aporphine, proto-opioid base, isoquinoline benzylimidazole, and benzophenanthridine. ¹⁹ Alkaloids are presented in Table 2, and their structures are shown in Figure 2.

Table 2

Alkaloids Isolated From Corydalis yanhusuo.

Identifier	Name	Plant part	References
1	Glaucine	Aerial part	20
2	Norglaucine	Aerial part	20
3	N-methyllaurotetanine	Roots	21
4	Isoboldine	Roots	22
5	Nantenine	Aerial part	23
6	Thaliporphine	Roots	6
7	Lirioferine	Roots	6
8	O-methylbulbocapnine	Roots	23
9	Dehydrocorydaline	Roots	24
10	Berberine	Roots	24
11	Palmatine	Roots	25
12	Coptisine	Roots	24
13	Columbamine	Roots	26
14	Dehydroyuanhunine	Roots	23
15	13-Methylpalmatrubine	Roots	24
16	Yanhusuine	Roots	27
17	Corydayanine	Roots	27
18	Dehydrocorybulbine	Roots	21
19	Jatrorrhizine	Roots	21
20	13-Methyl-dehydrocorydalmine	Roots	21
21	Tetrahydropalmatine	Roots	28
22	Tetrahydrocoptisine	Roots	24
23	Yuanhunine	Roots	21
24	(−)-Corypalmine	Roots	24
25	Corydalmine	Roots	29
26	Scoulerine	Roots	21
27	Tetrahydrojatrorrhizine	Roots	21
28	Tetrahydrocorysamine	Roots	26
29	Tetrahydroberberine	Roots	24
30	Corydaline	Roots	28
31	Isocorybulbine	Roots	24
32	Corybulbine	Roots	24
33	Didehydroglaucine	Roots	24
34	Dehydronantenine	Roots	30
35	7-Formyldidehydroglaucine	Roots	31
36	Protopine	Roots	28
37	α-Allocryptopine	Roots	32
38	Oxoglaucine	Roots	33
39	Corunine	Roots	29
40	Dihydrosanguinsrine	Roots	34
41	Dihydrochelerythrine	Roots	35
42	8-Oxocoptisine	Roots	24
43	Pontevedrine	Roots	24
44	6-Acetonyl-5,6 dihydrosanguinarine	Roots	29
45	Homochelidonine	Roots	29
46	Saulatine	Roots	21
47	Nordelporphine	Roots	21
48	Leonticine	Roots	34
49	Bicuculline	Roots	32
50	Coryphen-anthrine	Aerial part	21
51	N-methylcanadine	Roots	31
52	N-methyltetrahydropalmatine	Roots	31
53	1-[2-(N-methylaminoethy)]-3,4,6,7-tetramethoxyphenanthrene	Aerial part	20
54	N,N-dimethyl-N′,N′- dimethyl-diphenyl-one	Roots	33
55	N,N-dimethyl-N'-methyl-diphenyl-one	Roots	33
56	Noroxyhydrastinine	Roots	24
57	Taxilamine	Roots	21
58	Epiberberine	Roots	6
59	Dehydrocorydaline chloride	Roots	36
60	Cryptopine	Roots	32
61	8-Trichloromethyl-7,8-dihydrocoptisine	Roots	24
62	Tetrahydrocolumbamine	Roots	37
63	Stepharanine	Roots	26

Figure 2

Chemical structures of alkaloids in Corydalis yanhusuo.

Water-Soluble Nonalkaloids

Water-soluble nonalkaloids present in C. yanhusuo have high polarity due to their hydroxyl, amino, and carboxyl groups. Water-soluble components, such as organic acids, amino acids, and carbohydrates are commonly separated by alumina adsorption, column chromatography, gel column chromatography, reverse-phase adsorption column chromatography, and gas chromatography-mass spectrometry. ^{38 -40} Analysis of 80% ethanol extract of C. yanhusuo isolated using a DA201 type macroporous adsorption resin revealed that the fraction eluted with pure water shows anti-ischemic effects. ³⁹ Moreover, the polysaccharide YHP-1 extracted from C. yanhusuo exhibited antitumor activity. ⁴¹ Therefore, it is important to extract and isolate its water-soluble compounds. Organic acids, amino acids, and alcohols and sugars isolated from C. yanhusuo are presented in Tables 3 -5, respectively. The structures of these compounds are shown in Figures 3 -5, respectively.

