Irritancy and anti-inflammatory activity of bis(eta 5-cyclopentadienyl)titanium(IV) complexes in rats

Dichloro-bis(eta 5-cyclopentadienyl)titanium(IV) and some related complexes were compared with cis-dichlorodiammineplatinum(II) in rats for acute anti-inflammatory activity against carrageenan paw oedema, anti-arthritic activity against developing and established adjuvant-induced polyarthritis, immunosuppressant activity in a local graft-vs. host assay, irritant effects at sites of administration (paw, skin, peritoneum) and nephro- and gastro-toxicities. These titanium complexes, like cisplatin and its hydrolysis products, in vivo exhibited both anti-inflammatory and anti-arthritic activity as well as immunosuppressant effects. Nephro- and gastro-toxicity were much less severe than in rats given platinum complexes. In vitro they selectively inhibited [3H]thymidine incorporation by isolated thymocytes and prevented the germination of radish seeds. When given intraperitoneally, the anti-inflammatory activity may partly be due to a counter-irritant phenomenon since the titanium derivatives elicited an acute peritoneal effusion if they were injected towards the omentum. However, when injected subcutaneously or applied in dimethylformamide or dimethylsulfoxide to the skin, they manifested both anti-inflammatory and anti-arthritic activity without irritancy or much local skin damage. They might therefore have the potential of being useful drugs, especially if released slowly.     

Suppression of autoimmune arthritis by Celastrus-derived Celastrol through modulation of pro-inflammatory chemokines

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints, deformities, and disability. The prolonged use of conventional anti-inflammatory drugs is associated with severe adverse effects. Therefore, there is an urgent need for safer and less expensive therapeutic products. Celastrol is a bioactive component of Celastrus, a traditional Chinese medicine, and it possesses anti-arthritic activity. However, the mechanism of action of Celastrol remains to be fully defined. In this study based on the rat adjuvant-induced arthritis (AA) model of RA, we examined the effect of Celastrol on two of the key mediators of arthritic inflammation, namely chemokines and their receptors, and related pro-inflammatory cytokines. We treated arthritic Lewis rats with Celastrol (200μg/rat) or its vehicle by daily intraperitoneal (ip) injection beginning at the onset of AA. At the peak phase of AA, the sera, the draining lymph node cells, spleen adherent cells, and synovial-infiltrating cells of these rats were harvested and tested. Celastrol-treated rats showed a significant reduction in the levels of chemokines (RANTES, MCP-1, MIP-1α, and GRO/KC) as well as cytokines (TNF-α and IL-1β) that induce them, compared to the vehicle-treated rats. However, Celastrol did not have much effect on cellular expression of chemokine receptors except for an increase in CCR1. Further, Celastrol inhibited the migration of spleen adherent cells in vitro. Thus, Celastrol-induced suppression of various chemokines that mediate cellular infiltration into the joints might contribute to its anti-arthritic activity. Our results suggest that Celastrol might offer a promising alternative/adjunct treatment for RA.     

Animal models of rheumatoid arthritis

Animal models of arthritis are used to study pathogenesis of disease and to evaluate potential anti-arthritic drugs for clinical use. Therefore morphological similarities to human disease and capacity of the model to predict efficacy in humans are important criteria in model selection. Animal models of rheumatoid arthritis (RA) with a proven track record of predictability for efficacy in humans include: rat adjuvant arthritis, rat type II collagen arthritis, mouse type II collagen arthritis and antigen-induced arthritis in several species. Agents currently in clinical use (or trials) that are active in these models include: corticosteroids, methotrexate, nonsteroidal anti-inflammatory drugs, cyclosporin A, leflunomide interleukin-1 receptor antagonist (IL-1ra) and soluble TNF receptors. For some of these agents, the models also predict that toxicities seen at higher doses for prolonged dosing periods would preclude dosing in humans at levels that might provide disease modifying effects. Data, conduct and features of the various models of these commonly utilized models of RA as well as some transgenic mouse models and less commonly utilized rodent models will be discussed with emphasis on their similarities to human disease.     

