Medicinal plants with potential anti-arthritic activity.

ETHNO PHARMACOLOGICAL RELEVANCE: Traditional medicinal plants are practiced worldwide for treatment of arthritis especially in developing countries where resources are meager. This review presents the plants profiles inhabiting throughout the world regarding their traditional usage by various tribes/ethnic groups for treatment of arthritis.
MATERIALS AND METHODS: Bibliographic investigation was carried out by analyzing classical text books and peer reviewed papers, consulting worldwide accepted scientific databases from the last six decades. Plants/their parts/extracts/polyherbal formulations, toxicity studies for arthritis have been included in the review article. The profiles presented also include information about the scientific name, family, dose, methodology along with mechanism of action and toxicity profile. Research status of 20 potential plant species has been discussed. Further, geographical distribution of research, plants distribution according to families has been given in graphical form.
RESULTS: 485 plant species belonging to 100 families, traditionally used in arthritis are used. Among 100 plant families, malvaceae constitute 16, leguminasae 7, fabaceae 13, euphorbiaceae 7, compositae 20, araceae 7, solanaceae 12, liliaceae 9, apocynaceae, lauraceae, and rubiaceae 10, and remaining in lesser proportion. It was observed in our study that majority of researches are carried mainly in developing countries like India, China, Korea and Nigeria.
CONCLUSION: This review clearly indicates that list of medicinal plants presented in this review might be useful to researchers as well as practioners. This review can be useful for preliminary screening of potential anti-arthritis plants. Further toxicity profile given in the review can be useful for the researchers for finding the safe dose.

INTRODUCTION

Immune system of our body plays a crucial role, as an overactive immune system may lead to certain fatal disease because of various hypersensitive or allergic reactions which may cause numerous derangements; loss of normal capacity to differentiate self from non-self resulting in immune reactions against our own’s cells and tissues called autoimmune diseases. Certain common autoimmune diseases like myasthenia gravis, serum sickness, pernicious anemia, reactive arthritis etc., are the severe issues for medical and pharmaceutical community because of unknown etiology [1]. According to WHO, 0.3-1% of the world population is affected from rheumatoid arthritis (RA) and among them females are three times more prone to the disease as compared to males [2]. RA is a chronic, inflammatory, and systemic autoimmune disease [3]. The primary symptoms of RA include pain, swelling, and destruction of cartilage and bone as a result of which permanent disability occur. Although the exact etiology is unknown but several hypotheses said that it is triggered by the combination of genetic predisposition and exposure to environmental factors like viruses [4]. The exact pathophysiology is still unknown but release of certain free radicals such as nitrous oxide and superoxide radicals generated as by-products of cellular metabolism. The release of such free radicals may induce the production of interleukins (IL) and tumor necrosis factor (TNF-α) from T-cells which ultimately influence the production of growth factors, cytokines and adhesive molecules on immune cells as such factors may cause tissue destruction and inflammation [5]. Pathological changes in RA are hyperplasia of synovial membrane, infiltration of inflammatory cells and neovascularization, which results into cartilage erosion and articular destruction [3].

The goal of treatment for rheumatoid arthitic patients is to eliminate symptoms, slow disease progression, and optimize quality-of-life [6]. Therefore, before starting the treatment of RA certain goals must be kept in mind such as relief of analgesia, reduction of inflammation, protection of articular structure, maintenance of function, and control of systemic involvement [5]. Presently for the treatment of RA, strategies have changed from traditionally used non-steroidal anti-inflammatory drugs (NSAIDs) or disease modifying antirheumatic drugs (DMARDs) to novel biological agents, like TNF monoclonal antibody. Clinically, the treatment of RA includes five strategies. The foremost approach is the use of NSAIDs followed by mild doses of glucocorticoids to minimize the signs of inflammation as well as progression of disease. In chronic patients, the use of DMARDs such as methotrexate, sulfasalazine, gold salts or D-pencillamine can be included in the treatment. In certain cases, TNF-α neutralizing agents like infliximab, etanercept etc; IL-1 neutralizing agents like anakinra; and the drugs which interfere with T-cell activation such as abatacept can also be included in treatment of chronic cases. Finally, immunosuppressive and cytotoxic drugs such as cyclosporine, azathioprine, and cyclophosphamide are used for the treatment of chronic patients [5,7,8]. The above-mentioned therapeutic agents reduce the inflammation and joint destruction but their long-term risks are still unknown. However, long-term risks of drugs includes gastrointestinal ulcers, cardiovascular complications, hematologic toxicity, nephrotoxicity, pulmonary toxicity, myelosuppression, hepatic fibrosis, stomatitis, cirrhosis, diarrhea, immune reactions, and local injection-site reactions. Moreover, higher costs and side effects which include high risks of infections and melagnancies reguires continous monitoring [1].

Herbal Therapy for the Treatment of Arthritis

Herbal medicines are used for the treatment of various ailments from ancient times and it is not an exaggeration to say that the use of the herbal drugs is as old as mankind [9]. Herbal medicines are synthesized from the therapeutic experience of generation of practicing physicians of ancient system of medicine for more than hundreds of years [10]. Nowadays, researcher shows a great interest in those medicinal agents that are derived from plants because the currently available drugs are either have certain side effects or are highly expensive [11]. Nature has blessed us with enormous wealth of herbal plants which are widely distributed all over the world as a source of therapeutic agents for the prevention and cure of various diseases [12]. According to WHO, world’s 80% population uses herbal medicines for their primary health care needs. Herbal medicines will act as parcels of human society to combat disease from the dawn of civilization [13]. The medicinally important parts of these herbal plants are chemical constituents that produce a desired physiological action on the body [14].

