A REVIEW ON SOME SELECTED TRADITIONAL INDIAN MEDICINAL PLANTS OF IMMUNOMODULATORY POTENTIAL AND THEIR THERAPEUTIC USE IN RHEUMATOID ARTHRITISHTML Full Text
A REVIEW ON SOME SELECTED TRADITIONAL INDIAN MEDICINAL PLANTS OF IMMUNOMODULATORY POTENTIAL AND THEIR THERAPEUTIC USE IN RHEUMATOID ARTHRITIS
Swati Bagde and Debasis Biswas *
Department of Microbiology, Medical College, All India Institute of Medical Sciences (AIIMS), Bhopal - 462020, Madhya Pradesh, India.
ABSTRACT: Rheumatoid arthritis is a very common auto-immune inflammatory disorder, causing disability in developed and developing countries. Conventional drugs are not only costly but are also associated with very serious adverse effects. Several Indian medicinal plants have been traditionally used for their anti-arthritic effect since time immemorial. Present review focused on the immunomodulatory potentials and anti-inflammatory action of some selected medicinal plants in order to generate the experimental evidence of their therapeutic efficacy in this disease and thereby putting the base for the designing of advanced and safer drugs for this condition, thereby leading to the finding of alternative therapeutic process that can offer enhanced management of the disease. Further, these plants extent studies can result in an eco-friendly cost effective anti-arthritic herbal drug with anti-inflammatory properties contributing to the better maintenance of human society. This review summarizes the different studies performed using these medicinal plants screened for rheumatoid arthritis concerning the chemical constituents, screening methods and therapeutic moieties which will be a remarkable tool for the researcher who involves in the field of the research area.
Anti-arthritic, Anti-inflammation, Immunomodulation, Medicinal plants, Rheumatoid arthritis
INTRODUCTION: Rheumatoid arthritis (RA) is a most prevalent chronic inflammatory, autoimmune, progressive, disabling and incurable disease that leads to painful inflammation, often irreversible joint damage, and eventually to functional loss. Its etiology is still obscure 1. However, to recognize the breakthrough in the pathogenesis of the disease has fostered the finding of new therapeutics with improved results.
The consequent morbidity and mortality have a substantial socio-economic impact 2. The prevalence of arthritis is higher in the West. In India the prevalence of RA is 0.75% of population 3, affecting females most to males at 3:1 ratio. According to the 2011 Census of India, with a population of 1.21 billion 4, an estimated 9 million people could be affected with RA.
Presently conventional treatments like nonsteroidal, steroidal and immunosuppressive drugs are used to control inflammatory symptoms and pain; they are associated with certain undesirable adverse effects. With these difficulties, the field of arthritis research has progressed exponentially towards herbal medicinal therapies as alternative medicine that has been considered safe and effective in all elevating chronic pain associated with arthritis 5. In Indian traditional medicines, Ayurvedic literature describes portions containing parts of certain plants for treating pain and inflammatory conditions like arthritis 6. A large number of medicinal plants have been tested and found to contain active principles with curative properties against arthritis 7.
Inflammation is a universal host defense mechanism involving a complex network of cell, cell-mediated and tissue interactions. It occurs in response to a variety of harmful stimuli, physical, chemical, traumatic, antigen challenge, infections, and ionization, etc. The immune system gets activated, communication and coordination occur between different classes as well as the actions of immune cells to produce inflammation 8.
According to research inflammation is regulated by a large number of pro and anti-inflammatory mediators 9, 10. World Health Organization (WHO) report, about 80% of the world’s population relies on traditional medicine 11. There are over 1.5 million practitioners of traditional medicinal system using medicinal plants in preventive, promotional and curative applications 12.
Pathophysiology of Rheumatoid Arthritis: RA an autoimmune disease, whereby the body's immune system attacks its tissues as if it were a foreign invader 13 in which for some known reason, the immune system considers its joint tissues foreign. White blood cells that normally protect the body migrate to the joint cavity. The synovium becomes inflamed and engorged with fluid, causing synovitis. Lymphocytes, macrophages, continue to enter the joint cavity and multiply, differentiate and release inflammatory mediators, cytokines, leukotrienes and prostaglandins that initiate inflammation, attract other immune cells to the site, activate resident cells and cause excess synovial fluid production.
Within weeks the synovium becomes thickened. The mass of synovial tissue that spreads over the top of cartilage in a rheumatoid joint is called a pannus, made of WBC’s: macrophages, B and T cells, neutrophils, plasma cells, NK cells, and T Helper cells. These cells produce the Rheumatoid Factor, prostaglandins, cytokines, and other mediators. As the disease established, the chemicals from the cells damage cartilage, ligaments, tendons, and bone.