Table 3

Organic Acids Isolated From Corydalis yanhusuo.

Identifier	Name	Plant part	References
1	4-Hydroxybenzoic acid	Roots	38
2	Vanillic acid	Roots	38
3	Lactic acid	Roots	39
4	Butanedioic acid	Roots	40
5	2,3-Dihydroxypropionic acid	Roots	39
6	Malic acid	Roots	39
7	Palmitic acid	Roots	39
8	Stearic acid	Roots	39
9	Citric acid	Roots	39
10	2-Piperidinecarboxylic acid	Roots	40
11	trans-9-Octadecenoic acid	Roots	40
12	Docosanoic acid	Roots	22
13	trans-13-Octadecenoic acid	Roots	40
14	Ethanedioic acid	Roots	40
15	Propionic acid	Roots	18
16	Benzoic acid	Roots	40
17	Dodecanoic acid	Roots	40
18	Xylonic acid	Roots	40
19	Propanetricarboxylic acid	Roots	40
20	2-Propenoic acid	Roots	40
21	Glucaric acid	Roots	40
22	Pantothenic acid	Roots	40
23	2-Hydroxyacrylic acid	Roots	39
24	2-Butenedioic acid	Roots	40
25	Ribonic acid	Roots	40
26	Galacturonic acid	Roots	40

Table 4

Amino Acids Isolated From Corydalis yanhusuo.

Identifier	Name	Plant part	References
1	l-Valine	Roots	40
2	l-Threonine	Roots	40
3	d-Ornithine	Roots	40
4	l-Isoleucine	Roots	40
5	l-Aspartic acid	Roots	40
6	N-α-acetyl-l-lysine	Roots	40
7	l-Proline	Roots	40
8	l-Citrulline	Roots	40
9	N5-acetylornithine	Roots	38
10	l-Tyrosine	Roots	40
11	Serine	Roots	1
12	Alanine	Roots	40
13	Phenylalanine	Roots	26

Table 5

Alcohols and Sugars Isolated From Corydalis yanhusuo.

Identifier	Name	References
1	Cyclohexane-1,2,3,4,5,6-hexol	39
2	Glycerol	39
3	Ribonolactone	39
4	d-Glucopyranose	39
5	Lactose	39
6	d(+)-Ribonic acid gamma-lactone	40
7	d-Glucuronic acid	40
8	d-Fructose	40
9	d-Mannose	40
10	d-Turanose	40
11	Galacturonic acid	40
12	Polysaccharide	41

Figure 5

Chemical structures of alcohols and sugars in Corydalis yanhusuo.

Figure 4

Chemical structures of amino acids in Corydalis yanhusuo.

Figure 3

Chemical structures of organic acids in Corydalis yanhusuo.

Volatile Oils

Most volatile oils obtained from plants have various medicinal and health-promoting effects. The most abundant volatile oil in C. yanhusuo is 2′-hydroxy-4′-methoxyacetophenone, which is known to show analgesic, antimicrobial, anti-inflammatory, and antitumor activities and can be used to treat cardiovascular diseases. ⁴² Moreover, another volatile oil in C. yanhusuo—α-bisabolol—has been demonstrated to have anti-inflammatory and spasmolytic properties and is widely used in some European countries. ⁴³ Volatile oil from the rhizoma of C. yanhusuo is extracted using the heating reflux, rope extraction, and ultrasonic extraction methods. ⁴⁴ The chemical constituents of volatile oils have been analyzed using Fourier-transform infrared spectroscopy and gas chromatography-mass spectrometry. ⁴² Volatile oils from C. yanhusuo are presented in Table 6, and their structures are shown in Figure 6.

Table 6

Volatile Oils From Corydalis yanhusuo.