Since ancient time India uses herbal medicines in the officially alternative systems of health such as Ayurveda, Unani, Sidha, Homeopathy, and Naturopathy [15]. In India, there are more than 2500 plants species which are currently used as herbal medicaments. For than 3000 years, the herbal medicines are used either directly as folk medication or indirectly in the preparation of recent pharmaceuticals [16]. Thus, from the knowledge of traditional plants, one might be able to discover new effective and cheaper drugs [17]. In this review article, we have tried to cover all the ayurvedic strategies that are followed for the treatment of RA without any possible side effects. The future treatment of RA should provide more effective relief [5].

MATERIALS AND METHODS

In this review, bibliographic investigation was carried out during July 2011-December 2013, by refering various text books and certain review papers and research papers, consulting globally accepted databases from last some decades. The data were gathered from various databases i.e. Science Direct, PubMed, and Google and the information is compiled by reviewing more than 250 research and review articles. The data which are relevant would be considered. The botanical correct names and families were mentioned after verification from published literature and databases.

The method of scrutining the data for this review article includes those plants: (i) Which are native to India and other countries such as America, Africa or Europe, (ii) used in traditional systems and in various polyherbal preparations, (iii) with reported anti-arthritic activity, (iv) appropriate dosage, (v) mechanism of action, (vi) safety profile, and (vii) models used. Plants/their parts/extracts used traditionally in acute rheumatic attacks, chronic analgesia, and chronic rheumatism have been considered as anti-arthritic agents. Further, detailed information on research status of 20 plant species has been explained.

Polyherbal Formulations for Arthritis

Analgesics and NSAIDs are helpful in reducing pain and inflammation in either acute or chronic RA patients [18]. Although the treatment of RA is available but due to potential adverse effects or irreversible organ damage the new approaches are developed for maintaining the balance between these potential risks and acknowledged benefits [19]. Currently for the treatment of RA safer and more potent medicaments are developed from oriental sources. Large number of herbal extracts and products such as polyherbal formulations are prepared to reduce such side effects and increase the benefits [18].

Rheum off Gold is a poyherbal formulation that is commonly recommended by Ayurvedic medical practitioners for the treatment of arthritis. The anti-arthritic activity was confirmed on complete Freund’s adjuvant (CFA) induced arthritis model in wistar rats and it was observed that significant reduction in arthritis index, paw thickness and inflammatory markers such as C-reactive protein, serum rheumatoid factor and erythrocyte sedimentation rate (ESR) when compared with dexamethasone. Thus, the formulation possesses a potential anti-arthritic activity [20].

A Unani polyherbal formulation was evaluated for its anti-arthritic activity in rats. The anti-arthritic efficacy of Manjoon Suranjan was evaluated using formaldehyde and CFA induced arthritis models. The data obtained suggested the anti-arthritic activity of the formulation [21].

Evaluation of Sudard as a potent anti-arthritic polyherbal formulation was studied using formaldehyde and adjuvant induced arthritis models in wistar rats. The formulation at the doses of 150 mg/kg and 300 mg/kg p.o. proves to have an anti-inflammatory and anti-arthrtic activity [22].

Anti-arthritic potential of Tongbiling (TBL-II) which was prepared by some modification in Chinese herbal formulation TBL. The anti-arthritic efficacy of formulation was studied using the collagen induced arthritis model in wistar rats and it was revealed that at the doses of 100 and 300 mg/kg p.o. the levels of IL-1β and TNF-α was significantly reduced. Thus it was concluded that the formulation have an anti-arthritic potential [23].

Chinese herbal formula HLXL was used in the treatment from last hundred years for the treatmnent of inflammation and arthritis. Moreover, after certain modifications in HLXL herbal formulation it was evaluated for its anti-arthritic property using CFA model in rats. It was concluded that the polyherbal formulation shows an anti-arthritic activity through significant inhibition of paw edema and levels of TNF-α and IL-β [24].

The therapeutic effect of Ganghwaljetongyeum on RA in rabbit knee synovial membrane was evaluated. It was observed that there would be significant inhibition of proliferation of HG-82 cells which shows that the polyherbal formulation have an anti-arthritic activity. Moreover, there was significant reduction in TNF-α, IL-10 and NO species [18]. Various polyherbal formulations are described in Table 1.

Table 1

Polyherbal formulations

RESULTS

About more than 350 articles were reviewed. More than 20 articles were studied for searching the traditional use of plants in arthritis [Table 2]. Around 108 articles were referred for citing the proved anti-inflammatory and anti-arthritic activities of plants along with mechanism of action, acute toxicity profile, and doses [Table 3].

Table 2

Traditionally used anti-arthritic plants

Table 3

Plants with reported anti-arthritic activity

The detailed information on research status of following 20 plant species was gathered from multiple references.

Alstonia scholaris Linn. (AS)(Family-Apocynaceae)

AS is commonly known as saptaparni or devil’s tree, widely distributed in dried forests of India as Western Himalayas, Western Ghats, and in the Southern region. AS is a medium to large tree about 40 m high with a somewhat tessellated corky grey to grey-white bark [25]. Traditionally, bark of AS is used in the treatment of rheumatism, malarial fevers, abdominal disorders, leprosy, asthma, bronchitis, pruritis, and chronic ulcers [12]. Milky juice is mixed with oil and was applied in rheumatic pains. The chief alkaloids present in AS are echitamine, tubotaiwine, akaummicine, echitamidine, picrinine, and strictamine. AS flowers also contains amino acids, carbohydrates, phenol, tannins, cardiac glycosides, saponins, flavanoids, steroids, fixed oil, and fats [26]. The plant showsimmune-stimulatory, hepato-protective [27], anti-cancer [28], anti-plasmodial [29], and anti-hypertensive [30] activities. Extract of AS possess an anti-diabetic, anti-hyperlipidemic [31], anti-bacterial [32], anti-inflammatory, analgesic [33], antioxidant [27], immunostimulant [34], anti-cancer [35], anti-asthmatic [36], hepatoprotective [37], and anti-anxiety activity [12,25,38]. The ethanolic extract of AS leavesat doses of 100 and 200 mg/kg confirmed anti-arthritic activity in male wistar rats. The anti-arthritic activity was mainly by reducing the total leukocyte migration as well as lymphocytes and monocytes/macrophages migration. It can be concluded that AS shows an anti-arthritic activity on male wistar rats [39].