TABLE 1: ROLE OF CD4+ (HELPER) T-CELL SUBSETS, CYTOKINES AND THEIR FUNCTIONS IN RHEUMATOID ARTHRITIS
|TH1||Produces IL-2, interferon- γ, tumor necrosis factor-α, LT, IL-3, and granulocyte-macrophage-colony-stimulating factor|
|TH2||Produces IL-4, IL-5, IL-10, IL-3, and granulocyte-macrophage-colony-stimulating factor
Cooperates with B cells to generate vigorous IgM, IgG1, IgA, and IgE responses
|Interleukin-1||Activates T cells; activates metalloproteinases that destroy cartilage|
|Interleukin-2||Stimulates proliferation of activated T cells and production of many other cytokines|
|Enhances expression of class II human leukocyte antigen on antigen-presenting cells; enhances intercellular adhesion molecule expression and favors TH1 cell growth|
|Anti-inflammatory, downregulates TH1 cytokine production; stimulates B-cell differentiation and antibody production|
|Causes B-cell differentiation and enhances antibody production; stimulates the production of acute-phase reactants by hepatocytes|
|Interleukin-8||Neutrophil chemotactic factor; attracts neutrophils to the synovial compartment|
|Anti-inflammatory; in concert with IL-4, inhibits interferon-induced expression of class II human leukocyte antigen|
|Interleukin-12||Activates and causes proliferation of natural killer cells; favors activation and growth of TH1 cells|
|Tumor necrosis factor-α||Enhances class II expression on antigen-presenting cells; enhances expression of intercellular adhesion molecules|
|Profibrotic; enhances the production of tissue inhibitor of metalloproteinase, causing decreased production of collagenase and other destructive enzymes; possibly also responsible for late-stage fibrosis and ankylosis; suppresses the expression of class II major histocompatibility complex antigens induced by interferon-γ|
Ig: immunoglobulin; IL: interleukin; LT: lymphotoxin; TH: T helper.
B lymphocytes that involve the presence of CD19 and CD20; T lymphocytes are defined by the presence of CD3 and CD4 (T-helper cells) or CD8 (cytotoxic cells). TH1 cells T-helper 1 cells characteristically produce a series of proinflammatory molecules (such as IL-2, interferon-γ, TNF-α, granulocyte-macrophage-colony-stimulating factor) that mediate delayed-type hypersensitivity reactions. In contrast, TH2 cells produce a group of cytokines (IL-4, IL-5, IL-6, and IL-10), all of which affect B-cell differentiation and activation, shown in Table 1. The complex interactive control of the immune system is well illustrated by the observation that some of the cytokines produced by TH2 cells (IL-4, IL-5, IL-10 and transforming growth factor-β) also have potent anti-inflammatory activity that can down-regulate TH1 immune responses 14. The balance swings towards the pro-inflammatory cytokines in rheumatoid joints 15. This can be up-regulated by the expression of cell adhesion molecules on endothelial cells by introducing IL-1 and TNF-α.
Medicinal Plants of Immunomodulatory Potential: RA is a complex disease, combination drugs acting on several targets relevant to the disease may prove very effective and safe, rather than high doses of a single compound acting on a crucial target. In RA, hyperactivity of macrophages, T cells, B cells, etc. in the inflamed joint with concomitant elevation of cytokines such as IL-1 and TNF-α are occurring. Further, cartilage destruction, bone erosion, the proliferation of cells in the synovium, etc. are major pathological events. The medicine should contain chemical agents to counteract each of the pathological processes.
Medicinal plants contain herbal formulation with their essential phytoconstituents, such properties like Ginger which inhibits both cyclooxygenases and lipoxygenases. Boswellia serrata inhibits lipopolysaccharide-mediated TNF-α induction in monocytes 16. Therefore, a systematic approach should be made to find out the efficacy of plants against arthritis and inflammation to exploit them as herbal anti-arthritic agents and to use medicinal plant resources could result in the development of satisfactory medicines to treat RA patients.
Withania somnifera: In traditional Indian systems of medicine, Ayurveda and Unani the roots of ashwagandha have been using. The pharmacological activity of the root shows the presence of alkaloids and steroidal lactones. Among the alkaloids, withanine, withanine, pseudowithanine, tropine, pseudo-tropine, somniferine, somnine are mainly present. Oral administration of ashwagandha, root powder exhibit the anti-arthritic effect in adjuvant-induced arthritic rats and helps in providing progressive, long lasting results for various health concerns like aging, anemia, arthritis, fatigue, and stress-disorders 17, 18.
Zingiber officinale: Exhibit a vital role to lessen the unbearable pain and inflammation associated with RA 19, 20. Ginger is obtained from rhizomes. It has been widely used as a medicinal herb and spice, since ancient times 21. Anti-inflammatory effect of ginger was scientifically proved first by Kiuchi et al., in 1982. 22 They isolated four new different compounds from ginger, and all showed the potential inhibitory effect to reduce prostaglandin synthesis, which is the key to inflammation. Active components include gingerols, gingerdiols and gingerdiones and their dehydration products, the shogaols 23.
Z. officinale blocks inflammatory prostaglandins and thromboxane. The volatile and essential oils, beta-phellendrene and zingiberine, decompose on drying. The warming gingerol principle transforms into shogaols on drying making it more centrally heating. Fresh ginger is more peripherally active while dry ginger is more centrally stimulating and warming; it is considered as effective as acetylsalicylic acid in reducing carrageenan-induced paw swelling in rats. It is thought that these anti-inflammatory actions are the result of inhibition of prostaglandin release and hence ginger may act similarly as NSAID, which interfere with prostaglandin biosynthesis. It is found that 6-gingerol and 6-shagol have analgesic and antipyretic activities 24.
