Traditional uses,phytochemistry,and pharmacological properties of Sophora alopecuroides L

Abstract

Sophora alopecuroides L., known as ku dou zi in China, has a long history as a traditional Chinese medicine for the treatment of bacillary dysentery, enteritis, hepatitis, and other diseases, and exerts a critical role in anti-tumor. It contains abundant of alkaloids such as oxymatrine, matrine, and total alkaloids, which have been developed in China as anti-disease drugs related with inhibition of the angiogenesis-associated factors, anti-inflammatory response, and regulation of JNK, p38 MAP kinase, and NF-κB signal pathways and so on. The purpose of this review is to take comprehensive summary of the botany, traditional uses, phytochemistry, and pharmacological properties of Sophora alopecuroides L. so as to provide opportunities for further study and clinical application.

Introduction

Sophora alopecuroides L. belongs to the Legum inosaelocust species, which is a perennial herb, also named as the European Sophora or Sophora grass. Sophora alopecuroides L. prefers the desert plains, and is widely distributed in Xinjiang, Gansu, Qinghai, Ningxia, and other western provinces in China. This herb’s roots, stems, seeds, and the whole plant can be used as medicine for the treatment of refractory tinea, bacillary dysentery, and other gastrointestinal diseases. The medicinal plants show a wide spectrum of pharmacological activities, including detoxification, anti-bacterial, anti-inflammatory, pain killing, asthma cough, anti-tumor, and so on. As a traditional Chinese herbal medicine, it is mainly applied in the treatment of gastrointestinal diseases and other diseases such as viral hepatitis, cancer, cardiac diseases, and skin diseases.

Traditional Usages

Sophora alopecuroides L. has been used as a traditional medicine for many years in China. It is bitter in flavor and cold in nature with a little toxicity. The Xinjiang Chinese Herbal Medicine Handbook has reported that it exerts detoxification, pain-relieving, and insecticidal effects. Local people use it to treat dysentery, stomach ache, leucorrhea disorder, eczema, psoriasis, etc. It has been recorded in the Chinese Pharmacopoeia, National Herbal Compendium, Uygur medicine Chi, and used as an oral medication or for external use.

Chemical Constituents

There are many chemical constituents in Sophora alopecuroides L., and the main bioactive components of this plant include alkaloids, flavones, volatile oils, and quinones. ¹ In the 1980s, there were more than 20 kinds of alkaloids isolated and identified from Sophora alopecuroides L., such as sophocarpine (C₁₅H₂₂N₂O), matrine (C₁₅H₂₄N₂O), oxymatrine (C₁₅H₂₄N₂O₂), sophoridine (C₁₅H₂₄N₂O), sophoramine (C₁₅H₂₀N₂O), Aloperine (C₁₅H₂₄N₂), Cytisine (C₁₁H₁₄N₂O), etc. In 2000, Attaur-Rahman ² found five new alkaloids from the parts of Sophora alopecuroides L., which are identified as 7α-hydroxysophoramine (C₁₅H₂₀N₂O₂), 14β-hydroxylmatrine (C₁₅H₂₄N₂O₂), adenocarpine, 12β-hydroxysophocarpine (C₁₅H₂₂N₂O₂), and baptifo line. Moreover, derived from the seed of Sophora alopecuroides L., a new compound named indolyl-3-carbaldehyde is isolated. Sophora alopecuroides L. contains a variety of flavonoids in the roots and seeds. By using various chromatographic methods, five compounds are isolated and purified from this plant, which are identified as butein, 5″-methoxy-6-C-β-D-glucopyranosyl-6″-C-β-D-xylopyranosyl cupressuflavone, 5, 6-dihydroxy-3, 7, 3', 4'-tetramethoxyflavone, β-daucosterol, and 3'-methoxyluteolin.

Potential Applications and Pharmacodynamics

Clinical Application

Sophora alopecuroides L. has been widely applied to the clinical therapy: (1) kexieling tablets are used for the treatment of dysentery, acute and chronic enteritis, and colitis; (2) Fu Yan suppository is used for gynecological inflammation and cervical erosion; (3) Total alkaloids of Sophora alopecuroides L. (TASA) are used for chronic prostatitis; (4) Oxymatrine (OMT) and OMT capsules are used for the treatment of chronic hepatitis B; (5) Compounds of Sophora alopecuroides L. are used for oral ulcers and have the potential of anti-bacterial inflammation, and alleviating swelling, pain and sore myogenic; (6) Sophora alopecuroides L. oil liniment is used for eczema and neurodermatitis; (7) Sophora alopecuroides L. is used for the treatment of psoriasis.

