In vitro and in vivo anti-inflammatory effects of 4-methoxy-5- hydroxycanthin-6-one, a natural alkaloid from Picrasma quassioides

doi:10.1016/j.phymed.2012.11.016

Phytomedicine

Volume 20, Issues 3–4, 15 February 2013, Pages 319-323

https://doi.org/10.1016/j.phymed.2012.11.016 Get rights and content

Abstract

In the present study, we evaluated the anti-inflammatory effect of 4-methoxy-5- hydroxycanthin-6-one (CAN), a natural alkaloid isolated from Picrasma quassioides. CAN significantly inhibited the production of NO and the release of TNF-α induced by LPS in macrophage RAW 264.7. Western blot showed that CAN can downregulate the expression of iNOS protein. After oral administration, CAN (3, 9, and 27 mg/kg) reduced the development of carrageenan-induced paw edema and complete Freund's adjuvant (CFA)-induced chronic arthritis in rats. The observed results indicated that pre-treatment with CAN might be an effective therapeutic intervention against inflammatory diseases including chronic arthritis.

Introduction

Picrasma quassioides (D. Don) Bennet (Simaroubaceae), recorded in the Pharmacopeia of China, is used in traditional Chinese medicine for the treatment of numerous diseases, including inflammation, diarrhea, dysentery, microbial infection and fever. Among the β-carboline and cathinone alkaloids isolated from P. quassioides, CAN (Fig. 1) is one major active constituent. It has been reported to have significant antibacterial properties (Yang and Song 1996), high inhibitory activity against cAMP phosphodiesterase (Sung et al. 1984), and the ability to increase intestinal blood flow rate (Ohmoto et al. 1985). In our previous study, CAN has been purified and identified from the alcohol extract of twigs of P. quassioides through silica gel chromatography and crystallization in acetone (HPLC ≥ 98%) (Chen et al. 2007). It has also been reported to inhibit ulcerative colitis induced by dextran sulfate sodium (DSS) in rats (Liu et al. 2009). In the present study, we evaluated the anti-inflammatory effect of CAN, including in vitro inhibitory effect on the production of NO and the release of TNF-α in LPS-activated macrophage, and in vivo inhibitory effect on the development of xylene-induced ear edema in mice, carrageenan-induced paw edema in rats, adjuvant-induced arthritis (AA) in rats.

Section snippets

Cell line

Mouse macrophage RAW 264.7 cells were purchased from ATCC (TIB-71) and cultured in RPMI 1640 medium supplemented with 10% heat-inactivated FBS, 100 U/ml penicillin and 100 μg/ml streptomycin, 2 mM L-glutamine in a humidified atmosphere of 5% CO₂ and 95% air at 37 °C.

Animals

Male Sprague-Dawley (SD) rats (weight, 200–280 g) were purchased from Animal Department of College of Medicine, Beijing University (certificate No. SCXK (Jing) 2006-0008). Animals were acclimated for at least 1 week at a temperature of 24

Results and discussion

RAW 264.7 cells were treated with various concentrations of CAN (Fig. 1) for 24 h and the cell viability was tested by MTT assay. As shown in Fig. 2, CAN did not exhibit cytotoxicity at the range of 1–100 μM against RAW 264.7 cells. This dose range was used for treatment of CAN in the following experiments.

RAW 264.7 cells were treated with 1 μg/ml of LPS with or without indicated concentrations of CAN or hydrocortisone. The concentration of nitrite was monitored as the NO production after 24 h. As

Acknowledgements

This work was supported by the Project of National Natural Science Foundation of China (Grant No. 81102781) and Taishan Scholar Project to Fenghua Fu.