Identifier	Name	Plant part	References
1	2′-Hydroxy-4′-methoxyacetophenone	Roots	42
2	Benzene, 1-(1,5-dimethyl-4-hexen-1-yl)-4-methyl	Roots	42
3	Linoleic alcohol	Roots	42
4	Eicosane	Roots	42
5	Heneicosane	Roots	42
6	Carveol	Roots	42
7	2,3-Dihydroxypropanal	Roots	43
8	3,4-Dimethylpentanol	Roots	43
9	2-Methyl-2-phenylpropane	Roots	43
10	γ-Terpinene	Roots	43
11	Verbenone	Roots	43
12	1-Methoxy-4-(1-propenyl) -benzene	Roots	43
13	Diphenylamine	Roots	43
14	2-Beta-methoxy-5-alpha- cholestan-19-oic acid	Roots	43
15	α-Bisabolol	Roots	43
16	Abietic acid	Roots	43
17	Spiro[2.4]hepta-4,6-diene	Roots	44
18	Heptacosane	Roots	43
19	(Methoxymethyl)trimethylsilane	Roots	44
20	Heptadecane	Roots	45
21	Hexadecane	Roots	45
22	Caryophyllene oxide	Roots	45
23	Pentadecane	Roots	45

Figure 6

Chemical structures of volatile oils in Corydalis yanhusuo.

Nucleosides

Nucleosides have various biological functions and are crucial for living cells. They participate in deoxyribonucleic acid metabolic processes, show anticancer and antiviral activities, and can be used in gene therapy. For example, adenosine improves cardio-cerebral blood circulation, prevents arrhythmia, inhibits neurotransmitter release, and regulates adenylate cyclase activity. ⁴⁶ Nucleosides isolated from C. yanhusuo are presented in Table 7, and their structures are shown in Figure 7.

Table 7

Nucleosides Isolated From Corydalis yanhusuo.

Identifier	Name	Plant part	References
1	Cytidine	Roots	46
2	Uridine	Roots	46
3	Adenosine	Roots	26
4	2′-Deoxyadenosine	Roots	46
5	Thymidine	Roots	46
6	Guanosine	Roots	46
7	Xanthosine	Roots	21

Figure 7

Chemical structures of nucleosides in Corydalis yanhusuo.

Other Compounds

In addition to the aforementioned components, anthraquinones (emodin and physcion), terpenoids (3β-hydroxy-olean-11,13(18)-dien-28-oic acid), steroids (stigmasterol, β-sitosterol, and daucosterol), ³⁵ inorganic acids (phosphoric acid), ³⁹ some trace elements (Pb, Cr, Cd, Cu, Mn, Fe, Zn, Al, Ba, B, Ca, Mg, P, Sr, Ti, and V), ^{47 -49} and some unsaturated fatty acids (trans-linoleic acid and hexadecanoic acid) have also been isolated from C. yanhusuo. ⁵⁰

Pharmacology

Corydalis yanhusuo has various pharmacological effects on the digestive, nervous, and cardiovascular systems and has therapeutic benefits in treating complications associated with thrombosis and cancer. In the following section, the primary pharmacological activities of C. yanhusuo, including its active ingredients, minimum effective concentration, and relevant in vitro and in vivo research, are discussed (Table 8).

Table 8

Pharmacological Effects of Corydalis yanhusuo.