Ethno biological usage of zoo products in rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most common autoimmune disorder which causes swelling, redness, pain, stiffness, restriction of limb movements, decreases life expectancy and early death of the patients. Available drugs include non steroidal anti-inflammatory and analgesics, disease modifying anti-rheumatic drugs and steroids (glucocorticoids etc). All these drugs have their own limitations such as gastrointestinal irritations, cardiovascular problems, and drug dependency. Search for alternative therapy from natural products are being ventured throughout the world. Zoo therapy in arthritis, a common practice of the ancient times that have been mentioned in traditional and folk medicine. The scientific basis of some of the zoo products are being explored and have been showing promising results in experimental rheumatoid arthritis. These therapies have minimum side effects and many of them have potential to give rise to drug development clues against rheumatoid arthritis. The present review is an effort to establish the folk and traditional treatment of rheumatoid arthritis using zoo products.     

Anti-inflammatory natural products as potential therapeutic agents of rheumatoid arthritis: A systematic review

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease causing severe locomotor disability and deterioration in the quality of life. Existing treatments for RA mainly focus on the use of immunomodulators and the suppression of synovial inflammation, and many have significant side effects. Medicinal plants are regarded as important alternative sources for treating RA.PurposeThis review summarizes the bioactive compounds of medicinal plants, which have been shown to modulate the immune response by regulating interleukins in vitro and in vivo experimental models, and that may be promising substances for use in the treatment of RA.MethodsArticles on natural products used for the management of arthritis were retrieved from PubMed, Embase, Scopus, and Web of Science through electronic and manual search in English. In total, 576 publications were identified, and 34 were included in this systematic review.ResultsTwo articles presented findings on the role of natural components in the treatment of arthritis in both in vitro and in vivo studies. Nine reports defined the role of plant-derived natural molecules in the treatment of arthritis using cell lines, and 27 in vivo studies assessed the anti-arthritic efficacy and immunomodulation effects of phytoconstituents on interleukin production and inflammatory responses.ConclusionThis systematic review broadly reports that, in contrast to other classes of phytochemicals, flavonoids have the greatest therapeutic potential against arthritis by modulating the expression of pro-inflammatory TNF-α, IL-1β, IL-6, IL-8, and IL-17, as well as anti-inflammatory IL-2 and IL-10 cytokines, through the suppression of dynamic inflammatory biomarkers.     

Proteasome inhibitors as experimental therapeutics of autoimmune diseases

Current treatment strategies for rheumatoid arthritis (RA) consisting of disease-modifying anti-rheumatic drugs or biological agents are not always effective, hence driving the demand for new experimental therapeutics. The antiproliferative capacity of proteasome inhibitors (PIs) has received considerable attention given the success of their first prototypical representative, bortezomib (BTZ), in the treatment of B cell and plasma cell-related hematological malignancies. Therapeutic application of PIs in an autoimmune disease setting is much less explored, despite a clear rationale of (immuno) proteasome involvement in (auto)antigen presentation, and PIs harboring the capacity to inhibit the activation of nuclear factor-κB and suppress the release of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. Here, we review the clinical positioning of (immuno) proteasomes in autoimmune diseases, in particular RA, systemic lupus erythematosus, Sjögren’s syndrome and sclerodema, and elaborate on (pre)clinical data related to the impact of BTZ and next generation PIs on immune effector cells (T cells, B cells, dendritic cells, macrophages, osteoclasts) implicated in their pathophysiology. Finally, factors influencing long-term efficacy of PIs, their current (pre)clinical status and future perspectives as anti-inflammatory and anti-arthritic agents are discussed.     

Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee – A randomized double blind placebo controlled trial

Osteoarthritis is a common, chronic, progressive, skeletal, degenerative disorder, which commonly affects the knee joint. Boswellia serrata tree is commonly found in India. The therapeutic value of its gum (guggulu) has been known. It posses good anti-inflammatory, anti-arthritic and analgesic activity. A randomized double blind placebo controlled crossover study was conducted to assess the efficacy, safety and tolerability of Boswellia serrata Extract (BSE) in 30 patients of osteoarthritis of knee, 15 each receiving active drug or placebo for eight weeks. After the first intervention, washout was given and then the groups were crossed over to receive the opposite intervention for eight weeks. All patients receiving drug treatment reported decrease in knee pain, increased knee flexion and increased walking distance. The frequency of swelling in the knee joint was decreased. Radiologically there was no change. The observed differences between drug treated and placebo being statistically significant, are clinically relevant. BSE was well tolerated by the subjects except for minor gastrointestinal ADRs. BSE is recommended in the patients of osteoarthritis of the knee with possible therapeutic use in other arthritis.     