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Enhanced Anti-Rheumatoid Arthritis Activity of Total Alkaloids from Picrasma Quassioides in Collagen-Induced Arthritis Rats by a Targeted Drug Delivery System
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New drug delivery systems have rarely been used in the formulation of traditional Chinese medicine, especially those that are crude active Chinese medicinal ingredients. In the present study, hyaluronic acid decorated lipid-polymer hybrid nanoparticles were used to prepare a targeted drug delivery system (TDDS) for total alkaloid extract from Picrasma quassioides (TAPQ) to improve its targeting property and anti-inflammatory activity. Picrasma quassioides, a common-used traditional Chinese medicine (TCM), containing a series of hydrophobic total alkaloids including β-carboline and canthin-6-one alkaloids show great anti-inflammatory activity. However, its high toxicity (IC₅₀= 8.088±0.903 μg/ml), poor water solubility (need to dissolve with 0.8% Tween-80) and poor targeting property severely limits its clinical application. Herein, hyaluronic acid (HA) decorated lipid-polymer hybrid nanoparticles loaded with TAPQ (TAPQ-NPs) were designed to overcome above mentioned deficiencies. TAPQ-NPs have good water solubility, strong anti-inflammatory activity and great joint targeting property. The in vitro anti-inflammatory activity assay showed that the efficacy of TAPQ-NPs was significantly higher than TAPQ(P<0.001). Animal experiments showed that the nanoparticles had good joint targeting property and had strong inhibitory activity against collagen-induced arthritis (CIA). These results indicate that the application of this novel targeted drug delivery system in the formulation of traditional Chinese medicine is feasible.
β-Carboline alkaloids from Picrasma quassioides and their 3D-QSAR study on anti-inflammation in LPS-induced RAW 264.7 cells
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Two new β-carboline alkaloids (1–2), 1-pyrrolidone propionyl-β-carboline (1) and 1-(3-hydroxy-2-oxopiperidine-1-ethyl)-4,8-dimethoxyl-β-carboline (2), named kumujantine W and J respectively, together with ten known compounds (3−12) were isolated from the stems of Picrasma quassioides (D. Don) Benn. Their structures were elucidated from spectral data including 1D and 2D NMR, UV, IR, HR-ESI-MS spectroscopic analysis and ECD calculations as well as by comparison to the reference databases or literature. The anti-inflammatory effects of these alkaloids (1−12) and six other β-carboline alkaloids (13–18) in LPS-induced RAW 264.7 cells were evaluated by measuring nitric oxide (NO) concentrations. Among them, compounds 1, 3, 6, 15, and 17 could inhibit the secretion of NO, displaying significant anti-inflammatory activity without affecting cell viability in vitro, and 3D-QSAR analysis further revealed the influence of groups on the activity in β-carboline alkaloids.
Chemical constituents from the twigs and leaves of Picrasma quassioides
2023, Journal of Asian Natural Products Research
Two new compounds, including a norsesquiterpenoid, annuionone H (1), and a quassinoid, picraqualide G (2), along with eleven known compounds (3–13), were isolated from the twigs and leaves of Picrasma quassioides. Comprehensive spectroscopic analyses and NMR calculation with DP4+ analysis were used to identify their structures. Moreover, of all these compounds, compound 4 showed a week inhibition rate in the anti-inflammatory screening results against mouse macrophage J774A.1 cell.
Canthin-6-one (CO) from Picrasma quassioides (D.Don) Benn. ameliorates lipopolysaccharide (LPS)-induced astrocyte activation and associated brain endothelial disruption
2022, Phytomedicine
Canthin-6-one (CO) is an active ingredient found in Picrasma quassioides (D.Don) Benn. (PQ) that displays various biological activities including anti-inflammatory properties. Several studies reported PQ displayed neuroprotective activities, but its effects on astrocytes have not yet been investigated. Astrocytes are crucial regulators of neuroinflammatory responses under pathological conditions in the central nervous system (CNS). Proinflammatory astrocytes can induce the blood-brain barrier (BBB) breakdown, which plays a key role in the progression of neurodegenerative disorder (ND).
This study aims to investigate the anti-neuroinflammatory effects of CO in LPS-induced astrocyte activation and its underlying mechanisms in protecting the blood-brain barrier (BBB) in vitro.