Pharmacological effects	Details	Extracts/compounds	Minimal toxicconcentration/dose	Type of experiment	References
Effect on the nervous system	Analgesic effects	Water extract	100 mg/kg (i.p.)	In vivo	9
		Corydaline	10 mg/kg (i.p.)	In vivo	8
		Tetrahydropalmatine	10 mg/kg (i.p.)	In vivo	51
		Tetrahydropalmatine	1 mg/kg (i.p.)	In vivo	9
		Corydaline	30 mg/kg (i.v.)	In vivo	52
		Tetrahydropalmatine	15 mg/kg (i.v.)	In vivo	52
		Tetrahydrocolumbamine	10 mg/kg (i.v.)	In vivo	52
	Sedative and hypnotic effects	Tetrahydropalmatine	40 mg/kg (i.p.)	In vivo	53
		Tetrahydrocolumbamine	40 mg/kg (i.p.)	In vivo	53
		d-Glaucine	10 mg/kg (i.p.)	In vivo	53
	Anxiolytic effects	Tetrahydropalmatine	25 mg/kg (i.p.)	In vivo	54
		Total alkaloids	6 g/kg (i.g.)	In vivo	55
	Antihypoxia ability	Total alkaloids	50 mg /kg (i.g.)	In vivo	56
Effects on the digestive system	Protection of liver function	Tetrahydropalmatine	20 mg/kg (i.g.)	In vivo	57
	Inhibiting smooth muscle activity	Tetrahydropalmatine	20 mg/kg (i.g.)	In vitro	58
	Promote gastric emptying and small intestinal transit	Corydaline	0.1 µg/kg (p.o.)	In vivo	59
Effects on the cardio-cerebrovascular system	Reduced blood pressure	Tetrahydropalmatine	20 mg/kg (i.v.)	In vivo	60
		Tetrahydropalmatine	5 mg/kg (i.g.)	In vivo	61
		Tetrahydropalmatine	10 μmol/L	In vitro	62
	Protective effects on myocardium	Total alkaloids	1 mg/kg (i.g.)	In vivo	63,64
		Alcohol extract	50 mg/kg (p.o.)	In vivo	65
		Total alkaloids	27.9 mg/kg (enteral)	In vivo	66
		Tetrahydropalmatine	5 mg/kg (i.v.)	In vivo	67
		Tetrahydropalmatine	1 μmol/L	In vitro	68,69
		Tetrahydropalmatine	10 mg/kg (i.v.)	In vivo	70
		Tetrahydropalmatine	50 mg/L	In vitro	71
		Dehydrocorybulbine	1.25 mg/L	In vitro	71
		Coptisine	4 mg/L	In vitro	71
		Palmatine	30 mg/L	In vitro	71
		Alcohol extract	100 mg/kg (p.o.)	In vivo	72
		Total alkaloids	0.2 g/kg (i.g.)	In vivo	73
	Antiarrhythmic effects	Tetrahydropalmatine	5 mg/kg (i.v.)	In vivo	67
		Total alkaloids	0.5 g/kg (i.g.)	In vivo	73
		Tertiary alkaloids	30 mg/L	In vitro	74
		Quaternary alkaloids	1 mg/L	In vitro	74
		Alcohol extract	0.81 g/kg (i.g.)	In vitro	75
	Antithrombotic effects	Tetrahydropalmatine	20 mg/kg (i.g.)	In vivo	76
		Water extract	1.44 g/kg (i.p.)	In vivo	77
		Tetrahydropalmatine	7.5 mg/kg (i.v.)	In vivo	78
Antitumor effects	Angiogenesis-limiting effect	Alkaloid extract	10 µg/mL	In vitro	79,80
	Inhibitory effect on the growth of sarcoma 180 andLewis lung cancer in mice	Polysaccharide	100 mg/kg (i.p.)	In vivo	41
	Inhibit P-glycoprotein activity	Tetrahydropalmatine	2.5 µg/mL	In vitro	81,82
	Inhibitory effects on 10 human tumor cells	Total alkaloids	IC50 = 18.39 µg/mL	In vitro	83
	Inhibitory effects on the proliferation of 6 humangastric cancer cells	Total alkaloids	200 mg/mL	In vitro	84
	Inhibit HepG2 cells	Total alkaloids	200 mg/mL	In vitro	84
	Inhibit the growth of A549 cells	13-methyl-palmatrubine	3 mg/kg	In vitro	85
	Inhibit MDA-MB-231 cell line	Alcohol extract	3 mg/mL	In vitro	86
	Inhibits MCF-7 cell	Alcohol extract	50 µg/mL	In vitro	87
	Antimouse liver cancer H22	Powder suspension	1 mg/kg (i.g.)	In vivo	88
	Inhibit U251MG cell line	Tetrahydropalmatine	1 mg/kg (i.p.)	In vivo	89
	Inhibits HL-60 and K562 cell	Tetrahydropalmatine	0.1 mmol	In vitro	90
Antibacterial and anti-inflammatory effects	Inhibit white rot fungus and Curvularia leaf spotfungus	Chloroform extract	125 mg/L	In vitro	91
	Inhibit Clostridium perfringens	Palmatine, berberine	IC50 = 18.39 µM	In vitro	92
	Anti-inflammatory	Alcohol extract	1μmol/L	In vitro	93
	Inhibitory effect on human immunodeficiency virus-1 reverse transcriptase	Total alkaloids	5 mg/mL	In vitro	94
	Promoting effect on the secretion of anti-inflammatory factors IL-10 and IL-13	Berberine	100 mol/L	In vitro	95
Other pharmacological effects	Portal vein pressure-lowering effect	Tetrahydropalmatine	1 mg/kg (i.v.)	In vivo	96
	Protects lung injury	Tetrahydropalmatine	40 mg/kg (i.p.)	In vivo	97

Abbreviations: IC₅₀, half-maximal inhibitory concentration; i.g., intragastric; IL, interleukin; i.p., intraperitoneal; i.v., intravenous; p.o., orally.