Sphingosine-1-phosphate: a potential therapeutic target for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, which has as its primary target, the synovial tissues and articular cartilage. The current pharmacological treatment of RA includes non-steroidal anti-inflammatory drugs, corticosteroids, and disease-modifying anti-rheumatic drugs. Newer biological agents that work by inactivation of proinflammatory cytokines are available for treatment of RA. Sphingosine-1-phosphate (S1P) is a bioactive lipid that is generated from phosphorylation of sphingosine by activation of sphingosine kinase, and has been implicated as an important mediator in pathophysiological processes, including cell growth, differentiation, migration and survival, and angiogenesis. Several studies have explored the role of S1P in the pathogenesis of RA. The aim of this article was to review the biology and distribution of S1P, together with its role in RA, and to discuss its potential as a therapeutic target for RA.     

The gastric ulcer protective effect of boswellic acids, a leukotriene inhibitor from Boswellia serrata, in rats

Aim of the study is to evaluate the anti-ulcer efficacy of the boswellic acids (BA), a triterpenoid known as anti-inflammatory/anti-arthritic agent, which is in clinical use. The reason for the study is that, the known non-steroidal anti-inflammatory drugs (NSAIDs) are full of side effects especially ulceration which is at the top. BA, although, used as an anti-arthritic agent yet it is not only devoid of ulcer production but protective also. The activity evaluation was done by the following universally accepted animal models viz., pyloric ligation, ethanol–HCl, acetylsalicylic acid, indomethacin and cold restrained stress-induced ulceration in rats. Results of the present study revealed that BA possess a dose dependent antiulcer effect against different experimental models. It showed different degree of inhibition of the ulcer score towards different ulcerogenic agents. The ulcer score against various ulcer inducing agents viz., pyloric ligation, ethanol/HCl, (acute and chronic) acetylsalicylic acid, indomethacin and cold restraint stress, was inhibited by 39%, 38%, 51%, 31%, 37% and 42% respectively at 250 mg/kg. From the data it is concluded that BA inhibited ulcer production non-specifically in all the experimental models, whereby, it is not possible to propose a single specific mechanism. Nevertheless it is possible that BA might be acting by increasing the gastric mucosal resistance and local synthesis of cytoprotective prostaglandins and inhibiting the leukotriene synthesis.     

In vitro assessment of anti-inflammatory and anti-arthritic effects of Helicanthes elasticus (Desv.) Danser accessions collected from six different hosts

Arthritis and other rheumatoid or non-rheumatoid joint inflammations are prevalent among people all around the world. The plant-derived drugs and other herbal therapeutic practices are widely used against these malfunctions. Helicanthes elasticus (Desv.) Danser, an endemic hemiparasite was found less exploited for these types of disorders and this plant collected from different hosts might be having differential expression towards such ailments. In order to asses this differential expression, in the present study, methanolic extract of Helicanthes elasticus collected from six different hosts were examined for HRBC membrane stabilization assay for anti-inflammatory responses and the protein denaturation method for anti-arthritic assay. Anti-inflammatory and anti-arthritic potential were observed in H. elasticus growing on different hosts. The hemiparasitic plant obtained from Hevea brasiliensis, Nerium oleander and Anacardium occidentale showed high anti-inflammatory responses whereas those from Nerium oleander had high anti-arthritic efficacy. H. elasticus showed a therapeutically significant effect on arthritis and inflammatory responses in humans and the efficacy of the curative property showed variation with respect to the host plant in which the parasite has hemiparasite found growing.     

Wutou decoction ameliorates experimental rheumatoid arthritis via regulating NF-kB and Nrf2: Integrating efficacy-oriented compatibility of traditional Chinese medicine

BackgroundThousands of years of clinical application of Wutou decoction (WTD) support its reliable efficacy and safety in treating rheumatoid arthritis (RA). However, the underlying molecular mechanism remains unclear, and the synergistic involvement of assistant herbs in WTD in enhancing the sovereign herb in treating RA is unknown.PurposeThis study aimed to investigate the efficacy-oriented compatibility of five herbs in WTD and the underlying mechanisms.MethodsThe anti-arthritic effects of WTD and the compatibilities of the five herbs in WTD were studied in vivo with adjuvant-induced arthritis (AIA) rat model and in vitro with LPS-induced RAW264.7 macrophage. Network pharmacology analysis was conducted to identify the dominant pathways involved in the anti-arthritis mechanisms of WTD and how the five herbs work synergistically. The results were further verified by in vivo and in vitro experiments.ResultsOur data revealed that the five herbs in WTD exert synergistic anti-arthritic effects on RA. Moreover, Radix Aconite (AC) is the principal anti-inflammatory component in WTD according to the extent of therapeutic effects exerted on the AIA rats. In vivo and in vitro experiments demonstrated that WTD inhibited NF-κB phosphorylation and simultaneously increased the expression of Nrf2, which were the major pathways identified by the network pharmacology analysis. The major assistant component, Herba Ephedrae (EP), evidently inhibited NF-κB mediated inflammatory response. The other assistant component, Radix Astragali (AS), considerably enhanced the expression of Nrf2 when used alone or in combination with AC. These combinations improved the anti-arthritis effects on the AIA rats better than that of AC alone. Nevertheless, WTD always achieved the best effects than any combinations both in vivo and in vitro.ConclusionThe ministerial herbs EP and AS intensify the anti-arthritic effects of AC by regulating the NF-κB-mediated inflammatory pathway and the Nrf2-mediated anti-oxidation pathway which are the major pathways of WTD for alleviating the symptoms of RA.     