Boswellia serrata: This is a promising antiarthritis plant with anti-inflammatory and other beneficial pharmacological properties with antiatherosclerotic, analgesic and hepatoprotective effect 25. Resin derived from it used to treat arthritis associated with chronic inflammatory illnesses from centuries 26.
TABLE 2: ACTIVE COMPOUNDS OF MEDICINAL PLANTS WITH THEIR PHARMACEUTICAL AND BIOLOGICAL IMPORTANCE
|Botanical/ Family Name||Common
|Plant Parts /
|Withania somnifera / Solanaceae||Ashwagandha, winter cherry, withania root, Indian ginseng||Root extract/95% ethanol; 2% gum acacia, 50% aqueous alcohol, aqueous hot water; leaves / n-hexane||Withanolides, alkaloids, withanine, pseudowithanine, tropine, pseudo-tropine, somniferine, somnine, somnine-alkaloids and steroidal lactones; 2-acyl glucosides viz sitoindoside-7 & sitoindoside-8 (isolated from root); Withaferin A and 3- b- hydroxy-2, 3-dihydro-withanolide F||Antibacterial, antitumoral, anti-inflammatory, antiarthritic, antioxidant, immunomodulating; Increase total WBC count, bone marrow cellularity, circulating antibody titer, plaque forming cells in the spleen, phagocytic activity of macrophages||Budhiraja, 198742; Mirjalili, 200917; Patwardhan, 201018; Kumar, 201543; Singh, 200744; Ghosal, 198945; Grover, 201046|
|Vitex negundo / Verbenaceae||Nirgundi, sambhalu,
|Fresh berries, seeds, leaf (oil form), roots, bark & flowers /ethanol, petroleum ether extract, water
|Carbohydrates, sterols, C-glycosides, flavanoids, polyphenolic compounds, terpenoids, glycosidic iridoids and alkaloids, casticin, essential oil, benzoic acid, vitamin c, flavones; 3β-Aceto-xyolean-12-en-27-oic acid, 2α, 3α-dihydroxyleana-5, 12-dien-28-oic acid; 2β, 3α-diacetoxyolean-5, 12-dien-28-oic acid and 2α, 3β-diacetoxy-18-hydroxy-olean-5, 12-dien-28-oic acid isolated from seeds||Antiseptic, ophthalmic, anti-gonorrhoeic, depurative, anti-inflammatory; Control pain and inflammation; useful in dispersing swellings of the joints from acute rheumatism; A tincture of fresh berries are used for treatment of paralysis, pain in limbs, rheumatic disorder, weakness, etc./ CFA induced rat model, Carrageenan induced hind paw edema, anti-adjuvant induced arthritis in rat||Ramesh petchi, 201147; Rose, 201148; Subramani, 200949; Vishwanathan, 201050; Dharamasiri, 200351; Chawla, 199252|
|Boswellia serrata/ Burseraceae||Shallaki, salai guggul, Indian frankincense, salallai||Oleogum resin, bark, whole plant/ n-hexane, petroleum ether
|Carbohydrates, Terpenoids, gums, mucilages, β-boswellic acid in resin portion (acetyl-β-boswellic acid, keto-β-boswellic acid and acetyl-11-keto-β-boswllic acid), volatile oil & sugar||Shows-anti-inflammatory, immuno-modulatory and anti-arthritic activities. Inhibits passive paw anaphylaxis reaction and mast cell protection; Bowellic acid Showed anti-inflammatory and complement inhibitory activities in rats; down-regulation of TNF-α and IL-1/CFA induced (rat) model, anti-adjuvant induced arthritis in rats||Mishra, 201153; Sharma, 199828; Kumar, 201054; Reddy, 201455; Kapil, 199456; Manjula, 200657|
|Zingiber officinale/ Zingiberaceae||Shunthi, sonth, dry ginger, adrak||Dry ginger extract powder, rhizome (dry), root poultice/ethanol, Hydroxy-methoxyphenyl compounds||Terpenes, monoterpene hydrocarbon, sesquiterpene hydrocarbons and oxygenated monoterpinecineol, borneol, citral, camphene, phelandrene, ginerol, shogaol, zingefone, zinziberin, Phenylpropanoids, 6- Shogaol, Gingerdiols and sesquiterpenoids, with (-) zingiberene||Anti-arthritic, antiseptic, anticarcinogenic, antifungal, anti-microbial, as a stomachic, an aromatic, a carminative, stimulant, flavoring agent, analgesic activity; Inhibition of prostaglandin and leukotriene bio-synthesis||Rehman, 201158; Nievergelt, 201159; Shimoda, 201060; Park, 199861; Subramoniam, 200462|
|Pluchea lanceolata/ Asteraceae||Rasna||Leaf, stem, root, callus, tuber/ethanol (50%), 90% alcohol, methanol||Moretenol, moretenol acetate, neolupeol, neolupenol, octacoanoic, hexacosanoic and tetracoanoic acid, tetrcosanol, hexacoanol, triacontanol, stigmasterol andbeta-Sitosterol-DGlucoside (leaves and stems) quercetin & isorhamnetin (air-dried leaves); triterpenoids sorghumol, sorghumol acetate, boehmerol acetate from the roots, psi-taraxasterol acetate||Anti-inflammatory, Immunosuppressive, anti-oxidant activity, and anti-arthritic activity/ inhibition protein denaturation and HRBC||Goyal, 201363; Srivastava, 199064; Feroz, 198239; Arya, 201365; Srivastava, 201266|
WBC: White blood cells; CFA: Complete Freund’s adjuvant; IL-1: Interleukin-1; HRBC: Human red blood cell
TABLE 3: LIST OF MEDICINAL PLANTS USED IN THE TREATMENT OF RHEUMATOID ARTHRITIS
|N (experiment/ control/
|Plant part/Solvent used/Dosage, no. of days/ Control drug||Screening methods/
Model/ Active compound
|Studied on anti-inflammatory properties of WS in an animal model||info not provided||WS root extract suspended in 2% gum acacia / 50 mg/ mL) orally administered, 3 days/ Phenylbutazone (100 mg/kg) to positive control||FCA induced rat model