Aristolochia bractaeta Lam. (AB)(Family-Aristolochiaceae)

AB commonly known as worm killer or kidamari is a shrub found in Deccan Gujarat, western and southern India, Bihar, Sindh, and Bengal [16]. Traditional use of AB was found in gonorrhea, syphilis, inflammation, ulcer, amenorrhea, skin disease, dermatitis, leprosy, jaundice, and helminthiasis [16]. The major chemical constituents of the AB are alkaloids, triterpenoids, steroids, flavonoids, saponins, carbohydrates, proteins, and cardiac glycosides [40,41]. The studies of extract have shown anti-pyretic [42], anti-allergic [43], anti-inflammatory, anti-arthritic [1], anti-ulcer [44], anti-fungal [45], anti-microbial [46], antioxidant [47], wound healing [48], anti-implantation, and abortificient activities [49]. The petroleum ether, methanol, and chloroform extract of whole plant of AB possess comparable anti-arthritic activity at doses of 100, 200, and 400 mg/kg body weight. AB revealed anti-arthritic activity by maintaining the synovial membrane and vascular permeability thus inhibiting cytokines and leukotriene infiltration. In conclusion, AB possesses an anti-arthritic effect on wistar albino rats of either sex [1].

Boerhaavia diffusa Linn. (BD)(Family-Nyctagineae)

BD is found all over India especially during rain. Two varieties of BD are explored, one with white flowers called “shwethpurna” and other flowers called “raktapurna.” The medicinally important part is root (MateriaMedica, 1982). BD is traditionally significant due to their laxative, diuretic, expectorant, diaphoretic, and emetic properties [50]. A paste made up of roots together with Colchicum, Solanum nigrum, Tamarind stone, Stag’s horn and dried ginger, all in equal parts, are used in rheumatic and gouty painful joints. Root is used as powder in drachm doses or decoction or infusion for the treatment of inflammatory disorders like arthritis. Chakradatta used it in the treatment of chronic alcoholism and various other ailments i.e. phthisis, insominia, and rheumatism [51]. The air-dried plant was found to contain large quantities of potassium nitrate and also contains an alkaloid, panarnavine, present in very small quantity of 0.01%. Recent investigations reported that BD possess an antistress, adaptogenic [52], antioxidant [53], immunosuppressive [54], anti-carcinogenic [55], hepatoprotective [56,57], diuretic [58], anti-diabetic [59], anti-viral [60], and anti-inflammatory activities [61,62]. The petroleum ether extract of roots at dose 1000 mg/kg has been evaluated as anti-arthritic using CFA model and showed 81.5% response as compared to indomethacin [63].

Boswellia serrate Roxb. (BS)(Family-Burseraceae)

BS is a deciduous middle-sized tree, grown in tropical parts of Asia and Africa [64]. Boswellic acid is the first terpenoids isolated from oleo gum resins. The oleo gum resin of BS is used in various Unani and Ayurvedic preparations. Folkloric uses of BS are in the treatment of bronchitis, rheumatism, asthma, cough, intestinal problems, syphilitic, jaundice, dysentery, and pulmonary diseases. It acts as both internal and external stimulant, expectorant, diuretic, and stomachic [51,64]. Boswellia is a traditional natural remedy that has been used for thousands of years to treat swelling and inflamation in Ayurvedic medicine and traditional Chinese medicine. In 2003, medical researchers conducted a randomized blind placebo controlled trial of BS on 30 patients suffering from osteoarthritis of the knee. The data showed an increased range of motion and less swelling in their knees from arthritis than before they began the treatment. The essential oil of BS predominantly comprised monoterpenoids, of which β-pineneis the major constituent. Other monoterpenoids includes β-pinene, cis-verbenol, trans-pinocarveol, borneol, myrcene, verbenone, limonene, and p-cymene, while a-copaene was the only sesquiterpene identified [65,66]. BS possess an anti-inflammatory [67], analgesics [68], immunomodulatory [69], anticancer [70,71,72], hepatoprotective, hypolipidemic [73], antiasthmatic [74], osteoarthritis, and hypoglycemic activities [75]. The n-hexane extract of gum resins of BS in combination with methanolic extract of rhizomes of Glycyrrhiza glabra (GY) exhibited anti-arthritic activity at doses of 50 or 100 mg/kg in male wistar rats. The anti-arthritic activity is mainly by decreasing the activity of membrane marker enzymes such as alkaline phosphatase, serum glutamic oxaloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), and by the prevention of leucocytes migration in the inflamed area. In conclusion, BS possesses a significant anti-arthritic activity on male albino wistar rats [76].