Synthesis and anti-rheumatoid arthritis activities of 3-(4-aminophenyl)-coumarin derivatives

Rheumatoid arthritis is a chronic systemic disease characterised by an unknown aetiology of inflammatory synovitis. A large number of studies have shown that synoviocytes show tumour-like dysplasia in the pathological process of RA, and the changes in the expression of related cytokines are closely related to the pathogenesis of RA. In this thesis, a series of novel 3-(4-aminophenyl) coumarins containing different substituents were synthesised to find new coumarin anti-inflammatory drugs for the treatment of rheumatoid arthritis. The results of preliminary activity screening showed that compound 5e had the strongest inhibitory activity on the proliferation of fibroid synovial cells, and it also had inhibitory effect on RA-related cytokines IL-1, IL-6, and TNF-α. The preliminary mechanism study showed that compound 5e could inhibit the activation of NF-κB and MAPKs signal pathway. The anti-inflammatory activity of compound 5e in vivo was further determined in the rat joint inflammation model.     

The water-soluble fraction of bee venom produces antinociceptive and anti-inflammatory effects on rheumatoid arthritis in rats

We recently demonstrated that bee venom (BV) injection into the Zusanli acupoint produced a significantly more potent anti-inflammatory and antinociceptive effect than injection into a non-acupoint in a Freund's adjuvant induced rheumatoid arthritis (RA) model. However, the precise BV constituents responsible for these antinociceptive and/or anti-inflammatory effects are not fully understood. In order to investigate the possible role of the soluble fraction of BV in producing the anti-arthritic actions of BV acupuncture, whole BV was extracted into two fractions according to solubility (a water soluble fraction, BVA and an ethylacetate soluble fraction, BVE) and the BVA fraction was further tested.Subcutaneous BVA injection (0.9 mg/kg/day) into the Zusanli acupoint was found to dramatically inhibit paw edema and radiological change (i.e. new bone proliferation and soft tissue swelling) caused by Freund's adjuvant injection. BVA treatment also reduced the increase in serum interleukin-6 caused by RA induction to levels observed in non-arthritic animals. In addition, BVA therapy significantly reduced arthritis-induced nociceptive behaviors (i.e. nociceptive scores for mechanical hyperalgesia and thermal hyperalgesia). Finally, BVA treatment significantly suppressed adjuvant-induced Fos expression in the lumbar spinal cord at 3 weeks post-adjuvant injection. In contrast, BVE treatment (0.05 mg/kg/day) failed to show any anti-inflammatory or antinociceptive effects on RA.The results of the present study demonstrate that BVA is the effective fraction of whole BV responsible for the antinociception and anti-inflammatory effects of BV acupuncture treatment. Thus it is recommended that this fraction of BV be used for long-term treatment of RA-induced pain and inflammation. However, further study is necessary to clarify which constituents of the BVA fraction are directly responsible for these anti-arthritis effects.     

Boswellic acids and glucosamine show synergistic effect in preclinical anti-inflammatory study in rats

The present study revealed the synergistic effect of boswellic acid mixture (BA) and glucosamine for anti-inflammatory and anti-arthritic activities in rats. Two studies were conducted, that is, acute anti-inflammatory by carrageenan edema and chronic anti-arthritic by Mycobacterium-induced developing arthritis. Five groups of animals were included in each of the study: the vehicle control, positive control (ibuprofen 100mg/kg), boswellic acids (250 mg/kg), glucosamine (250 mg/kg) and a combination of boswellic acids (125 mg/kg) and glucosamine (125 mg/kg). BA when administered at 250 mg/kg in rats, carrageenan-induced paw edema and Mycobacterium-induced developing arthritis were significantly inhibited. In comparison to boswellic acids, glucosamine when administered at 250 mg/kg showed a mild effect in carrageenan-induced edema and moderate inhibition of paw swelling against developing arthritis. Although the combination of boswellic acids and glucosamine did not affect the acute inflammation to a greater extent yet a significant anti-arthritic activity was observed in rats. In conclusion, a synergistic effect was observed in chronic inflammatory conditions when two chemical entities were administered in combination in preclinical study.     