Mouse astrocytes (C8-D1A) were activated with lipopolysaccharide (LPS) with or without CO pretreatment. Effects of CO on astrocyte cell viability, secretions of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β) and nitric oxide (NO) were determined. Intracellular transcriptions and translations of proinflammatory mediators, molecular signaling, [Ca²⁺] and the levels of reactive oxygen species (ROS) were evaluated by RT-PCR, western blotting, and flow cytometry, respectively. Astrocyte-conditioned medium (ACM) was further prepared for incubating endothelial monolayer (bEnd.3) grown on transwell. Endothelial disruptions were evaluated by transendothelial electrical resistance (TEER), FITC-dextran permeability and monocyte adhesion assays. Endothelial tight junctions (TJs) and molecular signaling pathways were evaluated by immunofluorescence staining and western blotting.
CO attenuated LPS-induced expression of astrocytic proinflammatory mediators (TNF-α, IL-1β, IL-6, NO) and inhibited deleterious molecular activities including inducible nitric oxide synthase (iNOS), p-NFκB and p-STAT3 in astrocytes. Incubation of ACM collected from CO-treated astrocytes significantly ameliorated endothelial disruptions, reduced expressions of endothelial cytokine receptors (IL-6R, gp130 (IL-6RB), TNFR and IL-1R), suppressed proinflammatory pathways, MAPKs (p-AKT, p-MEK, p-ERK, p-p38, p-JNK) and p-STAT3, restored endothelial stabilizing pathways (p-Rac 1) and upregulated beneficial endothelial nitric oxide synthase (eNOS).
Our study demonstrates for the first time CO exhibited potent protective effects against astrocyte-mediated proinflammatory responses and associated endothelial barrier disruptions.
Alkaloids from Picrasma quassioides: An overview of their NMR data, biosynthetic pathways and pharmacological effects
2022, Phytochemistry
Picrasma quassioides, a member of the Simaroubaceae family, is the subject of research in numerous pharmacological and chemical studies. This plant mainly contains alkaloids, quassinoids and terpenoids. These molecules exhibit various pharmacological benefits, such as anti-inflammatory, anticancer, and anti-viral effects, on the cardiovascular system. Alkaloids make up the majority of these molecules. This review describes 127 alkaloid substances from P. quassioides. These alkaloids can be divided into the following classes: β-carbolines, canthinones and alkaloid dimers. A compilation of their nuclear magnetic resonance spectroscopy data and possible biosynthetic pathways of these compounds and the pharmacological effects of P. quassioides are also included.
Genus Picrasma: A comprehensive review on its ethnopharmacology, phytochemistry and bioactivities
2021, Journal of Ethnopharmacology
Citation Excerpt :
The extract of P. quassioides showed anti-inflammatory effect by attenuating the infiltration of neutrophils and macrophages, and reducing the production of inflammatory mediators, such as ROS, TNF-α, IL-6 and iNOS (Lee et al., 2016). 4-Methoxy-5-hydroxycanthin-6-one (71) from P. quassioides inhibited the production of NO, the release of TNF-α induced by LPS in macrophage RAW 264.7 and downregulated the expression of iNOS protein (Fan et al., 2013). A variety of isolated compounds from the Picrasma species exerted anti-inflammatory activities.
The genus Picrasma belongs to the Simaroubaceae family and contains six species which are mainly distributed in tropical and subtropical regions of Asia and America. The barks, roots, stems, branches, or leaves of several Picrasma species have been applied as folk medicines to treat fever, sore throat, dysentery, eczema, nausea, loss of appetite, diabetes mellitus, cancer, and hypertension.
A systematic summary on the botanic characterization, ethnopharmacological uses, phytochemistry, bioactivities and toxicity of species belonging to Picrasma was presented to facilitate the exploitation of the therapeutic potential of these plants.
The literatures about Picrasma were retrieved from a series of scientific search engines including Web of Science, SciFinder, PubMed, CNKI, Google Scholar, Elsevier, Wiley, ACS publications, and SpringerLink between 1970 and 2020. Plant names were validated by “The Plant List” (www.theplantlist.org).
As ethnopharmacological uses, Picrasma species are valuable folk medicines to treat fever, inflammation, dysentery, eczema, cancer, diabetics, skin infection, and so on. Up to now, a total of 361 compounds including 126 alkaloids, 132 quassinoids, 67 triterpenoids, and 36 miscellaneous compounds were reported from Picrasma species. Quassinoids and alkaloids are the principal constituents in the genus. The extracts and phytochemical constituents of Picrasma species demonstrate a wide range of bioactivities including cytotoxic, anti-inflammatory, antimicrobial, and other activities.
Picrasma species are widely used as traditional medicines, have diverse chemical constituents with obvious biological activities. Nevertheless, further studies are required on the Picrasma species to assert the ethnopharmacological uses, clarify their bioactive constituents, determine pharmacological actions, and toxicity. Therefore, the present review may provide a critical clue for future studies and further exploitations on Picrasma species.