Effects on the Central Nervous System

Corydalis yanhusuo primarily shows analgesic, sedative, and hypnotic effects on the central nervous system, with alkaloids mostly contributing to the analgesic effects. Vinegar-processing can enhance the effects of Rhizoma Corydalis to facilitate blood flow and relieve stasis, ^98,99 while water extracts of C. yanhusuo effectively attenuate acute inflammatory and neuropathic pain in mice. ⁹ Tetrahydropalmatine extracted from C. yanhusuo is widely used to treat chronic dull pain and persistent pain. ²⁹ Moreover, both tetrahydropalmatine and corydaline significantly increase mechanical and thermal pain threshold in rats, ⁵¹ with similar analgesic effects. ⁸

Tetrahydropalmatine from Corydalis L and Corydalis J show sedative and hypnotic activities in rabbits, mice, dogs, and monkeys, and significantly reduce spontaneous and passive activities. ^52,53 Tetrahydropalmatine also has anxiolytic effects ⁵⁴ and is effective against depression. ⁵⁵ Lastly, the total alkaloid of C. yanhusuo showed antifatigue, antihypoxia, and antistress activity in mice. ⁵⁶

Effects on the Digestive System

The pharmacological effects of C. yanhusuo on the digestive system include antigastric ulcer and hepatoprotective activities and effects on smooth muscle activation and contraction. The active components of C. yanhusuo with such properties are tetrahydropalmatine and protopine. In particular, tetrahydropalmatine protected rats from gastrointestinal injury, an effect that may be associated with its impact on gastric mucosal blood flow and regulation of dopamine transmitters. ¹⁰⁰ Another study in mice demonstrated the hepatoprotective effect of tetrahydropalmatine. ⁵⁷ Oral administration of tetrahydropalmatine (20, 40, 80, 160, and 320 mg/kg) reduced intestinal motive force in healthy mice; at 320 mg/kg it inhibited spontaneous contractions in isolated rabbit duodenum, thereby inhibiting intestinal smooth muscle activity. ^58,101 Lastly, corydaline was shown to promote gastric emptying and small intestinal transit, as well as facilitate gastric accommodation. ⁵⁹

Effects on the Cardio-Cerebrovascular System

Corydalis yanhusuo can promote coronary artery dilation, protect against arrhythmia and myocardial and cerebral ischemia-reperfusion injury, and alleviate myocardial infarction. ^1,102 Tetrahydropalmatine can decrease norepinephrine and catecholamine in rat blood vessels and peripheral tissues, respectively, which may subsequently contribute to reduced heart rate and blood pressure. ^60,61 This compound can also lower blood pressure by blocking voltage-dependent calcium channels. ⁶² In contrast, the total alkaloids from C. yanhusuo were found to exhibit protective effects in experimental models of acute myocardial ischemia, alleviate oxidative stress induced by isoproterenol, protect cardiac function, and reduce myocardial injury and apoptosis in rats with myocardial infarction. ^{63 -65} Kang et al described similar effects of total alkaloids in dogs. ⁶⁶

Tetrahydropalmatine alleviates cerebral ischemia/reperfusion injury by antagonizing free radicals and calcium ions and by regulating Ca²⁺-ATPase activity. ⁶⁵ It significantly reduces arrhythmias during ischemia/reperfusion injury and reduces lipid peroxides in the myocardium to prevent myocardial injury. ⁶⁷ This compound significantly increased the activity of Na⁺-K⁺-ATPase and Ca²⁺-ATPase in the cell membrane, alleviated intracellular Ca²⁺ overload, and ultimately reduced cerebral ischemia-reperfusion injury in rats. ^68,69 Moreover, it showed protective effects in focal cerebral ischemia-reperfusion injury in rats, which is related to lipid peroxidation. ⁷⁰ However, another study showed that the antimyocardial ischemic effect of C. yanhusuo could be related to the direct protective effect of tetrahydropalmatine, dehydrocorydaline, berberine, and palmatine on myocardial cells, rather than its antioxidative mechanisms. ⁷¹ Corydalis yanhusuo rhizoma extract regulates the expression of Bcl-2 family proteins to inhibit cardiomyocyte apoptosis. ⁷²