Anti-Inflammatory Effects

Sophora alopecuroides L. has a great effect as an anti-inflammatory. The main effective substances associated with anti-inflammatory activity are considered to be the alkaloids of Sophora alopecuroides L. Matrine inhibits IL-1β-induced expression of matrix metalloproteinases by suppressing the activation of MAPK and NF-κB in human chondrocytes. ³ Aloperine, an alkaloid isolated from Sophora alopecuroides L., shows a markedly suppressive effect on the swelling of a rat’s hind paw induced by carrageenin, macostatin, PGE2, histamine, and 5-HT, and increases the permeability of capillaries caused by histamine and the leukocytic migratory response. ⁴

Hp-Associated Gastritis

Helicobacter pylori (Hp) infection is closely related to the digestive diseases and plays an important role in the process of chronic active gastritis-chronic atrophic gastritis-cancerous intestinal metaplasia stages, whose critical mechanism may be associated with initiating the inflammatory response. Sophora alopecuroides L. exerts an inhibitory effect on the growth of Hp. The minimum inhibitory concentration (MIC) of Sophora alopecuroides L. decoctions on to Hp is 100 mg/mL and the MIC is 25 mg/mL of ethanol extractions. In vitro, the total alkaloids’s antibacterial activity is very significant, and matrine and OMT have anti-Hp effects, while sophoridine shows relatively weak inhibitory effects. It is revealed that TASA combined with omeprazole or bismuth pectin has promising antimicrobial activity against Hp as well as conventional triple therapy through inhibition of Hp-induced IL-8, COX-2, and NF-кB expression. ⁵

Colitis

OMT has an anti-inflammatory effect by interfering with the IκB-α protein expression and inhibiting the nuclear transcription factor κB (NF-κB) activity in colitis cells. ⁶ The natural plant product sophocarpine ameliorates dextran sodium sulfate-induced colitis by regulating cytokine balance. Besides, TASA has a protective effect on DSS-induced colitis, associated with inhibition of NF-κB activation and its downstream pro-inflammatory mediators. ⁷ In addition, total alkaloids of Sophora alopecuroides L. increase the expression of CD4⁺ CD25⁺Tregs and IL-10 in experimental colitis. ⁸

Pancreatitis

OMT has been reported to exhibit beneficial effects on acute pancreatitis, whose mechanism is related to inhibiting the releasing and activity of inflammatory cytokines. Recently, OMT intervention markedly decreases plasma levels of endotoxin and D-lactic acid, increases claudin-1 mRNA and protein expression, and improves mucosal barrier dysfunction to prevent bacterial translocation. ⁹ The clinical effect of OMT intravenous drop combined with enteral and paranteral nutrition can remarkably reduce the incidence and complications of severe acute pancreatitis. Moreover, OMT decreases collagen production and pancreatic stellate cell activation and thereby inhibits the development of pancreatic fibrosis. ¹⁰

Antibacterial and Antiviral Activity

It is reported that TASA can enhance AcrAB-ToLC Efflux Pump susceptibility to Ciprofloxacin in clinical multidrug-resistant Escherichia coli isolates, and increase susceptibility of extended-spectrum β-Lactamases producing Escherichia coli isolates to Cefotaxime and Ceftazidime. ¹¹ In addition to antibacterial effects, OMT has been demonstrated to exert an inhibitory effect on the replication of hepatitis B and C viruses by interfering with the process of packaging RNA into the nucleocapsid or inhibiting the activity of the viral DNA polymerase. ¹² OMT has a beneficial effect on progression of CCl4-induced hepatic fibrosis in rats. Besides, OMT possesses anti-IAV activity via inhibiting the IAV-induced activation of TLR4-MyD88-TRAF6-NF-κB pathway. ¹³