|Acute phase reactants of the blood monitored by crossed immunoelectrophoresis showed changes in the concentration of many serum proteins (α2-glycoprotein, major acute phase α1- protein and pre-albumin) in the WS group. The α2-glycoprotein found only in inflamed rat serum was decreased to undetectable levels in the WS group. Phenylbutazone, on the other hand, caused a considerable increase in the α2- glycoprotein in both arthritic and healthy rats. Another acute phase protein (peak 2, α-1 major acute phase) which increased by approximately 200 percent by inflammation was brought back to normal levels by WS treatment but only to 132 percent of normal by phenylbutazone. WS influenced several modulator proteins in normal rats, suggesting that several plant chemicals in WS possibly interact with the liver protein synthesis process||Observed inflammation in rats and decreasing to undetectable levels the α2-glycoprotein found only in inflamed rat serum|
|Somasundaram68, 1983||Studied on the mechanism of action for the anti-inflammatory properties of WS in the animal model||Not clear||WS extract||Rats injected with 3.5-percent from a line in the hind leg footpad showed a decrease in absorption of 14C-glucose in rat jejunum||Glucose absorption was maintained at the normal level by both WS and the cyclooxygenase inhibitor oxyphenbutazone. Both drugs produced anti-inflammatory effects||The study observed rats injected with formalin in the hind leg footpad showed decreased absorption of 14 C-glucose in rat jejunum, glucose absorption is maintained at the normal level by Withania extracts, which produced an anti-inflammatory effect|
|Anbalagan69, 1984||The study investigates the role of a primary prostaglandin. PGE1, on α2M during the inflammatory process in the animal model
|6-8 rats in each test group||WS root/ethane/dose of 500, 1000, 1500, or 1200 mg/kg oral suspension, 3-4 hours/ PGE1 ethanol suspension(10 mg/ml)||Carrageenan-induced model (Male Wistar rats)||After doses of WS root powder administered induction of inflammation, paw edema (volume) was measured at a different time interval, and blood samples were collected by heart puncture. Electro-immuno-assay of α2M was performed followed by administration of PGE1, in-vitro-studies with liver slices, Effect of PGE1 to detect α2M protein||WS caused dose-dependent suppression of α2-macroglobulin (an indicator for anti-inflammatory drugs) in the serum of rats inflamed by sub-plantar injection of carrageenan suspension maximum effect (about 75%) was seen at 1000 mg/kg|
|Begum70, 1988||Study effect of WS on FCA rat model following physical and radiological methods||Not clear||WS root extract powder/ 1000 mg/kg, orally daily for 15 days/ hydrocortisone (15 mg/kg)||Freund’s complete adjuvant-induced rat model
|Physical (paw swelling), Biochemical and radiological (bony degenerative changes) methods performed||The extracts exhibited a significant reduction in both paw swelling and bony degenerative changes in FCA arthritis as observed by radiological examination|
|Ziauddin71, 1996||Immuno-modulatory study in an animal model||-||Root extract||Three myelosuppression models in mice: cyclophosphamide, azathioprine, or prednisolone
|Hemoglobin concentration, red blood cell count, white blood cell count, platelet count, and body weight were observed in WS-treated mice compared to untreated control mice||Observed significant increases in hemolytic antibody responses toward human erythrocytes which indicated immunostimulatory activity|
|Dhule72, 1997||Studied on the functions of macrophages obtained from mice treated with the carcinogen OTA||male albino mice||WS root and leaves extraction/80% ethanol/crude 100 mg/kg, orally once daily for 17 weeks/control OTA received DW 10 ml/kg||Carcinogen OTA induced model / Alkaloid and Steroids||The phytochemical study, Macrophage culture, and determination of macrophage chemotaxis, macrophages obtained from mice treated with OTA and Indian herbs were cultured, and the supernatant was obtained for further cytokines analysis (IL-1 and TNF-α)||A significant decrease in the chemotactic activity of the macrophages was seen. Interleukin-1 and TNF-α production was also markedly decreased|
|Ichikawa73, 2006||WS employed in the treatment of arthritis and are known to be potent inhibitors of angiogenesis, inflammation and oxidative stress using cell lines||-||Leaf/ n-hexane||Cell Lines KBM-5 (human chronic myeloid leukemia) cultured in Iscove’s modified Dulbecco’s medium with 15% fetal bovine serum, A293 (human embryonic kidney carcinoma) cultured in DMEM, MCF-7 (human breast adenocarcinoma) cultured in RPMI 1640 and RAW 264.7 (murine monocytic cell) cultured in DMEM/F-12 supplemented with 10% fetal bovine serum and 100 units/mL penicillin and 100 Ag/mL streptomycin/ isolation of withanolides||Electrophoretic Mobility shift assays, Western blot analysis, IKK Assay, NF-nB-dependent reporter gene expression assay was done to observe effects of withanolide on TNF-α, TNFR associated death domain, The effect of withanolide on the nuclear translocation of p65 was examined by immunocytochemistry, live and dead assay||This paper shows that those withanolides inhibit activation of NF-kB and NF-kB-regulated gene expression, which might explain the ability of withanolides to enhance apoptosis and inhibit invasion and osteoclastogenesis|