Caesalpinia sappan Linn. (CP)(Family-Leguminosae)

CP commonly known as sappanwood, bakam or patang, is a native of South India, Madhya Pradesh, Orissa, West Bengal, Malaya, and Sri Lanka. The tree spreads to a height of 10 m and is cultivated for its large, ornamental penicals of yellow flowers. A very strong barrier is formed by the branches when they are interlaced [11]. The heartwood of the CP is traditionally used for the treatment of ulcers, leprosy, rheumatism, skin disease, diarrhea, dysentery, epilepsy, convulsions, diabetes, odontopathy, stomatopathy, and leucorrhea. The heartwood of the CP is bitter, astringent, sweet, acrid, refrigerant, constipating, sedative, and hemostatic. In Yunani system, the decoction of wood was useful in rheumatism [77,78]. CP is reported to have an anti-anaphylactic [79], anti-coagulant [80], anti-bacterial [81-83], anti-fungal [83], anti-inflammatory [84], anti-tumor [85-87], anti-viral [88,89], immunostimulant [87], and semen coagulating activities [86]. CP also causes the inhibition of phosphodiesterase [90] and stimulation of glutamate pyruvate transaminase [91] and tyrosinase enzymes [92]. The ethanolic extract at doses 1.2, 2.4, and 3.6 g/kg of CP wood showed anti-arthritic activity on wistar rats by declining the levels of IL-1β, IL-6, TNF-α, and prostaglandin E2 (PGE2) in serum. The study concluded that CP possesses an anti-arthritic activity on rats [93].

Cannabis sativum Linn. (CT)(Family-Urticaceae)

CT, a pistillate plant, is a native of Persia, Western and central Asia, and is now largely cultivated all over India. Dried flowering or fruiting tops are medicinally important. CT possesses traditional significance in infections of eye, local inflammation, neuralgia, acute mania, whooping cough, asthma, and to relieve pain in dysmenorrhea and menorrhagia. Oil extracted from seeds is used in rheumatism. The chief chemical constituent is a resin volatile oil composed of canabene, canabene hydride, canabinon, and canabin; which consist of cannabinol, pseudo-cannabinol, cannabinin, and several terpenes [51,94]. Around more than 166 research papers confirm that cannabis and related therapies will be helpful in relieving the pain associated with arthritis. Moreover, cannabinoid component of cannabis shown to possess anti-arthritic activity. It has been claimed to use as anxiolytic, antidepressant [95,96] in schizophrenia [97] and RA. The active moiety of CT i.e. cannabidiol at a dose of 10 and 25 mg/kg, orally, administered in collagen-induced arthritic ratssignificantly decreases the arthritic score and inhibits the release of inflammatory mediators. Thus, it was concluded that the cannabidiol have an anti-arthritic activity by possessing anti-inflammatory and immunosuppressive action [98].

Cinnammomum zeylicanium Blume. (CZ)(Family-Lauraceae)

CZ a topical evergreen tree grows to a height of 7-10 m in its mild state and has deeply veined ovate leaves that are dark green underneath. It is commonly known as cinnamon or Ceylon cinnamon. CZ is cultivated in Sri Lanka, Mayanmar, and Southern Coastal strips of India. Treatment of vaginitis, rheumatism, neuralgia, wounds, toothache, diabetes, inflammation of eyes, impotence, and leucorrhea is its traditional uses. CZ was also used to treat abdominal pain associated with diarrhea, dysmenorrhea, and amenorrhea. The active constituents of the CZ are cinnamaldehyde and eugenol. The other constituents are cmphene, sibinene, myrcene, fenchone, nerol, bornyl acetate, cinnamyl acetate, and geranial [99]. The CZ is reported to have an analgesic, anti-pyretic [100], anti-fungal [101], anti-inflammatory, anti-microbial [102,103], insecticidal [104], anti-diabetic [105,106], and antioxidant activities [107,108]. The polyphenolic extract of the CZ bark at a dose of 8 mg/kg revealed anti-arthriticpotential in male wistar rats in CFA model by improving the body weight and the level of serum C-reactive proteins when compared with control group. Thus, anti-arthritic activity was mediated through inhibition of leukocyte emigration and prostaglandin synthesis [109].

Coriander sativum Linn. (CS)(Family-Umbelliferae)

CS is a herbaceous plant distributed all over India and used for its seeds, fruits and leaves. Traditionally, plant is used as stimulant, carminative, stomachic, diuretic, tonic, and aphrodisiac. Oil is very useful for rheumatism in a dose of 1-4 minim on sugar or in emulsion. Coriander oil which contains linalool/coriandrol, geraniol, and boborneol, extracted from its fruit, is volatile and essential [51,110]. Externally seeda can be used as a lotion or have been bruised and used as a poultice for the treatment of arthritis. Cineole, one of the 11 components of the essential oils, and linoleic acid, present in coriander, possess antirheumatic and anti-arthritic properties [111]. CS possesses an antibacterial [112,113], anti-spasmodic [114], antioxidant [115-117], anticarcinogenic [118], and hypolipidemic activities [119]. The hydroalcoholic extract of seeds at doses of 8, 16, and 32 mg/kg showed reduction in paw swelling induced by formaldehyde and CFA methods in male wistar rats by inhibiting the pro inflammatory cytokines and TNF-α. In conclusion, the extract of CS shows a potent anti-arthritic activity on rats [120].

Curcuma longa Linn. (CL)(Family-Scitaminaceae)

CL is a perennial herb that measures up to 1 m high with a short stem, distributed throughout tropical and subtropical regions of the world, and is widely cultivated in Asian countries, mainly in India and China [121]. There are two varieties of CL one with rich-colored oval rhizomes and other with softer, larger, lighter-colored long rhizomes which are edible. Turmeric paste mixed with lime and saltpeter can be used externally in rheumatism. The major chemical constituents are curcumin, methylcurcumin, demethoxy curcumin, sodium curcuminate, and Ar-turmerone. Traditionally, CL is used in wound healing, helminthic infections, fevers, skin eruption, conjunctivitis, cough, parasitic infections, and liver diseases [51,121]. Later on, it was investigated the effect of herbomineral formulation (comination of turmeric, ashwagandha, sallai guggul, and jasad bhasma based on Ayurveda medicinal system) on 90 patients suffering from arthritis. It was observed that there was significant reduction in disability and pain. The plant is reported to be highly valued as anti-inflammatory [122,123], antiprotozoal [124,125], nematocidal [126], antibacterial [127], anti-tumor [128], and hepatoprotective [129]. The anti-arthritic activity was shown by essential oils of rhizomes of CL with streptococcal cell wall induced arthritis. It can be concluded that the turmeric essential oil possess an anti-inflammatory as well as anti-arthritic activities [130].

