Suppression Of Adjuvant Arthritis Research Articles

Suppression of adjuvant arthritis by hesperidin in rats and its mechanisms

The citrus flavonoid hesperidin has been reported to possess a wide range of pharmacological properties. We have investigated the preventive and therapeutic effects of hesperidin on the development of adjuvant arthritis (AA), a rat model of rheumatoid arthritis (RA). Freund's complete adjuvant was used to induce AA in rats. Secondary paw swelling, polyarthritis index and histopathological assessment of ankle joints were used to evaluate the effects of hesperidin on AA rats. Concanavalin-A-induced T-lymphocyte proliferation and interleukin (IL)-2 production by splenocytes were measured using the MTT assay. Levels of IL-1, IL-6 and tumour necrosis factor (TNF)-alpha secreted by peritoneal macrophages (PM) were measured by RIA. Intragastric administration of hesperidin significantly attenuated secondary paw swelling and reduced the polyarthritis index of AA rats in a dose-dependent manner. In addition, hesperidin clearly ameliorated the pathological changes in AA rats. Hesperidin also restored the suppression of T-lymphocyte proliferation and IL-2 production, and downregulated production of IL-1, IL-6 and TNF-alpha by PM in AA rats. Our results suggest that hesperidin improves AA by downregulating the function of over-active macrophages and by up-regulating the activities of dysfunctional T lymphocytes. Hesperidin may therefore have therapeutic value for the clinical treatment of RA. Further research is required to clarify the detailed mechanisms of the protective effects of hesperidin on AA.

Suppression of adjuvant arthritis in rats with chronic bromocriptine treatment does not prevent associated oxidative stress.

We studied the effect of prolactin (PRL) inhibition by bromocriptine (BRC) in the first phase of adjuvant induced arthritis (AA), up to day 11(BRCl-AA), and in the whole time course of AA, up to day 23 (BRC-AA), on the development of the disease in male Lewis rats. On day 24, arthritic rats showed inhibition of PRL secretion, but not PRL mRNA expression in adenopituitaries. BRC treatment suppressed PRL serum levels and PRL mRNA expression in adenopituitaries. In BRC/-AA group PRL levels and PRLmRNA were at the level of rats with AA. Serum corticosterone (CORT) was stimulated by AA from 16.9+/-5.8 to 59.1+/-8.7 ngml(-1), p<0.05, to the same level in BRC-control (BRC-C) and BRC-AA group and further potentiated in BRCI-AA group (148.2+/-33.1 ngml(-1), p<0.05 vs. group with AA). Hind paw swelling was reduced but not completely inhibited in BRC1-AA group and totally prevented in BRC-AA rats as was the core temperature (36.5+/-0.1 degrees C vs. 37.4+/-.0.1 degrees C in AA rats on day 23, p<0.01). Serum concentration of NO-ZNO-3 rose in rats with AA to 28.7+/-2.5 &mgr;mo1L-1 against. 13.9+/-1.9 &mgr;molL(-1) in controls (p<0.01), remained elevated in BRC-AA group and was potentiated in BRC1-AA group (48.2+/-3.5 &mgr;mol(-1), p<0.01 vs. AA or BRC1-AA group) Thiobarbituric acid reactive substances (TBARS) and antioxidant capacity in the spleen were enhanced in rats with AA and to the same extent in BRC-AA or BRC1-AA groups. These results show a discrepancy between the suppression of clinical symptoms and persisting oxidative stress in AA rats after the BRC induced PRL inhibition. The potentiation of nintric oxide (NO-) production after the sudden cessation of PRL inhibition during the disease may promote further joint damage.

Suppression of adjuvant arthritis and synovial macrophage inducible nitric oxide by N-iminoethyl-L-ornithine, a nitric oxide synthase inhibitor.