|Singh44, 2007||Shows anti-inflammatory properties in PBMCs from RA patients and Healthy donors||PBMC and SFMC from RA patients/ Healthy donor (n= not mentioned)||The dried and powdered roots/ ethanol (95%)||Cell culture for isolation of PBMC from healthy and RA patients and SFMC were isolated from synovial fluid of RA patients (All patients fulfilled the ACR criteria)/ HPLC for sample preparation, Chromatography for standardization withaferin A from WS||Culture supernatants and cells were harvested for ELISA and RNA extraction. Cell viability, cytokines analysis; TNF-α, IL-1β, IL-6, and IL-12p40 by sandwich ELISA, nitric oxide measurement, EMSA, and Western blotting||This study demonstrated that the WS crude ethanol extract suppressed the production of proinflammatory molecules in-vitro. This activity is partly through the inhibition of transcription factors NF-κB and AP-1 by the constituent withanolide.|
|Khan74, 2009||The first study demonstrated that WSL activate the immune system in an animal model||BALB/c mice||Leaf extract / aqueous alcoholic (50%, v/v) /orally, 2 weeks||Ovalbumin-FCA induced animal model/ withanolides /glucowithanolides||Prepared and treated murine splenocytes in-vitro, measured Th1/Th2 cytokines by ELISA, Determined IgG2a and IgG1 isotypes by ELISA, Isolated, treated and estimate cytokines in mouse peritoneal macrophages, FCA and IFA immunization, Isolated splenic macrophages for cell supernatant for FACS analysis for surface markers and co-stimulatory molecules||The withanolide 2, 3 dihydro- 3- sulphonile with anyone is a major constituent of WSL responsible for skewing to Th1 immune polarization by stimulating the expression of IFN- γ and B cell switch over to secrete IgG2a while simultaneously enhancing the expression of co-stimulatory molecules and integrins|
|Kuma43, 2015||This study evaluates the efficacy and safety for treatment in RA patients||n= 125 (86 patients satisfied inclusion criteria)/ no control taken||5g of ashwagandha powder, twice a day for three weeks with lukewarm water or milk was given to RA patients||The follow up of patients was carried out every two weeks. The primary efficacy endpoint was based on the ACR 20 response. Secondary endpoints were ACR50, ACR70 responses, change from baseline in DAS 28 score and ACR parameters||Biochemical assessments hepatic function (ALT, AST, ALP, bilirubin and ß2 microglobulin), renal function (urea and creatinine and NGAL) tests and urine mercury level through ELISA||This study completed by 90.7 percent (78/86) patients. Patients with moderate and high disease activity were 57.7 percent (45/78) and 42.3% (33/78), respectively. Ashwagandha treatment decreased RA factor. A significant change in post-treatment scores of tender joint counts, swollen joint counts, physician global assessment score, patient global assessment score, pain assessment score, patient self-assessed disability index score and ESR level was observed as compared to baseline scores. ACR20 response was observed in 56.4 percent (44/78) patients and moderate response in 39.74% (31/78) patients Ayurvedic treatment for seven weeks in RA patients showed normal kidney and liver function tests. However, increased urinary mercury levels were was observed after treatment|
|Kiran75, 2016||This study compared the acute and chronic anti-inflammatory effect of Withania somnifera with a corticosteroid (Hydrocortisone) in the animal model||Albino rats of either sex, 4 groups (n=6)||Roots/ ethanolic extract/ 12mg/kg & 25 mg/kg p.o./ Hydrocortisone as standard control||Carrageenan and CFA rat model||Maximum percentage inhibition of edema exhibited with 12 mg/kg & 25 mg/kg of ethanolic extract of WS at 3 h were 36.36 % and 61.36 % with compare to Hydro-cortisone (40 mg/kg s.c.) 65.91%. Inthe CFA model, on 3rd day hydrocortisone percentage inhibition of paw edema is 31.58% as compare to WS i.e. 21.83%||Ethanolic extract of WS elicited significant dose dependent acute and chronic anti-inflammatory activity in carrageenan comparable to hydrocortisone|
|Srivastava76, 1992||This study shows the effect of ginger in arthritis and muscular discomfort and suggests a possible mechanism of action||n=56 (28 RA, 18 OA and 10 with muscular discomfort)||Dry ginger powder for three months||The analysis was based on questionnaires by patients||Bioactive components of ginger may act as dual inhibitors of cyclooxygenase and lipoxygenase pathways and may act by inhibiting PGE2 and leukotriene B4 synthesis||Majority of patients experienced some level of relief from pain and swelling