GY (Family-Fabaceae)

GY commonly known as mulethi is a herb/shrub of 2 m height mainly found in subtropical or temperate areas. The underground growth of stem is up to 2 m and is highly branched consisting short taproot with number of rhizomes. GY is commercially grown in Spain, Sicily and England. In India, it is mainly cultivated in Punjab and Sub Himalayan tracts [51]. The plant is reported to be traditionally used in anemia, gout, asthma, epilepsy, fever, cough, skin disease, rheumatism, paralysis, and hemorrhagic diseases. Roots in the form of infusion, decoction, extract or lozenge are useful as a demulcent in inflammatory affections [10,51]. The clinical trials reveal that glycyrrhizin has favorable effects on RA, when administered along adrenocorticotropic hormone or cortisone, in comparison, when administered alone. Hence, it was suggested that the main effect of liquorice is to potentiate rather than mimic endogenous steroids. The active chemical constituent is glycyrrhizin present in the form of potassium and calcium salts of glycyrrhizic acid. GY also contains sucrose, glucose, resins, bitter principles, mannites, asparagines, and fat [131]. GY have shown anti-microbial, hypolipidaemic, antiviral, hypotensive, anti-ulcer, anti-diuretic, anti-inflammatory, anti-mutagenic, expectorant, hepatoprotective, antioxidant, and antipyretic activities [132-134]. The methanolic extracts of rhizomes of GY at a dose of 150 mg/kg possess anti-arthritic activity in male wistar rats by inhibiting the leukocyte migration and auto antigens production and exhibit anti-protinase activity. The study concluded that GY possess a significant anti-arthritic activity [76].

Lantana camara Linn. (LC)(Family-Verbinaceae)

LC popular as lava or red sage is a low erect or subscandent vigorous shrub with tetrangular stem, stout recurved pickles and comprises strong odour ofblack currents. LC is native to India and reaches to a height of 1-3 m [135]. Traditionally, LC is used in the treatment of sores, chicken pox, measles, fever, cold, rheumatism, asthma, ulcers, and high blood pressure [135]. In Asian countries like India, the decoction of leaves of the plant LC was used traditionally for the treatment of rheumatism. In Ghana, the infusions of whole plant are used against arthritis. Nyctanthes arbor tristis is used in Bangladesh for treatment of fever, bacterial infections, and rheumatism as well as other ailments [136]. The active constituents are flavones, isoflavones, antocyanins, coumarins, lignins, alkaloids, tannins, saponins, triterpinoids, catechins, and isocatechins [137]. LC is reported to have an antioxidant [138], anti-diabetic [139,140], anti-inflammatory [141], anti-motility [142], anti-fungal [143,144], anti-bacterial [145,146], anti-fertility [147], cytotoxic [148], larvicidal [149], and wound healing activities [17,150]. The ethanolic extract of leaves of LC at doses 5, 10 and 20 mg/kg proved to have anti-arthritic activity by inhibiting the lipoxygenase and cyclooxygenase [151].

Phyllanthus amarus Schum and Thomm. (PA)(Family-Euphorbiaceae)

PA is a 10-60 cm tall herb which grows in tropical and subtropical sandy regions. Its common name is chancapiedra. Traditionally, PA is used in jaundice, dropsy, diarrhea, dysentery, urino-gental disease, scabies, ulcer, and wounds. In addition, it is used as astringent, stomachic, diuretic, antiseptic, bitter, and febrifuge [51,152]. In the Hand Book of African Medicinal Plants it is reported that PA was traditionally use for its anti-inflammatory activity. Moreover, in Amazonia and Brazil, the whole plant was used for the treatment of various inflammatory disorders like arthritis. PA comprised of active constituents found in all parts of the plant aslignans, glycosides, flavonoids, alkaloids, ellagitannins, and phenylpropanoids [152]. Studies have proved that PA have anti-inflammatory [153], anti-microbial [154,155], anti-cancer [156], anti-fertility [157], hepatoprotective [158], anti-diabetic [159], anti-diarrheal [160], antioxidant [161], anti-oedemotgenic [162], diuretic [163] and chmoprotective [164] activity. The aqueous extract of whole plant at a dose of 100, 200, and 400 mg/kg shows anti-arthritic activity in male wistar rats. The extract at various doses reduced the levels of aspartate transaminase and alanine transaminase and thus maintains its anti-arthritic activity [165].

Piper longum Linn. (PL)(Family-Piperaceae)

PL is a slender, climbing, under shrub, creeping, and rooting below. The young shoots are downy, the leaves are 5-10 cm long; 5 cm wide; ovate; cordate with broad rounded lobes at the base; sub-acute and entire. PL is indigenous to North-Eastern and Southern India and Ceylon [51]. PL is used in cold cough, asthma, hoarseness, and snake bite since ancient times. In rheumatism, roasted aments are bitten up with honey and taken in a prescribed dose. In Java and Indonesia, the whole plant was applied topically, as it relieves muscular pains and inflammation [51,166]. Major constituents are piperine, piperlongumine, piperlonguminine, and methyl 3,4,5-trimehoxycinnamate. Others include resin, volatile oil, starch, fatty oil, and inorganic matter [167]. Medicinally, PL finds its importance as an anti-inflammatory [168], anti-amoebic [169], anti-asthmatic [170], hepato-protective, and immune-modulatory activities [171]. The aqueous extract of seeds of PL at two doses (200 and 400 mg/kg) shows a 46.32% inhibition in paw swelling in Freund’s complete adjuvant induced arthritis in rats by inhibiting the adherence of neutrophils to endothelial monolayer by suppressing the TNF-α induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, and also inhibits the NF-κB. In conclusion, PL possess a significant anti-arthritic activity on male wistar rats [172].