Anti-tumor Activity

As one of the common anti-tumor Chinese medicines,^14,15 it has been specially recorded in the New Journal of Traditional Chinese Medicine in 1978 that sophocarpine is one of its active ingredients, which is used in the treatment of leukemia and trophoblastic tumors. ¹⁶ TASA can significantly inhibit the growth of osteosarcoma and the solid H22 tumor in a dose-dependent manner.^17,18 A derivative of natural alkaloid from Sophora alopecuroides named 9002# has great inhibitive effects on lymphoma and breast cancer, ¹⁹ and Sophora alopecuoride alkaloid derivative SPRIDA has a stronger therapeutic effect on liver cancer. ²⁰ Studies have suggested that either OMT or matrine has anti-cancer effects on cancer cells, including lung cancer, breast cancer, pancreatic cancer, gastric cancer, and liver cancer. ²¹ OMT also reverses the resistance of multidrugs to compound NM-3, a novel anti-angiogenic molecule isocoumarin derivatives, and compound hydrochloride irinotecan (CPT-11), and induces the apoptosis in gastric cancer. ²² These anti-tumor activities are related to inhibition of angiogenesis-associated factors, regulation of related signaling pathway, and protein expression. Aloperine executes anti-tumor effects against multiple myeloma through dual apoptotic mechanisms. ²³

Effects on the Cardiovascular System

Administration of sophocarpine significantly improves cardiac function and reduces infarct size via ameliorating the contents of inflammatory mediators, neutrophil infiltration, and myeloperoxidase (MPO) activity. Interestingly, sophocarpine inhibits translocation of NF-kB via inhibition of phosphorylation of p38 and c-Jun NH2-terminal protein kinase (JNK). ²⁴ Sophoramine reveals negative automaticity action, negative chronotropic action, and negative conduction, which may provide the pharmacological basis for anti-arrhythmia. Excessive reactive oxygen species (ROS) production activates the TLR-4/MyD-88 signaling, resulting in cardiomyocyte apoptosis whereas matrine improves cardiac function and suppresses ROS/TLR-4 signaling pathway. ²⁵ Additionally, OMT reverses adrenaline-induced cardiac arrhythmia of rabbits, increases cardiac contractility, and shortens the refractory period. ²⁶

Effects on the Central Nervous System

OMT exerts inhibitory effects on the central nervous system. Aloperine has significant neuroprotective effects attributing to its anti-oxidative stress. ²⁷ Sophoridine-induced synchronous oscillations in the basolateral amygdale (BLA) and hippocampus elicit the generation and development of seizure. Moreover, OMT downregulates TLR4, TLR2, MyD88, and NF-κB and protects rat brains against focal ischemia. ²⁸ Oxysophoridine has been shown to have a protective effect against ischemic brain damage. ²⁹

Toxicology

It is reported that the Sophora alopecuroides L. plant is toxic and has some adverse effects. Excessive Sophora alopecuroides L. causes indigestion and leads to cramps in animals. It causes dizziness, headache, nausea, vomiting, palpitations, irritability, pallor, and other symptoms in humans. Usually, when it is used to treat dysentery, it needs to be fried to decrease the toxicity. The main pathological changes caused by the toxicity of both the TASA and alkaloid monomers involve the hemorrhage of the internal organs of mice, including the liver, kidneys, and lungs. ³⁰ The order of several toxicities caused by Sophora alopecuroides L. are listed as follows: Lehmann base > Sophocarpine ⩾ Sophoridine > Aloperine > sophoramine > oxysophocarpine > oxysophoridine > oxymatrine. ³¹

Conclusions and Future Perspectives

Sophora alopecuroides L. has great advantages as an anti-inflammatory, especially for the digestive system, and its activity as anti-tumor, antibacterial, and antiviral is of significance. In addition, we pay attention to other pharmacological activities such as the protective effect on the cardiovascular system and inhibitory effects on central nervous system. Thousands of single entities and combination formulas in traditional Chinese medicine have been used to prevent and treat human diseases, and provide a rich source for identifying effective chemopreventive agents. Sophora alopecuroides L. has abundant compounds, and its plants are easy to obtain and can be cultivated in large amounts, which ensure sustainable production of the isolated active compounds. But, there are some deficiencies in Sophora alopecuroides L. such as its toxicity. Thus, profound research about its toxicity is needed to be considered. We expect that Sophora alopecuroides L. may be a potential candidate for the treatment of diseases.