Corydalis yanhusuo alkaloids were shown to protect against coronary heart disease and arrhythmia. ⁷³ High concentrations of tertiary amine base and quaternary ammonium hydroxide were also found to prolong the duration of action potentials in ventricular myocytes of guinea pigs. However, these 2 alkaloids can also have the opposite effect when administered at low concentrations. ⁷⁴ Corydalis yanhusuo extract can protect against myocardial damage and provide resistance to arrhythmia. ⁷⁵

Other studies have also revealed that C. yanhusuo extract can improve hemorheology in rats in a hypercoagulable state and inhibit the formation of venous, arterial, and arteriovenous bypass thromboses. ^76,77 Tetrahydropalmatine inhibits platelet aggregation induced by adenosine diphosphate, arachidonic acid, and collagen, resulting in antithrombotic activity. ⁷⁸

Antitumor Activity

Recently, in vitro studies have elucidated the antitumor effects of C. yanhusuo, which are primarily mediated by alkaloids and polysaccharides. Alkaloid extracts of C. yanhusuo and berberine markedly inhibit angiogenesis, ^79,80 which could have a significant impact on tumor growth and metastasis. The polysaccharide YHPS-1 inhibited the growth of murine sarcoma and lung cancer cell lines. ⁴¹ Corydalis yanhusuo alkaloids can also inhibit P-glycoprotein activity in tumor cells and reverse multidrug resistance. ^81,82 The total alkaloids from C. yanhusuo were found to significantly inhibit the proliferation of human liver cells as well as 10 human tumor cell lines derived from different tissues, ⁸³ notably, treatment-resistant gastric cancer cell lines. ⁸⁴ Liposoluble nonphenolic alkaloids and 13-methyl-palmatrubine from C. yanhusuo were also found to have cytotoxic effects against cancer cells and inhibit the growth of A549 and SMMC-7721 cancer cell lines. ^85,103 Corydalis yanhusuo extract also inhibits the proliferation of MCF-7 and MDA-MB-231 breast cancer cells, ^86,87 while it inhibits H22 hepatocellular carcinoma in mice. ⁸⁸ Tetrahydropalmatine was also shown to inhibit the proliferation and promote apoptosis of U251MG malignant glioma cells in vitro and significantly prevent malignant glioma growth in vivo. ⁸⁹ It also inhibits a human leukemia cell line. ⁹⁰

Antibacterial and Anti-Inflammatory Effects

The chloroform extract of C. yanhusuo has high microbiostatic activity against Fusarium, Helminthosporium, and anthracnose-related fungus, as well as against some bacteria. ⁹¹ Palmatine and berberine also inhibit the growth of Clostridium perfringens. ⁹² The 95% ethanol extract of C. yanhusuo was shown to have significant anti-inflammatory effects, which were mostly attributed to the activities of coptisine, berberine, palmatine, dihydrosanguinarine, and dehydrocorydaline. ⁹³ Corydalis yanhusuo alkaloids also inhibited the activity of human immunodeficiency virus type 1 reverse transcriptase. ⁹⁴ Furthermore, berberine shows antibacterial and anti-inflammatory effects by inducing the expression of toll-like receptor 2, activating IκB and interferon signaling pathways, and promoting the secretion of tumor necrosis factor. ⁹⁵

Other Pharmacological Effects

Besides the above-mentioned properties, tetrahydropalmatine can also prevent the formation of portal hypertension in cirrhosis and significantly reduce glucagon levels. ⁹⁶ Moreover, it protects against acute radiation-induced lung injury in rats by inhibiting apoptosis and reducing oxidative damage. ⁹⁷

