Therapeutic effects of dichloromethane fraction of Securidaca inappendiculata on adjuvant-induced arthritis in rat

doi:10.1016/j.jep.2014.02.015

Journal of Ethnopharmacology

Volume 153, Issue 2, 28 April 2014, Pages 352-358

https://doi.org/10.1016/j.jep.2014.02.015 Get rights and content

Abstract

Ethnopharmacological relevance

Securidaca inappendiculata (SI) is a traditional antirheumatic medicine used in China. The present study was designed to investigate the therapeutic efficacy of dichloromethane fraction of SI (SID) at three different doses on adjuvant induced arthritis (AA) rats.

Methods

Arthritis severity was evaluated by arthritic score, body weight loss, paw circumference, histological changes and hyperplasia of lymphatic tissues. Serum samples were collected for estimation of superoxide dismutase (SOD), glutathione (GSH), hydroxy radical (OH·), nitric oxide (NO), malondialdehyde (MDA), N-acetyl glucosaminidase (NAG), sialic acid (SA), alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT). The levels of GSH, MDA, NAG and SA in liver were also assessed. The levels of interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1) and vascular endothelial growth factor (VEGF) were determined using ELISA method. Another portion of blood was used for total and differential leucocyte counts.

Results

Administration with SID (at high dose with 100 mg/kg) significantly ameliorated the AA severity, suggested by the modulatory effects on body weight loss, paw swelling, hyperplasia of lymphatic tissues and synovial membrane, neutrocytosis and lymphocytosis. It also decreased levels of NO, MDA and OH·, restored SOD and GSH levels in serum. The abnormal increased levels of AST, ALT, ALP, NAG and SA significantly were reverted (compared with AA rats, P<0.01). A similar result was observed in livers. Levels of IL-1, TNF-α, MCP-1 and VEGF were reduced dramatically by SID too.

Conclusion

The results suggest SID possesses substantial anti-arthritic activity. The therapeutic efficacy may be due to immumodepressive effects, cytokines regulation, increasing membrane stability and antioxidantive activity.

Graphical abstract

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease, with synovial hyperplasia and chronic inflammation, and eventually results in articular destruction, and functional disability (Tarner and Muller-Ladner, 2008). Although non-steroidal anti-inflammatory drugs (NSAIDs) mostly used now are efficient in alleviating symptoms, they cannot hinder the disease progression and protect tissue or joint from erosion. Besides, they possess severe side effects (Payne, 2000). The use of biological therapies cannot resolve all the clinical problems because of the high cost, selective efficacy and potential unknown threat (Shanahan et al., 2003, Senolt et al., 2009). A lot of people suffering from RA are seeking an alternative medicine, such as herbal therapies (Efthimiou and Kukar, 2010). Herbal medicines are widely used in China and other countries for centuries to heal fractures and arthritis. And many of them were validated with anti-inflammation, anti-arthritis and other relative activities now days (Wong et al., 2007, Liu et al., 2009).

Securidaca inappendiculata Hassk. (SI), also known as Chan Yi Teng, is mainly yielded in the south of China. The plant is used as traditional medicine to cure fractures and RA (Yunnan Institute of Botany, 1983). Our previous research exhibited that SI possessed substantial anti-arthritis and antioxidant activities. It can ameliorate the rheumatoid arthritis, suppress the hyperplasia of the lymphatic tissues, and alleviate the inflammation of joints. And screening of the activity fractions of SI revealed that the dichloromethane fraction (SID) exerted obvious anti-inflammatory, analgesic and immumodepressive effects (Zuo et al., in press). The results indicated that SID probably was the main material base of SI for anti-arthritis. However, it is still not clear if SID possesses a substantial therapeutic effect on RA in vivo. This study is designed to investigate the therapeutic effect on adjuvant induced arthritis (AA) in rats, and provide clues to the plausible mechanism.

Section snippets

Agents

Complete Freund׳s adjuvant (CFA) [containing 1.0 mg of dry, heat-killed Mycobacterium tuberculosis (strain H37Ra) per 1.0 ml sterile, non-metabolizable oils] and the reference drug indomethacin were purchased from Sigma-Aldrich (St Louis, MO, USA).

Collection of sample and preparation of extract

Stem of Securidaca inappendiculata was collected in November 2012 at Nanning, Guangxi province, China. The plant was authenticated by Professor Jian-Wei Chen (College of Pharmacy, Nanjing University of Chinese Medicine, China). A voucher specimen of the

Basic physical parameters test results

It is observed that the body weight gain restored slightly in SID treated groups, while compared with the AA models the difference was not obvious (Fig. 1). Hind paws of rats in the groups treated with SID were remarkable less swollen than AA models. The average circumference of the inflammatory limbs decreased under the treatments with SID and indomethacin obviously (Fig. 2). The index of hind paw oedema also exhibited an obvious recovery from inflammation. The treatment with SID at 100 mg/kg

Discussion

Based on the previous study, we obtained the primary conclusion that the xanthone rich SID (Zuo et al., in press) possessed anti-inflammatory and immumodepressive effects, and was a potential component for anti-arthritis. It was also found that (Zuo et al., in press) SID did not exhibit toxicity in vivo at the dose up to 112 mg/kg for mice (relative to 20 g/kg of the crude drug), which indicated that SID was safe as a potential anti-arthritic agent. The present study was helpful to assess the

Conclusion

The present study revealed that SID possessed a substantial anti-arthritic activity in AA rats. The therapeutic efficacy may be due to immumodepressive effects, cytokines regulation, increasing membrane stability and antioxidantive activity. The results of the research validated the therapeutic efficacy of SID on AA rats, and are helpful for a further elucidation of the anti-arthritic mechanism.