Punica granatum Linn. (PG)(Family-Lythraceae)

PG is popular as pomegranate is a native of India, East Indies, Southern Asia, tropical Africa, California, and Arizona. PG grows tillan height of 12-16 feet with number of spiny branches and has long lifespan. Traditionally, PG is used in diarrhea, ulcers, and diabetes and also useful as antiparasitic agent and blood tonic [51,173]. In Iranian Traditional Medicinal system, the seeds and juice are considered as a tonic for the treatment of rheumatism. Pomegranate fruit consumption reduced composite disease activity index in RA patients, and this effect could be related to the anti-oxidative property of pomegranates. Dietary supplementation with pomegranates may be a useful complementary strategy to attenuate clinical symptoms in RA patients [174]. Some of the major chemical constituents present in the PG aregallic acid, anthocyanins, ellagitannins, flavones, flavonoids, antocyanidins, sterols, quercitin, rutin, and other fatty acids [173]. The plant is of high value due to its anti-inflammatory [175], anti-carcinogenic [176,177], antioxidant [178,179], hypotensive [180], hypolipidaemic [181], anti-artheroseclerotic [182], and anti-diabetic activities [183]. PG is also used in the treatment of myocardial ischemia [184], prostrate cancer [185,186], dental plaques [187], denture stomatitis [188], bacterial infections [189,190], erectile dysfunctions [191], male infertility [192], alzheimer’s disease [193], and ischemic brain injury [194,195]. The fruits of PG show an anti-arthritic activity at doses of 13.6-34 mg/kg by inhibiting the spectrum of signal transduction pathway in male wistar rats. Thus, it can be concluded that PG have potent anti-arthritic activity [196].

Ruta graveolens Linn. (RG)(Family-Rutaceae)

Rue is an herbaceous perennial plant, originally growing in the Mediterranean region [197]. RG is traditionally used as antiseptic, anthelminthic, antispasmodic, stimulant, abortificient, expectorant, and anti-rheumatic [51]. The major chemical constituents isolated from the RG are rutin, quercitin, rutacridone, rutacridone epoxide, graveoline, and gravacridonodiol [197]. RG is reported to have anti-inflammatory [198,199], analgesics [200], antiandrogenic [201,202], antihyperglycemic [203,204], antihyperlipidemic [205], anticancer activity [206], and anti-rheumatic properties. The polyphenolic fraction of aerial parts of RG at a dose of 10 mg/kg, b.w. showed an anti-arthritic activity in male wistar rats induced by CFA model. The polyphenolic fraction revealed its activity by inhibiting the prostaglandins synthesis, decreasing CRP level, ceruloplasmin, lipid peroxidation and release of other inflammatory mediators. In conclusion, RG possess anti-arthritic activity [207].

Saussurea lappa Clarke. (SL)(Family-Compositae)

SL herbs grow abundantly on the Himalayas and Valley of Kashmir. Roots contain odorous principle composed of a solid resin, salt of valeric acid and ash which contains manganese. SL is mainly useful in asthma, helminthiasis, fever, cough, skin disease, rheumatism, malaria, and leprosy. Roots in the form of infusion with little cardamoms are used in chronic rheumatism. Oil of the root composed of camphene, phellandrene, costene, aplotaxene, costol, and costic acid [51]. In the Southern part of Kashmir, Himalaya, and Punjab regions, the roots and root stalk are used for the treatment of rheumatism. In Unani system of medicine, it is useful in rheumatism [208]. The combination of Cyperus rotundus, Tinospora cordifolia and SL clinically proved to have an anti-arthritic activity through significant reduction of pain in double-blinded, comparative, parallel clinical trial design [209]. The SL extracts exhibited other biological activities including anti-diarrheal [210], antiulcerogenic [211,212], antibacterial [213], anticancer [214], anticonvusant [212], hepatoprotective [215], antiviral [216], anti-inflammatory, antioxidant [217], and anti-arthritic activities. The ethanolic extract of SL at dose levels of 50-400 mg/kg showed potent anti-arthritic activity. A sesquiterpene lactone “cynaropicrin” isolated from SL strongly inhibited TNF-α release from lipopolysaccharide (LPS) - stimulated murine macrophage cell line and dose-dependently suppressed the proliferation of lymphocytes stimulated. Another sesquiterpene lactone “dehydrocostus lactone” from SL suppressed LPS-induced nitric oxide production. The investigation concluded that the SL shows a significant anti-inflammatory and anti-arthritic activity [217].

Sida rhombifolia Linn. (SR)(Family-Malvaceae)

SR is a small erect under shrub having rough branches with stellate hairs commonly found in dry countries such as India and Ceylon [218]. Traditionally, the plant is used as nutritive, tonic and for the treatment of gonorrhea, piles, rheumatism, as diuretic, and aphrodisiac [51]. In Indonesia and Johore medicinal system, juice of whole plant pounded with little water is given indoses of ¼ seer for the treatment of rheumatism. β-phenethylamine, N-methyl-β-phenethylamine, S-(þ) N-β-methyl tryptophan methyl ester, vasicinol, vasicinone, vasicine, choline, hypaphorine methyl ester, hypaphorine, and betaine [219] have been isolated from the plant. The reported activities of plant include cytotoxic [220], antimicrobial [221], antibacterial [222], anti-inflammatory, antipyretic [223], and anti-arthritic. The aqueous and ethanol extract of aerial parts of the SR at doses 30 and 100 mg/kg reduced the paw edema induced by CFA method. Thus, it is concluded that the plant possess a potent anti-arthritic activity [218].