Network Pharmacology

The pharmacological effects of traditional Chinese medicines are complex, with multicomponent and multitarget characteristics. Network pharmacology explains the therapeutic effect of herb pairs. ¹⁰⁴ We cross-referenced the chemical compositions of C. yanhusuo with the pharmacological functions mentioned in the Chinese Medicine System Pharmacology Database. Using the systems pharmacology analysis platform TCMSP (http://bigd.big.ac.cn/databasecommons/database/id/4096), we designed a compound-target-disease network for C. yanhusuo (). The screening conditions were set to oral bioavailability ≥30% and drug-likeness ≥0.18. All TCMSP drug targets were imported into the Uniprot (https://www.uniprot.org/) database, and the target gene name was entered to define the species as Homo-sapiens. Overall, 20 chemical components were screened, corresponding to 55 related targets. Based on the information available in the GeneCards (http://www.genecards.org/) database, we identified 6017 pain-related targets, 4479 gastric ulcer-related targets, 3679 cardiac arrhythmia-related targets, and 9921 inflammation-related targets. After analysis of the potential intersections between these identified targets and the chemical components, we found 20 potentially active compounds and 54 corresponding targets (Figure 8). Based on the degree, the most active constituents were leonticine (degree = 31), tetrahydroberberine (degree = 28), and corydalmine (degree = 25), all of which showed properties for treating pain, gastric ulcers, inflammation, and cardiac arrhythmias through the regulation of PTGS2, PTGS1, KCNH2, SCN5A, RXRA, CAMKK2, NCOA2, and ESR1.

Figure 8

Compound-target-disease network associated with C. yanhusuo. The underlying network between C. yanhusuo components and their targets was designed using Cytoscape 3.7.2 (https://cytoscape.org/). Green circles – chemical compounds of C. yanhusuo; yellow circles – potential targets; and red circles – related diseases.

Pharmacokinetics

To date, few studies have investigated the pharmacokinetics of C. yanhusuo extracts and compounds. The pharmacokinetics of intramuscularly injected tetrahydropalmatine sulfate and polycystic liposomes of tetrahydropalmatine sulfate (both at 10 mg/kg) were evaluated in mice. The time taken for the plasma drug concentration to decline to half (t _1/2) was 3.09 ± 0.37 and 33.97 ± 4.78 hours, respectively, while the peak concentration (C _max) was 289.05 ± 30.37 and 68.34 ± 8.72 µg/L, respectively. The time taken to reach C _max (T _max) for intramuscularly injected tetrahydropalmatine sulfate and polycystic liposomes of tetrahydropalmatine sulfate was 0.93 ± 0.15 and 3.92 ± 0.43 hours, respectively. These data indicate significant differences in pharmacokinetics depending on the route of administration. ¹⁰⁵ Tetrahydropalmatine orally administered to mice at 6.5 mg/kg had a t _1/2 of 3.13 ± 0.35 hours, C _max of 289.05 ± 30.37 µg/L, and T _max of 1.16 ± 0.28 hours. ¹⁰⁶ These findings suggest that the bioavailability of tetrahydropalmatine can be improved using polycystic liposomes. Moreover, intragastric administration of total alkaloids of C. yanhusuo at doses of 125, 250, and 500 mg/kg in rats revealed that the blood concentration of tetrahydropalmatine was positively correlated with its C _max and T _max. ¹⁰⁷ Additional studies on rabbits and rats also demonstrated that tetrahydropalmatine and corydaline plasma concentrations were positively correlated with their C _max and T_max. ^108,109 Furthermore, the plasma concentration of l-tetrahydropalmatine was shown to always exceed that of d-tetrahydropalmatine in rats treated with 40 mg/kg tetrahydropalmatine. ^110,111 The combination of P-glycoprotein and d-tetrahydropalmatine may be responsible for the difference in stereoselective absorption. ¹¹¹ d-tetrahydropalmatine was found to have no significant inhibitory effect on the CYP450 subtypes of phase I drug-metabolizing enzymes in human liver microsomes. However, l-tetrahydropalmatine had strong inhibitory effects on CYP2D6 (half-maximal inhibitory concentration = 0.46 μmol/L). ¹¹² Rats treated intragastrically with tetrahydropalmatine at a dose of 40 mg/kg revealed that tetrahydropalmatine is distributed in all tissues, except the lungs, with higher accumulation in the liver. ¹¹³ These findings indicate that, in rats, the pharmacokinetics of C. yanhusuo extract and tetrahydropalmatine show stereoselectivity.