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Securidaca inappendiculata (SI) Hassk. is a traditional medicine used to treat rheumatoid arthritis. Recent studies have reported that macrophages are the primary regulators of joint homeostasis and their polarization is closely related to their metabolic mode. Here, we aimed to investigate the relationship between the joint protective effect of SI’s xanthone-rich fraction (XRF) on collagen-induced arthritis (CIA) in rats and the nicotinamide phosphoribosyltransferase (NAMPT)-glycolysis-polarization axis of macrophages. CIA model rats were treated with oral XRF and therapeutic efficacy was assessed based on arthritis score, degree of paw swelling, histological examination, and immunohistochemical analysis. Serum levels of cytokines, cellular metabolite concentrations, and protein and mRNA expression were determined by enzyme-linked immunosorbent assay (ELISA), western blotting (WB), and quantitative real-time PCR (RT-qPCR), respectively. The effects of dihydroxy-3,4-dimethoxyxanthone (XAN), a representative SI-derived compound, on RAW264.7 macrophages was analyzed in vitro using confocal laser scanning and flow cytometry. We found that XRF treatment significantly alleviated disease severity in CIA model rats. Levels of pro-inflammatory cytokines in the serum and M1 markers in synovium were reduced after XRF treatment, accompanied by an increase in the levels of anti-inflammatory cytokines and M2 markers. Further, XRF significantly suppressed synovial glycolysis by regulating NAMPT. In vitro studies further showed that XAN induced repolarization of lipopolysaccharide (LPS)-induced RAW264.7 macrophages with M1-M2 phenotype. Moreover, XAN negatively regulated glycolysis in the LPS-induced RAW264.7 macrophages in correlation with changes in NAMPT expression. Overall, the findings of this study suggest that the joint protective effects of XRF are achieved by inhibiting the NAMPT/glycolysis pathway and thereby regulating macrophage polarization.
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Securidaca inappendiculata is a medicinal plant frequently used in the treatment of inflammatory diseases in south China. In this study, we aimed to explore its bioactive constituent which contributes to the anti-inflammatory activity.
Polyphenol-enriched and polyphenol-deprived fractions (PRF and PDF, respectively) were separated from the ethanolic extract by HPD300 macroporous resin-based method, and their anti-inflammatory activities were investigated on a lipopolysaccharide (LPS)-induced acute lung injury (ALI) model in rats. The possible mechanism of action in alleviating acute inflammation was studied using RAW264.7 cells.
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As an antioxidant, PRF exhibited potent anti-inflammatory activity under both in vivo and in vitro conditions by downregulating NAMPT and TLR4/NF-κB. Accordingly, polyphenols were identified as important bioactive constituents in S. inappendiculata targeting oxidative stress-sensitive pro-inflammatory pathways.
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Citation Excerpt :
Rheumatoid factor (RF), which is an important marker of RA, was also measured on the last day of study. Serum was used for the estimation of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and total protein levels [38]. The concentrations of TNF-α and IL-6 in serum were determined with ELISA kits.
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Therapeutic effects of dichloromethane fraction of Securidaca inappendiculata on adjuvant-induced arthritis in rat

Abstract

Ethnopharmacological relevance

Methods

Results

Conclusion

Graphical abstract

Introduction

Section snippets

Agents

Collection of sample and preparation of extract

Basic physical parameters test results

Discussion

Conclusion

Osteoarthritis Cartilage

J. Ethnopharmacol.

J. Ethnopharmacol.

Food Chem. Toxicol.

J. Pain

Autoimmun. Rev.

J. Ethnopharmacol.

Pathophysiology

Int. J. Biochem. Cell Biol.

The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders

Clin. Exp. Immunol.

Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors

Nature

Collagen induced arthritis: reversal by mercaptoethylguanidine, a novel anti-inflammatory agent with a combined mechanism of action

J. Rheumatol.

Evidence that cytokines play a role in rheumatoid arthritis

J. Clin. Invest.

Therapeutic effect of anti-vascular endothelial growth factor receptor I antibody in the established collagen-induced arthritis mouse model

Clin. Rheumatol.

MAP kinases in the immune response

Annu. Rev. Immunol.

Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efﬁcacy of commonly used modalities

Rheumatol. Int.

Anti-inflammatory and anti-oxidant properties of Curcuma longa (turmeric) versus Zingiber officinale (ginger) rhizomes in rat adjuvant-induced arthritis

Inflammation

An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model

J. Exp. Med.