Nitric oxide (NO.) is a pro-inflammatory effector molecule in certain inflammatory diseases, including arthritis. We investigated the production of NO. by adjuvant arthritis (AA) synovial macrophages, and studied the effects of a NO. synthase inhibitor. N-iminoethyl-L-ornithine (L-NIO). Compared to control rats, rats treated with L-NIO in vivo exhibited significantly lower articular index (p < 0.05), paw volume (p < 0.05), and synovial fluid cell count (p < 0.05). No effect on cutaneous delayed-type hypersensitivity to the disease-initiating antigen was observed. Inducible NO. synthase (iNOS) was detected in AA synovial macrophages, and cultured AA synovial macrophage iNOS levels were increased by a factor of 138 +/- 17% (p < 0.01) by 1 microgram/ml LPS in vitro. Constitutive NO. production by AA synovial macrophages (43 +/- 1 nmol/10(5) cells/24 h) was significantly inhibited by 10 nM L-NIO in vitro (32 +/- 0.5, p < 0.01). NO. production induced by 1 microgram/ml LPS (48 +/- 2) was also decreased by L-NIO (39 +/- 2, p < 0.05). In vivo L-NIO treatment also inhibited alveolar macrophage NO. production (p < 0.05). The ability of L-NIO to decrease iNOS-mediated synovial macrophage NO. production and inhibit the clinical parameters of AA implicate macrophage-derived NO. in the pathogenesis of this disease.

Suppression of adjuvant arthritis in rats by induction of oral tolerance to mycobacterial 65-kDa heat shock protein.

Oral administration of mycobacterial 65-kDa heat shock protein (HSP) given daily for 5 days prior to immunization with Mycobacterium tuberculosis (Mt) suppressed the development of adjuvant arthritis (AA) in rats. AA was significantly suppressed by 30 and 300 micrograms HSP, and variably by 0.3, 3 micrograms or 1 mg. Histological analysis of joint samples obtained from control and test rats confirmed the suppression of AA in the fed group. Feeding Mt or hen egg lysozyme (HEL) failed to affect AA, indicating that the suppression was HSP specific. The oral administration of 30 micrograms HSP decreased both delayed-type hypersensitivity (DTH) reactions and proliferative responses to HSP and Mt. In addition, the proliferation of lymph node cells (LNC) from Mt-sensitized rats was inhibited by the addition of spleen cells (SPC) from HSP-fed animals, possibly by the secretion of transforming growth factor (TGF)-beta. Spleen cells obtained from tolerized donors were capable of transferring the tolerance to naive recipients. These results demonstrate that feeding HSP is an effective way to suppress AA and that the suppression of AA may be mediated by regulatory T cells generated following oral administration of mycobacterial 65-kDa HSP.

Suppression of adjuvant arthritis by k-opioid receptor agonist: Effect of route of administration and strain differences

It is well established that k-opioid receptor agonists exert antiinflammatory and antihyperalgesic effects during nonspecific inflammation as well as suppressive effects on the development of humoral and cell-mediated immune responses to foreign antigens. The aim of this study was to investigate the ability of the k-opioid receptor agonist MR 2034 to modulate adjuvant arthritis in the rat. In the first series of experiments, treatments of Wistar rats were performed using several routes of drug administration: intraperitoneal (ip), intracaudal (ic), intracerebroventricular (icv) and intraplantar (ipl). MR 2034 significantly suppressed joint swelling after ip and ic treatment, slightly reduced inflammation after ipl treatment, and did not produce any effect after icv treatment. In the second series of experiments, the suppressive effect of ip injected MR 2034 was investigated using Wistar, Dark August (DA) and Lewis rats. In Wistar rats, MR 2034 significantly decreased the incidence of adjuvant arthritis, and suppressed mean joint score and aggregate joint score. Similarly, in DA rats treated with MR 2034, mean arthritic score was significantly suppressed, but other clinical parameters were not affected. In Lewis rats, however, ip treatment with MR 2034 failed to produce any suppressive effect on joint disease and even potentiated the initial development of arthritis. These data suggest that immunosuppressive and antiinflammatory action of MR 2034 markedly depend on the route of drug administration and strain susceptibility to opioids.