|Tripathi77, 2008||This study examined the effect of ginger extract on macrophage activation in the presence of LPS stimulation in an animal model||Male and female C57Bl and Balb/C mice (6-8 weeks)||Ginger extract||Murine animal model||Murine peritoneal macrophages were stimulated by LPS in the presence or absence of ginger extract and production of pro-inflammatory cytokines (TNF-α, IL-12, and IL-1β) and chemokines (RANTES, MCP-1, IP-10) by ELISA. Also studied the effect of ginger extract on the LPS induced expression of MHC II, B7.1, B7.2, and CD40 molecules. The function of the antigen presenting of ginger extract treated macrophages by primary mixed lymphocyte reaction||Ginger extract inhibits macrophage activation and APC function and indirectly inhibits T cell activation|
|Ribel-Madsen78, 2012||This study aimed at determining if synovial cell cultures from RA, OA, and HC differ and are suitable disease models in pharmacological studies, and tested their response to some anti-inflammatory drugs||OA n= 12; males 0, females 12, RA n= 10; males 2, females 8, HC n=6; males 6, females 0||EV.EXT77extraction of the rhizomes of the herbs Zingiber officinale and Alpinia galanga, both of which belong to the ginger family/ betamethasone-base, ibuprofen as control drug 77/15 was 100 μg/mL in the cell culture medium||Synovial cells were isolated from the synovial membrane or joint fluid. Cells were cultivated and exposed to no or TNF-α stimulation without, or in the presence of, betamethasone, ibuprofen, or a standardized ginger extract||Concentrations of a panel of cytokines, growth factors and chemokines were mapped for each culture and condition||Cells secreted an increased amount of the cytokines IL-1β, IL-6, and IL-8 in response to TNF-α stimulation in all conditions. OA cells showed a higher IL-6 and IL-8 and a lower IL-1β production, when not stimulated than RA and HC cells, which were similar. TNF-α stimulation caused similar IL-1β, IL-6, and IL-8 release in all groups. Ibuprofen showed no effect on cytokine production, while ginger extract was similar to betamethasone. Ginger extract was as effective an anti-inflammatory agent as betamethasone in this in-vitro model|
|Boswellia serrata||Etzel79, 1996||Studied special extract of Boswellia serrata (H15) in the treatment of rheumatoid arthritis||n=260/Control not clear (placebo)||H15, a standardized extract of the gum resin of BS. A tablet of 400 mg of the dried extract (lipophile)/Dose of 3x2 or 3x3 of the tablet to RA patients,6 month||Clinical study / TLC and HPLC of the CHCl3 extract of H15||The criteria for assessment were mainly joint swelling, pain, ESR, stiffness, additional use of NSAID, side effects and tolerance||H15 produced a significant reduction in swelling and pain compared to the placebo, ESR and morning stiffness was often reduced. The patients often could considerably reduce their intake of NSAID during treatment. The patients' general health and well-being improved|
|Kapil56 1994||This study evaluated the influence of BA on com-plement-related inflammation in the experimental animal models of inflammation||n=30, male albino rats||Boswellic acid/100 mg/kg twice a day, 5 days/ control drug ibuprofen injected IP||Arthritis induced by CFA and carrageenan-induced paw edema in rats / Boswellic acid||Inflammatory assays: measurement of left hind foot thickness before and over 5 days after adjuvant induced; Complement activity and the immuno-haemolysing effect of the test samples via the classical pathway was determined spectrophotometrically||In both the rat model, BA was found to possess significant anti-inflammatory and complement inhibitor activities. Significantly reduced footpad thickness of experimental animal models and simultaneously also reduced complement activity|
|Sharma80, 2010||The study was designed to investigate the anti-inflammatory and analgesic effect of different fractions of Boswellia serrata in an animal model||Albino rats||Oleo-gum-resin/ petroleum ether (100 mg/kg)||Carrageenan-induced paw edema /5-lipoxygenase enzyme||Anti-inflammatory and analgesic activity by the acetic acid-induced writhing response, formalin-induced pain, hot plate, and tail flick method||The different fractions of B. serrata showed prompt anti-inflammatory and analgesic activity due to the inhibition of 5-lipoxygenase enzyme|
|Sengupta81, 2011||Studied anti-inflammatory properties of gum resin extracts of B. Serrata in an animal model||n=5, Not clear||BE-30 [30% 3-O-acetyl-11-keto-boswellic acid (AKBA)] / 20 mg orally and Aflapin 30 mg for 14 days||Freund’s adjuvant-induced inflammation model of rat||TNFα ELISA, Cell culture (HCH), Cell proliferation assay, cartilage matrix production assay, MMP-3 ELISA||Both the Boswellia products, BE-30 (5-Loxin) and Aflapin, exhibit powerful anti-inflammatory efficacy and anti-arthritic potential.|
|Ismail82, 2016||Studied the efficacy of anti-inflammatory potential of B. serrata in experimental rats||30 Male wistar rats, 5 groups n= 6||Whole plant extract/ normal saline/ low dose (50 mg/kg/ bw), mid dose (100 mg/kg/ bw) and high dose (200 mg/kg /bw) of B. serrata through oral gavage/ Indomethacin (10 mg/kg/bw)||Carrageenan-induced rat model||Performed physical parameters such as paw edema measurement, percentage of paw edema inhibition, Histopathological analysis||Treatment of B. serrata inhibited the edema and decreases the cellular infiltrates probably by inhibiting the inflammatory mediators. B. serrata has high anti-inflammatory activity and suggests as herbal anti-inflammatory medicine|