Beneficial actions of hyaluronan (HA) on arthritic joints: effects of molecular weight of HA on elasticity of cartilage matrix

Hyaluronan (HA) has viscoelastic, anti-inflammatory and protective actions in joint tissues, and is being widely used for treatment of OA and RA patients. However, the mechanisms underlying the pharmacological action of HA on OA and RA have not been fully understood. In this article, we review the molecular weight-dependent, anti-inflammatory actions of HA preparations - produced in Japan - in joint tissues, and show that the molecular weight of HA, but not its concentration, is crucial for maintenance of cartilage elasticity.     

Differential regulation of prostaglandin E2 and thromboxane A2 production in human monocytes: implications for the use of cyclooxygenase inhibitors

There is an autocrine relationship between eicosanoid and cytokine synthesis, with the ratio of prostaglandin E2 (PGE2)/thromboxane A2 (TXA2) being one of the determinants of the level of cytokine synthesis. In monocytes, cyclooxygenase type 1 (COX-1) activity appears to favor TXA2 production and COX-2 activity appears to favor PGE2 production. This has led to speculation regarding possible linkage of COX isozymes with PGE and TXA synthase. We have studied the kinetics of PGE2 and TXA2 synthesis under conditions that rely on COX-1 or -2 activity. With small amounts of endogenously generated prostaglandin H2 (PGH2), TXA2 synthesis was greater than PGE2. With greater amounts of endogenously generated PGH2, PGE2 synthesis was greater than TXA2. Also, TXA synthase was saturated at lower substrate concentrations than PGE synthase. This pattern was observed irrespective of whether PGH2 was produced by COX-1 or COX-2 or whether it was added directly. Furthermore, the inhibition of eicosanoid production by the action of nonsteroidal anti-inflammatory drugs or by the prevention of COX-2 induction with the p38 mitogen-activated protein kinase inhibitor SKF86002 was greater for PGE2 than for TXA2. It is proposed that different kinetics of PGE synthase and TXA synthase account for the patterns of production of these eicosanoids in monocytes under a variety of experimental conditions. These properties provide an alternative explanation to notional linkage or compartmentalization of COX-1 or -2 with the respective terminal synthases and that therapeutically induced changes in eicosanoid ratios toward predominance of TXA2 may have unwanted effects in long-term anti-inflammatory and anti-arthritic therapy.     

The supplementary therapeutic DMARD role of low-dose glucocorticoids in rheumatoid arthritis

The management of rheumatoid arthritis (RA) is primarily based on the use of disease-modifying antirheumatic drugs (DMARDs), mainly comprising synthetic chemical compounds (that is, methotrexate or leflunomide) and biological agents (tumor necrosis factor inhibitors or abatacept). On the other hand, glucocorticoids (GCs), used for decades in the treatment of RA, are effective in relieving signs and symptoms of the disease, but also interfere with radiographic progression, either as monotherapy or in combination with conventional synthetic DMARDs. GCs exert most of their biological effects through a genomic action, using the cytosolic GC receptor and then interacting with the target genes within target cells that can result in increased expression of regulatory - including anti-inflammatory - proteins (transactivation) or decreased production of proinflammatory proteins (transrepression). An inadequate secretion of GCs from the adrenal gland, in relation to stress and inflammation, seems to play an important role in the pathogenesis and disease progression of RA. At present there is clear evidence that GC therapy, especially long-term low-dose treatment, slows radiographic progression by at least 50% when given to patients with early RA, hence satisfying the conventional definition of a DMARD. In addition, long-term follow-up studies suggest that RA treatment strategies which include GC therapy may favorably alter the disease course even after their discontinuation. Finally, a low-dose, modified night-release formulation of prednisone, although administered in the evening (replacement therapy), has been developed to counteract the circadian (night) rise in proinflammatory cytokine levels that contributes to disease activity, and might represent the way to further optimize the DMARD activity exerted by GCs in RA.