Suppression of the development of adjuvant arthritis by a conditioned aversive stimulus

The present study evaluated the effect of a conditioned aversive stimulus (CS) on the development of adjuvant-induced arthritis in Lewis rats. Experiment 1 showed that presentation of a CS, on days 12, 14, and 16 following injection with adjuvant containing mycobacterium tuberculosis, resulted in a pronounced suppression of the development of arthritis as measured by a clinical disease severity rating scale and spleen weight. In contrast, presentation of the CS on days 0, 2, and 4 following injection did not have any effect on the development of arthritis. Experiment 2 showed that the suppression of adjuvant arthritis by exposure to the CS was blocked by administration of propranolol, a nonselective β-adrenergic receptor antagonist. These results demonstrate that a CS can alter the development of adjuvant-induced arthritis, but the effect is dependent upon the timing of the antigen exposure and the presentation of the CS. Moreover, the present findings suggest that blocking β-adrenergic receptors during presentations of the CS prevents the suppressive effect of the CS.

Suppression of adjuvant arthritis in Lewis rats by oral administration of type II collagen.

Adjuvant arthritis is induced by intradermal injection of Mycobacterium tuberculosis (MT) in oil. The role of immunity to type II collagen (CII) in adjuvant arthritis (AA) has not been well defined. We found that oral administration of chicken CII given 3 micrograms per feeding on days -7, -5, and -2 before disease induction consistently suppressed the development of AA. A decrease in delayed-type hypersensitivity responses to CII was also observed that correlated with suppression of AA. AA was optimally suppressed by 3 and 30 micrograms of collagen type II variably by 300 micrograms, and not by 0.3 microgram or 1 mg. Oral administration of collagen type I also suppressed AA; only minimal effects were seen with collagen type III. Suppression was Ag specific: feeding CII did not suppress experimental autoimmune encephalomyelitis; feeding myelin basic protein suppressed experimental autoimmune encephalomyelitis, but not AA. Suppression of AA could not be consistently obtained by feeding MT. Suppression of AA could be adoptively transferred by T cells from CII fed animals and could be obtained when CII was fed after disease onset. Our results suggest that autoimmunity to CII has a pathogenic role in AA and raise the possibility that cross-reactive epitopes exist between CII and MT. Alternatively, the pathogenesis of AA may be dependent on developing immunity to CII. These results further demonstrate the effectiveness of oral tolerance as a means to suppress experimental autoimmune diseases.

Suppression of Adjuvant Arthritis in Rats by Cholesterol

Dietary cholesterol suppressed adjuvant arthritis, a chronic inflammatory disease, in rats, but did not significantly affect carrageenin edema, an acute inflammation. When rats were fed a high-cholesterol diet beginning 10 days before injection of adjuvant, the development of the adjuvant-induced arthritis was greatly suppressed. Cholesterol feeding prevented hypertrophy of the adrenal gland in arthritic rats, but had little influence on the serum corticosterone level. A significant positive correlation was observed between the adrenal weight and the severity of the arthritis. These findings suggest that the effect of cholesterol feeding is not due to increased adrenal sterol synthesis. Dietary cholesterol also prevented hypertrophy of the spleen, but had no effect on atrophy of the thymus in adjuvant-treated rats. Cholesterol-fed rats showed a significant decrease in the serum lipid peroxide level and a significant increase in the serum copper level. Adjuvant treatment not only enhanced hypercholesterolemia produced by cholesterol feeding, but also the level of free cholesterol in serum. These results suggest that dietary cholesterol may exert some effect on the immune response through changes in spleen and liver functions.