|Pluchea lanceolata||Srivastava64, 1990||Studied anti-inflammatory activity in an animal model||5 groups of mice and rats||Aerial parts extract/ethanol/ indomethacin (2 mg/kg/po) to mice, phenylbutazone (30 mg/kg/po) to rats||Acute carrageenan-induced edema model in both mice and rats / Ψ-taraxasterol acetate||Performed physical parameters such as paw edema measurement, percentage of paw edema inhibition||The ethanol extract of P. lunceolata has anti-inflammatory activity in mice as well as rats|
|Bhagwat83, 2010||Investigated the immune-suppressive properties of PL extract and its corresponding chloroform fraction PLC, as also its plausible role in relieving the inflammatory conditions of the body||Male Balb/c mice (Mus musculus) n=6||Leaves extract/50% ethanol, chloroform and n-butanol/ PL extract in doses of 50, 100, 200, 400, 600, and 800 mg/kg and PLC fraction in doses of 25, 50, 100, and 200 mg/kg in 1% w/v gum acacia/ Standard control; Cyclophosphamide 250 mg/ kg and cyclosporine-A 5 mg/kg administered orally, once daily||Immunomodulation model for humoral antibody response, cell-mediated immune response||hemagglutination antibody titers, delayed-type hypersensitivity, skin allograft rejection test, in-vitro (C. albicans method), and in-vivo phagocytosis (carbon clearance test), Extraction and fractionation with chloroform, n-butanol, and water, fractions were employed for flow cytometry to study the T-cell specific immunosuppressive potential of these fractions||P. lanceolata causes immunosuppression by inhibiting Th1 cytokines|
|Arya65, 2013||Comparative analysis of in-vitro anti-arthritic and anti-inflammatory activities in methanolic extracts of in-vivo and in-vitro||Not clear||Leaves, root stem and callus in powdered form/methanol/ 100,250,500 and 1000 μg/ml/ standard, diclofenac sodium||HRBC (human red blood cell)/ flavonoids (quercetin, isorhamnetin, daidzein), triterpenes, sitosterols, taraxosterols, pluchine||In-vitro anti-inflammatory activity by HRBC membrane stabilization method; In-vitro anti-arthritic activity by inhibition of protein denaturation method||1000μg/ml dose of leaves extract exhibited notable anti-inflammatory activity. Active constituents from in-vivo and in-vitro plant parts of P. lanceolata support in treating inflammation and rheumatism|
|Chokshi84, 2012||Studied anti-inflammatory activity in an animal model||7 groups of Albino Wistar rats/6 rats in each group||Plant parts/combination of different organic solvents: methanol, ethanol, chloroform and petroleum ether/1ml/kg/ mahanarayan oil as a standard control for 24 hours||Carrageenan-induced rat paw edema||After topical application and Sub-cutaneous administration of respective formulation, Paw Volume was evaluated at a different time interval (1, 2, 3 h) up to 24 h||The main aim of the study was to replace water by different organic solvents and obtain oil which has much better efficacy than the traditionally extracted oil. The ethanolic extract has shown to be having high extract yield in the literature on comparison to control|
|Vitex negundo||Ramesh47, 2011||Studied anti-inflammatory property in an animal model||Not clear||Fresh berries, leaves (oil form)/ethanol
|CFA induced rat model/ Carbo-hydrates, sterols, alkaloids, glycosides, flavonoids, phenolic compounds||-||Plant extract controls pain and inflammation in RA|
CFA: Complete freund’s adjuvant; PGE: prostaglandins; α2M: α2-macroglobulin; OTA: Ochratoxin A; NF-kB: Nuclear factor-kappaB; DMEM: Dulbecco's Modified Eagle's Medium; RPMI: Roswell Park Memorial Institute; IKK: IκB kinase; TNFR: TNF receptor; PBMC: Peripheral blood mononuclear cells; SFMC: Synovial fluid mononuclear cells; EMSA: Electrophoretic mobility shift assay; GAPDH: Glyceraldehyde-3-Phosphate Dehydrogenase; HPLC: High Performance Liquid Chromatography; WSL: Withania somnifera leaf; IFA: Incomplete Freund's Adjuvant; Th: T helper; ELISA: Enzyme-linked immunosorbent assay; RA: Rheumatoid Arthritis; ACR: American College of Rheumatology criteria; EULAR: European League Against Rheumatism criteria; DAS: Disease activity score; ESR: Erythrocyte sedimentation rate; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; NGAL: Neutrophil gelatinase associated lipocalin; PGE2: prostaglandin E2; APCs: antigen presenting cells; LPS: lipopolysaccharide; FITC: Fluorescein isothiocyanate; MHC II: Major histocompatibility complex class II; MCP-1:Monocyte chemoattractant protein-1; RANTES: regulated on activation, normal T cell expressed and secreted; CD-40: Cluster of differentiation 40; NSAID: nonsteroidal anti-inflammatory drugs; BS: Boswellia serrata; ESR: erythrocyte sedimentation rate; TLC: Thin-layer chromatography; AKBA: 3-O-acetyl-11-ketob-boswellic acid; CMC: Carboxymethyl cellulose; HCH: Human primary Chondrocytes; TCA: Trichloroacetic Acid; TNF-α: Tumor necrosis factor alpha; MMp-3: Matrix metalloproteinase; PL: Pluchea lanceolata; PLC: Pluchea lanceolata chloroform; SRBC: Sheep red blood cells.