Toxicology

The Chinese Pharmacopeia provides no information regarding C. yanhusuo’s toxicity. ⁴ However, there are some reports on this matter. One study evaluated the impact of intraperitoneal injection of 150 mg/kg of glaucine in mice. After only 5 minutes following the injection, the mice started to convulse and died quickly of paralysis. The median lethal dose (LD₅₀) of glaucine was calculated to be 127 mg/kg. ⁵² Furthermore, the administration of fumarole extract at 40 g/kg resulted in reduced overall activity, slow breathing, changes in movement and posture, and increased heart and breathing rates in mice, In this study, the mortality rate on the following day was 10%. ¹¹⁴ The LD₅₀ of the total alkaloids in C. yanhusuo acetic acid extract was 0.86 g/kg in mice, with most mice having died 3 hours following the gastric administration of the extract. This study demonstrated the toxicity and lethality of these alkaloids in mice. Moreover, microscopic examination of tissue samples revealed renal arteriole hemorrhage in some mice. ¹¹⁵ Administration of water extracts of Rhizoma Corydalis processed with industrial and edible acetic acid by oral gavage also was found to be toxic to mice, with all animals being reported dead after 72 hours. ¹¹⁶

To date, the number of studies investigating the toxicity of C. yanhusuo remains limited, and most studies have focused on extracts (Table 9). Certain populations should consume this plant cautiously, including pregnant women and women with postpartum blood deficiency and metrorrhagia. ¹¹⁷

Table 9

Toxicologic Effects of Corydalis yanhusuo.

Extracts/compounds	Animal	Minimal toxic concentration/dose	Toxic effect	References
Glaucine	Mice	LD50 = 127 mg/kg (i.p.)	Death	52
Alcohol extract	Mice	40 g/kg (i.g.)	Death	114
Acetic acid extract	Mice	LD50 = 0.86 g/kg (i.g.)	Death	115
Water extract	Mice	-	Death	116

Abbreviations: i.g., intragastric; i.p., intraperitoneal; LD₅₀, median lethal dose.

Future Perspectives and Conclusions

In summary, as traditional Chinese medicine, C. yanhusuo is used to treat Qi stagnation and blood stasis. Although various chemical components have been isolated and identified from the plant, alkaloids are its main active ingredients. Over the past decade, major breakthroughs have been made toward elucidating the active constituents and therapeutic efficacy of C. yanhusuo. However, the development of new drugs derived from this plant remains challenging. Thus, it warrants further studies.

Studies have primarily focused on the active components of tetrahydropalmatine, corydaline, berberine, palmatine, and coptisine, among others. For example, C. yanhusuo has been reported to contain high glaucine and corydaline content. ¹¹⁸ Glaucine can inhibit breast cancer cell migration and invasion. ¹¹⁹ Therefore, this plant could be a potential source for a novel antitumor drug. In contrast, few studies have evaluated the activity and impact of papaverine and corydaline. Hence, their pharmacodynamics and pharmacokinetics remain unclear. ⁷⁹

Evaluation of the medicinal potential of C. yanhusuo has mostly focused on its tubers and on the chemical components and pharmacological activities of its stems, leaves, and fibrous roots. Presently, commercially available products labeled to contain C. yanhusuo have been found to contain similar Corydalis species like Corydalis turtschaninovii Bess, Corydalis repens Mandl et Kuhldorf, Corydalis ambigua Cham. Et Sch. and Corydalis decumbent (Thunb.) Pers. Because these species are highly toxic, it is important to identify the actual species in such products to ensure public safety. Researchers have designed a polymerase chain reaction method based on the ITS2 sequence to distinguish C. yanhusuo from its counterfeit products. ¹²⁰ Authentic Corydalis generates a single band of approximately 200‐300 bp, whereas counterfeit products do not. ^121,122 Therefore, future studies should aim to improve the quality of medicinal materials extracted from C. yanhusuo.

Traditional Chinese medicine has multicomponent and multitarget characteristics, and its pharmacological properties cannot be completely attributed to a single component. Quality markers (Q-markers) in Yuanhu Zhitong Dropping Pills include tetrahydropalmatine, corydaline, protopine, imperatorin, and isoimperatorin. Q-markers are the best choice for quality control indicators. It is especially crucial to establish appropriate and feasible Q-markers for Chinese herbal medicines. The Q-marker system can be established from the morphological, chemical, and biological aspects of C. yanhusuo. Lastly, the potential cellular targets of C. yanhusuo for the treatment of pain, gastric ulcers, arrhythmias, and inflammation were determined using network pharmacology. However, follow-up studies should aim to verify these targets using in vitro and in vivo experiments.

In conclusion, we provide a comprehensive review of the traditional uses, botany, phytochemistry, pharmacology, pharmacokinetics, and toxicology of C. yanhusuo. Altogether, growing evidence paves the way for the development of novel C. yanhusuo-based therapeutic agents with broad medicinal applications.