Suppression of adjuvant arthritis and other inflammatory lesion by aminomethyl cyclohexane carboxilic acid derivative (AMA-60) . Fundmental study on it's antiinflammatory and immunomodurative effect

Suppression of adjuvant arthritis and other inflammatory lesion by aminomethyl cyclohexane carboxilic acid derivative (AMA-60) . Fundmental study on it's antiinflammatory and immunomodurative effect

A novel antiarthritic agent, CCA (Lobenzarit disodium), and the role of thymus-derived lymphocytes in the inhibition of rat adjuvant arthritis

Lobenzarit disodium (CCA) has been reported to have an inhibitory effect on the development of adjuvant arthritis (AA) in rats. Earlier studies have suggested that the therapeutic effect of CCA might be based on its immunoregulatory activity, although the precise mechanisms of action are unclear. In this paper, possible involvement of thymus-derived lymphocytes in the suppression of AA was studied. It was found that CCA failed to inhibit the development of AA in rats whose T lymphocytes were depleted by the injection of rabbit antithymocyte serum (ATS), whereas the same schedule of treatment with CCA significantly suppressed AA developed in control rats which were injected with normal rabbit serum. In addition, adult thymectomy abrogated the antiarthritic effect of CCA. These data suggest the possibility that the therapeutic effect of CCA in AA might be mediated by ATS-sensitive, short-lived, thymus-derived lymphocytes.

A pharmacological study of the anti-inflammatory activity of Chinese herbs. A review.

A considerable number of Chinese medical herbs have been found to be anti-inflammatory upon screening for the inhibition of acute inflammation and allergic reaction, and for the suppression of adjuvant arthritis. Most of this research has been published exclusively in Japanese, and consequently is little known internationally. In this review, we will introduce the most recent conclusions drawn from current pharmacological research on the anti-inflammatory action of various Chinese medicinal herbs being undertaken in Japan. Due to limitations of space, we mention only herbs showing anti-inflammatory activity in vivo when administered intra-orally, and having low toxicity. We will also introduce some popular Chinese medical prescriptions used in the treatment of arthritis, hepatitis and nephritis and attempt to explain their anti-inflammatory action resulting from the synergistic action of the herbs contained in these prescriptions. All references cited in this review were either written originally in English or have an English abstract.

Suppression of adjuvant arthritis by antibodies specific for collagen type II.

Immunization of Lewis rats with an alum flocculate of collagen type II, prior to the induction of arthritis by an intradermal injection of Mycobacterium butyricum in oil, caused reduced arthritic responses when compared with non-pretreated control animals. The majority of collagen-immunized animals that expressed diminished disease possessed low levels of serum antibody to collagen type II whereas most rats with undiminished disease did not. Passive immunization of Lewis rats with antibody to collagen type II also effectively reduced the severity of adjuvant-induced arthritis. Two possible mechanisms that might explain suppression of this disease by antibodies to collagen type II are discussed.

Mechanisms underlying the suppression of adjuvant-induced arthritis by 6-mercaptopurine.

Daily oral administration of 6-mercaptopurine suppressed the development of the secondary (immune) lesions of adjuvant arthritis in a dose-related manner. The degrees of arthritis suppression corresponded closely to suppressions of concurrent development of the humoral and the cellular immune response to El4 cells. A short course of therapy during the sensitization period (day - 1 to day 5 when the day of adjuvant injection is designated as day 0) appeared to be almost as effective as continued daily dosing (day - 1 to day 15). The drug did not influence the development of the primary (nonimmune) lesions of adjuvant arthritis at all dosage levels investigated. Chronic pretreatment with 10 mg/kg/day PO for 17 days had no effect on the development of carrageenin-induced acute inflammation in the rat. The suppression of adjuvant arthritis by 6-mercaptopurine, unlike suppression by cyclophosphamide, appears to result primarily from its suppressive action on the immune response.

Suppression of adjuvant arthritis by infection with a strain of the rodent malaria parasite Plasmodium berghei.

Suppression of adjuvant arthritis by infection with a strain of the rodent malaria parasite Plasmodium berghei.

Suppression of adjuvant arthritis by estrone in adrenalectomized and ovariectomized rats.

Die Adjuvans-Arthritis konnte durch Ostrontherapie gehemmt werden auf gleiche Weise bei intakten Ratten wie bei Ratten nach bilateraler Adrenalektomie, Ovariektomie oder nach Adrenal- und Ovariektomie. Bei hypophysektomierten Tieren (ohne Ostrontherapie) war das Krankheitsbild bedeutend milder als bei intaken Kontrollratten.