Alcohol extract of salai guggul (B. serrata) displayed marked anti-inflammatory activity in carrageenan-induced paw edema in rats and mice. It was equally effective in adrenal-itemized rats 27. Alcohol extract of salai guggul strongly inhibited antibody production and the infiltration of polymorphonuclear leukocyte; it decreased the volume of pleural exudates 28.
The plant extract has antihyperlipidemic activity also 29, 30. The compound also protected mice against galactosamine / endotoxin-induced hepatitis in mice 31. The protection was interpreted in terms of its ability to inhibit the formation of leukotrienes. Acetylboswellic acids inhibit lipo-polysaccharide-mediated TNF-α induction in monocytes by direct interaction with IκB kinases 32. Besides, acetyl-keto-β-boswellic acid inhibits cellular proliferation through a p21-dependent pathway in colon cancer cells 33.
Pluchea lanceolata: In an indigenous system of medicine all parts of the plant are broadly used. It shows anti-inflammatory and analgesic activity and is significantly used in rheumatoid arthritis, neurological diseases, sciatica, edema, bronchitis, dyspepsia, cough, psoriasis and piles 34, 35. The plant involves different secondary metabolites viz. flavonoids (quercetin, isorhamnetin, daidzein), triterpenes, sitosterols, taraxosterols, pluchine, etc. which contribute it anti-inflammatory and analgesic properties 36, 37, 38. In Albino rats, the water-soluble fraction of the 90% alcohol extract showed significant anti-inflammatory activity in induced formalin arthritis and granuloma pouch. The decoction of the plant has been used in arthritis. The leaves are aperients and used as a laxative, analgesic and antipyretic 39.
Vitex negundo L.: Also known as “nirgundi” (Blue flowered plant). It is a hardy plant, flourishing mainly in the Indian region. It has analgesic, anti-bacterial and anti-inflammatory properties. It is useful in the treatment of fever, arthritis, headaches, swelling, digestion problems and mouth related problems. The sub-effective dose of nirgundi potentiated the anti-inflammatory activity of phenylbutazone and ibuprofen significantly in carrageenin-induced hind paw edema and cotton pellet granuloma models. The synergy of anti-inflammatory activities phenylbutazone and ibuprofen by nirgundi indicates that it may be useful as an adjuvant therapy along with standard anti-inflammatory drugs. One of a study done by Yunos et al., and Jana et al., who investigated anti-inflammatory properties of nirgundi extracts in acute and sub-acute inflammation which are attributed to prostaglandin synthesis inhibition 40, 41.
Therapeutic Potential of Traditional Medicinal Plants against RA: Ayurveda, a traditional system of medicine, emphasized the use of medicinal plants in the form of various formulations for the treatment of arthritis. Present review elaborates the isolated constituents from plant origin, which showed promising activity against RA in Table 2.
These plant is exhibiting active constituents which act by different mechanisms such as suppression of the immune system and control of inflammation to bring relief to painful conditions. Here are some key findings validating the therapeutic approach against arthritis by using these alternative potential medicinal plants as shown in Table 3. A systematic literature review was carried out using Pubmed, Google Scholar; Medicinal plants database, as well as the journals.
CONCLUSION: In India, in traditional medicine, many plants are used as a single drug or combination of one or two medicinal plants of herbal formulations to treat RA and other inflammatory diseases. Numerous plants were tested for their anti-arthritis and anti-inflammatory activities using experimental animal models. Although many studies were carried out, the studies were not concentrating on the expansion of therapeutic agents against RA. Most studies are preliminary.
However, plants such as Boswellia serrata, Withania somnifera, and Zingiber officinale are promising for further studies leading to possible growth of satisfactory medicine for arthritis. From the above review, it should be evident that these medicinal plants which exert anti-arthritic activity, anti-inflammatory and immunomodulatory property at a particular dose. This review attempts to give a scientific account of the use of valuable medicinal plants extracts in rheumatoid arthritis.
ACKNOWLEDGEMENT: Financial support provided by the University Grants Commission (UGC), New Delhi under the Post Doctoral fellowship scheme for women candidates for the year 2016-17 is gratefully acknowledged.
CONFLICT OF INTEREST: The authors confirm that this article content has no conflicts of interest.
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How to cite this article:Bagde S and Biswas D: A review on some selected traditional Indian medicinal plants of immunomodulatory potential and their therapeutic use in rheumatoid arthritis. Int J Pharm Sci & Res 2019; 10(5): 2087-00. doi: 10.13040/IJPSR.0975-8232.10(5).2087-00.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
S. Bagde and D. Biswas *
Department of Microbiology, Medical College, All India Institute of Medical Sciences (AIIMS), Bhopal, Madhya Pradesh, India.
11 August 2018
01 November 2018
13 November 2018
01 May 2019