Terminalia chebula Retz. (TC)(Family-Combrataceae)

TC is a well-known traditional plant of Indian traditional medicinal system and the most frequently used herb in ayurveda. In tribal of Tamil Nadu in India, the TC is commonly known as Kadukkai and was used for treating various ailments such as fever, cough, diarrhea, gastroenteritis, skin diseases, candidiasis, urinary tract infections, and wound infections [51]. TC is a medium-sized deciduous tree of variable appearance with usually short cylindrical bole of 5-10 m length and 60-80 cm diameter. The phytoconstituents of TC are tannins, flavonoids, resins, fixed oil, fructose, amino acids, and sterols. Moreover, the active constituents of tannins include chebulic acid, ellagic acid, chebulagic acid, chebulinic acid, and gallic acid. TC was used in Thai traditional system as a carminative, expectorant, and antioxidant. A polyherbal formulation “Triphala” of TC, Terminalia bellerica and Emblica officinalis is commonly used in chronic constipation, detoxification, poor digestion and rejuvenator of the body [224]. TC possesses an anti-bacterial [225], anti-viral [226], anthemintic [227], anti-fungal [228], anti-ameobic [229], anti-neoplastic [230], anti-plasmodial [231], antioxidant [232], anti-diabetic [233] and anti-ulcerogenic [234] activity. The TC reported to have an immunomodulatory [229], radioprotective [235], cytoprotective [236], cardioprotective [237], and hepatoprotective [238] activity. Moreover, the hydroalcoholic extract of TC produces a significant inhibition of joint swelling in formaldehyde induced arthritis and CFA induced arthritis models. The anti-arthritic potential of the extract was due to significant reduction in the levels of TNF-α, IL-6, and IL-1β [239].

Trigonella foenum-graecum Linn. (TF)(Family-Papilionaceae)

TF, commonly known as Fenugreek, is an herbaceous plant which has found wide applications as a food, a food additive, and as a traditional medicine. Albuminoids, soluble carbohydrates, woody fibers, and ash are present in TF [240,241]. The plant has wide uses in the traditional medicine and reportedly used to treat diabetes, high cholesterol, wounds, inflammation, and gastrointestinal ailments. Several confections of TF like methi modaka, Svalpamethimodaka etc., are used in rheumatism [51]. Fenugreek seeds have high content of mucilage, choline, and trigonelline. Studies of its extract have shownantihyperglycemic [242], estrogenic [243], antioxidant [244], anticancer [245], anti-inflammatory [246], and antirheumatic activities. The fenugreek mucilage obtained from seeds of the TF at dose 75 mg/kg possess an anti-arthritic activity anddecreased the elevated levels of SGOT, SGPT, CRP, nitrites, ESR, and white blood cell count. The TF may act by decreasing the oxidative stress, cell influx, and release of mediators associated with arthritis. In conclusion, TF showed anti-arthritic activity [247].

Vitex negundo Linn. (VN)(Family-Verbenaceae)

VN is referred to as five leaved chaste tree and a large aromatic shrub or sometimes a smaller slender tree with quadrangular, densely whitish tomentosebranchets. VN is originated in Southern India and Burma [51]. VN have its traditional use in rheumatism, headache, enlarged liver, syphilis, diarrhea, and cholera. Leaves along with garlic, rice and gul is a remedy for rheumatism. In Ayurvedic, Unani and Chinese medicine system the leaves extract of VN was used to treat the rheumatism and inflammation of joints. The Konkan community in Maharashtra used the plant for rheumatism [248]. The chief chemical constituents are nishindine, flavones, luteolin-7-glucoside, casticin, iridoid glycosides, vitamin C, β-sitisterol, and phthalic acid [249]. VN possess different pharmacological activities including anti-inflammatory, analgesic [250-253], anticonvulsant [254], antioxidant [250,255], insecticidal [256,257], and antirheumatic [249]. The active compound agnusideisolated from ethanolic extract of leaves administered at doses of 1.56 mg/10 ml, 3.12 mg/10 ml, 6.25 mg/10 ml and 1.25 mg/10 ml p.o. decreased the elevated levels of ESR, leukotriene B4, PGE2, cytokines, IL-17, TNF-α and interferon gamma. Hence, it can be concluded that the VN possess an anti-arthritic activity [258].

Xanthium strumarium Linn. (XS)(Family-Compositae)

XS commonly known as cochlebur, burweed or burdock datura is anindigenous of tropical parts of India. XS is an annual herb of 1m height with a short, stout, hairy stems, and commonly grows in waste places, roadsides and along river banks in warmer parts. Traditionally, it is used as laxative, anthelmintic, tonic, digestive, antipyretic and also improves appetite, voice, complexion, and memory. XS is also used to cure leukoderma, biliousness, poisonous bites of insects, epilepsy, salivation, and fever. The infusion of plant has been used in treatment of rheumatism in ayurvedic and Chinese medicine system. The active principle of aerial parts of XS are alkaloids; sesquiterpenes lactones such as xanthinin, xanthumin, xanthatin; sulphated glycoside such as xanthostrumarin, atractyloside, carboxyatractyloside; phytosterols, xanthanol, isoxanthanol, xanthosin, 4-oxo-bedfordia acid, hydroquinone, xanthanolides, and deacetylxanthumin [259]. However, recently investigated that XS possess an anti-bacterial [260], anti-tumor [261], anti-cancer [262], anti-tussive [263], anti-fungal [264,265], anti-inflammatory [266,267], vasorelaxant [268], hypoglycaemic [269], antimitotic [270], anti-malarial [271], anti-trypanosomal [272], diuretic [273], anti-allergic [274], and antioxidant activity [275,276]. Oral doses (200 and 400 mg/kg) ofethanolic extract of XS when administered exhibited anti-arthritic activity by inhibiting the release of inflammatory mediators. In conclusion, XS have a potent anti-arthritic activity [277].