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Phytomedicine

Abstract

Introduction

Section snippets

Cell line

Animals

Results and discussion

Acknowledgements

References (17)

Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability

Journal of Immunology

Serum levels of cytokines in chronic liver diseases

Gastroenterology

In vitro anti-inflammatory effects of arctigenin, a lignan from Arctium lappa L., through inhibition on iNOS pathway

Journal of Ethnopharmacology

Animal models of osteoarthritis

Journal of Musculoskeletal and Neuronal Interactions

Alkaloids from twigs and leaves of Picrasma quassioides

Chinese Traditional and Herbal Drugs

The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia

British Journal of Pharmacology

A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity

British Journal of Pharmacology

Pro- and anti-inflammatory cytokines in rheumatoid arthritis

Annals of Medicine

Cited by (55)

Enhanced Anti-Rheumatoid Arthritis Activity of Total Alkaloids from Picrasma Quassioides in Collagen-Induced Arthritis Rats by a Targeted Drug Delivery System

β-Carboline alkaloids from Picrasma quassioides and their 3D-QSAR study on anti-inflammation in LPS-induced RAW 264.7 cells

Chemical constituents from the twigs and leaves of Picrasma quassioides

Canthin-6-one (CO) from Picrasma quassioides (D.Don) Benn. ameliorates lipopolysaccharide (LPS)-induced astrocyte activation and associated brain endothelial disruption

Alkaloids from Picrasma quassioides: An overview of their NMR data, biosynthetic pathways and pharmacological effects

Genus Picrasma: A comprehensive review on its ethnopharmacology, phytochemistry and bioactivities

Short communicationIn vitro and in vivo anti-inflammatory effects of 4-methoxy-5- hydroxycanthin-6-one, a natural alkaloid from Picrasma quassioides

Abstract

Introduction

Section snippets

Cell line

Animals

Results and discussion

Acknowledgements

Journal of Immunology

Gastroenterology

Journal of Ethnopharmacology

Animal models of osteoarthritis

Journal of Musculoskeletal and Neuronal Interactions

Alkaloids from twigs and leaves of Picrasma quassioides

Chinese Traditional and Herbal Drugs

The pivotal role of tumour necrosis factor alpha in the development of inflammatory hyperalgesia

British Journal of Pharmacology

A comparison of the effects of L-NAME, 7-NI and L-NIL on carrageenan-induced hindpaw oedema and NOS activity

British Journal of Pharmacology

Pro- and anti-inflammatory cytokines in rheumatoid arthritis

Annals of Medicine

Short communication
In vitro and in vivo anti-inflammatory effects of 4-methoxy-5- hydroxycanthin-6-one, a natural alkaloid from Picrasma quassioides