DISCUSSION

Since Neanderthal times, the plants had been used for the prevention and cure of various ailments such as RA and other inflammatory diseases. Natural sources such as plants have been considered as the safest and valuable treatment for the disease. From the ethno botanical knowledge, we included the plants that are used in Indian traditional systems such as herbalism, folklore and shamanism. The review article includes more than 485 different plant species that are used for the prevention and cure of RA during last few decades. The botanical name of the plant, family, common name, part used, and various dosage forms studied are summarized in the Table 2. Around more than 100 families are included for 485 plants among them papilionaceae, fabaceae, euphorbiaceae, acanthaceae, compositae, ranunculaceae, malvaceae, rutaceae, liliaceae, labiatae, solanaceae, cruciferae, verbenaceae, lauraceae, and rubiaceae are in major proportion. As shown in Figure 1, around 485 plants have been mentioned in which 19 (4.4%) belongs to family papilonaceae, 17 (4%) to compositae and euphorbiaceae, 15 (3.5%) to rutaceae, 14 (3.3%) to vabenaceae, 13 (3%) to labiatae and fabaceae, 12 (2.7%) to malavaceae and crucuferae, 11 (2.5%) to solanaceae and acanthaceae, 10 (2.3%) to ranunculaceae and liliaceae, 9 (2.1%) to apocynaceae, lauraceae and rubiaceae, 8 (1.8%) to graminae, meliaceae, and umbelliferae, and remaining (48.2%) are categorized as others [Figure 1].

Figure 1

Plants in diverse families with % anti-arthritic activity

From our review, we have noticed that majority of researches were carried mainly in developing countries such as India, China, Korea, and Nigeria. But some developed countries like USA and Japan also continue their research on RA so as to increase the potential benefits [Figure 2].

Figure 2

Geographical distribution of researches in the review

For the treatment of RA, various parts of plants are used such as leaves, roots, fruits, rhizomes, and seeds in distinguished dosage forms like extract, decoction, juice, infusion, paste, oil etc. The most potent anti-arthritic plants such as Aconitum ferox, Balsamodendron mukul, BD, Boswellia serrata, CS, CL, PL, Ricinus communis, Plumbago zeylanica, SL, SR, and Strychnos nux vomica have been elaborated in the review article. Among these listed plants, certain plants have been used in acute attack or in chronic pain or chronic rheumatism.

CONCLUSION

Traditional medicines used for the treatment of arthritis are used in various tribal/rural cultures worldwide. At present, investigation of anti-arthritic activity of traditional medicine has led to the development and studies of many herbal remedies employed for such purpose. The information that has been gathered from various sources is helpful in preserving folk indigenous knowledge as well as discovery of potential compounds having promising anti-arthritic activity. The information gathered from the data provides the information on toxicity profile and mechanism of action of tested extracts. Therefore, this review article has been prepared to provide the plants/their parts having specific traditional use in the treatment of arthritis upto year 2013. Moreover, this review has included latest data on new plant species/polyherbal formulations which are not covered in previews reviews on arthritis therapy as per our knowledge.

In conclusion, about 485 plant species mentioned in the list would have a promising anti-arthritic activity in humans. Information about the ethnic proof of the traditionally used anti-arthritic plants was cross-validated from various articles/reviews published in journals. Till know, no such review has analyzed which correlates the plant family, parts used, dosage form with anti-arthritic effects of the plants. Data mentioned in Table 2 show that papilonaceae family contains more plants with anti-arthritic activity whereas among parts, leaves have been maximally used in oil dosage form for the treatment of arthritis. Table 1 provides wealth of information indicates the beneficial effects of polyherbal formulations in the treatment of the arthritis. These includes Rumalaya forte, Rumalaya-liniment, arthacure, ortho joint oil, rheum off gold, Majoon suranjan, HLXL, GHJTY, Sudard, and TBL-II [18,20-24]. The data mentioned in Table 3 in addition provides the dose, toxicity profile, and models with mechanism of action for anti-arthritic activity.

The data discussed in this review might be quite useful in obtaining monographs on plants and recommendations on their use. In this review, we mainly deal with the safety profile, mechanism of action, and toxicity studies of plant extracts. The plant extracts and polyherbal formulations would be served as an alternate therapy for the treatment of arthritis with lesser side effects. Moreover, current knowledge can be helpful in materializing the commercial products, where the evidence can be quite limited.

Future Needs

Majority of traditionally used plants which have been mentioned in Table 2, have not been experimentally proved to have anti-arthritic activity. In addition, data in Table 3 show experimentally, the plants possess anti-arthritic activity only on animals but no clinical data are provided for proving the activity in humans. The data also lack information on exact activity of isolated compounds. However, the emphasis should be given in an area that needs further investigations as studied in animals needs to be translates to humans in order for a natural extract to be recommended for the treatment of arthritis. Therefore, further research of such less explored plants is still needed to determine their anti-arthritic activity.

Limitations

The data studied and prepared had been collected from the literature published in English language only and ignoring the studies published in other languages. The data mentioned in other languages, if had been included, will also be helpful in validating the current data. Further studies on isolated compounds of plants are not included, which otherwise, might be useful in scruitning the cause of anti-arthritic activity of plants.