Recipient-mediated effect of a traditional chinese herbal medicine,Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to), on hematopoietic recovery following lethal irradiation and syngeneic bone marrow transplantation

Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NYT), a traditional Chinese herbal medicine, was evaluated for recipient-mediated effect on hematopoietic recovery in a murine model of syngeneic bone marrow transplantation (BMT). BALB/c recipient mice were preconditioned with a lethal total body irradiation (TBI) at a dose of 6.5 Gy and transplanted with syngeneic bone marrow (BM) cells. NYT treatments, given intraperitoneally (i.p.) once per day for 3 consecutive days in a dose of 0.625 mg, were performed either before or after TBI and BMT to assess any recipient-mediated effect of this compound. NYT pretreatment was as effective as NYT posttreatment in enhancing the total number of colony-forming unit erythroid (CFU-E) and colony-forming unit granulocyte-macrophage (CFU-GM) per marrow and spleen after TBI and BMT. NYT pretreatment caused a significant increase in marrow and splenic CFU-E and CFU-GM numbers over a prolonged period following TBI and BMT, and affected late-stage erythropoiesis (CFU-E) more profoundly than early-stage erythropoiesis (burst-forming unit erythroid, BFU-E). NYT pretreatment significantly accelerate recovery of not only erythrocyte and leukocyte counts but also platelet counts after transplantation with a limited number (1 × 10⁵) of BM cells. The same treatment, however, was significantly less effective in hematopoietic recovery after transplantation with a minimal number (1 × 10⁴) of BM cells, indicating that NYT accelerates recovery of donor-derived rather than recipient-derived cells. The data are consistent with the idea that NYT has an enhancing effect on hematopoiesis via the recipient microenvironment, and suggest that NYT may have an important role in the acceleration of hematopoietic recovery of donor-derived cells following BMT.     

Influence of prednisolone andl-thyroxine on the changes in collagen metabolism in rats with adjuvant-induced arthritis

In rats with adjuvant-induced arthritis the effects of prednisolone andl-thyroxine on the changes in collagen metabolism were investigated both in the skin and tendon during the acute and chronic phase of the arthritis. In untreated animals with adjuvant-induced arthritis, a decrease in the collagen synthesis accompanied by an increase in the catabolism of collagen and a retardation in the conversion of soluble to insoluble collagen were noted both in the skin and tendon during the course of the disease. Prednisolone was found to accelerate the conversion of soluble to insoluble collagen and to inhibit the enhanced catabolism of collagen in rats with adjuvant-induced arthritis.l-Thyroxine accelerated the conversion of soluble to insoluble collagen in adjuvant-induced arthritic rats more effectively than prednisolone but was less effective with regard to the inhibition of enhanced catabolism of collagen. However, the synthesis of collagen in adjuvant-induced arthritis was improved by both prednisolone andl-thyroxine.     

The effect of immunomodulating drugs on adjuvant-induced arthritis in Lewis rats

The purpose of this study was to investigate the effects of cyclosporine A (CSA) and methotrexate (MTX) as potential immunomodulators in a nonestablished adjuvant arthritis (AA) model. Non-injected hind paw volumes were reduced when AA rats were treated for 18 dayswith CSA (100% at 10 mg/kg) or MTX (100% at 0.1 mg/kg). Body weights of drug treated AA rats were increased above untreated AA rats and were similar to non-arthritic controls. AA rats show elevated T helper (W3/25⁺)/T suppressor (OX 8⁺) cell ratios (2.0 vs. 3.1,p<0.01). The immunomodulators tested all returned these elevated ratios to control non-arthritic levels. Similarly, these drugs returned the reduced mitogen responses and elevated blood granulocyte numbers toward normal non-arthritic control values.     

Diet and adjuvant-induced arthritis in the rat

Rats fed a high carbohydrate or a high protein diet deficient in copper, magnesium or zinc, or in the three trace elements together, failed to develop adjuvant-induced arthritis, yet a deficiency of both copper and magnesium in the diets exhibited no such inhibition. On the other hand, only a magnesium deficiency reduced the severity of the dextran anaphylactoid reaction.     

Treatment effect of a traditional Chinese medicine,Ren-shen-yang-rong-tang (Japanese name: Ninjin-Youeito), on autoimmune MRL/MP-lpr/lpr mice

MRL/Mp-lpr/lpr(MRL/lpr) mice were treated with a traditional Chinese herbal medicine, Ren-shen-yang-rong-tang (Japanese name: Ninjin-youei-to, NYT) intraperitoneally (i.p.) every 3 days or per os (p.o.) 6 times/week from before the onset of autoimmune disease (6 weeks of age). Fifty percent survival time was found in placebo-controlled male and female mice of 28 and 22 weeks of age, respectively. NYT-treatment markedly prolonged the survival time of MRL/lpr mice. That is, 50% survival time was 43 weeks in the i.p.-treated male mice and 30 weeks of age in the p.o.-treated female mice. Further, NYT-treatment significantly reduced occurence of thymic atrophy and prevented the anomalous accumulation of B220⁺ T-cells in lymphnode and spleen, both of which are characteristic in MRL/lpr mice. Moreover, grades of proteinuria were significantly reduced in both the i.p.- and p.o.-treated groups compared with the control groups. Such clinical benefit and increased survival time were interestingly not associated with the decrease in the level of autoantibodies.     

Cis-dichlorodiammineplatinum (II): Suppression of adjuvant-induced arthritis in rats

Cis-Dichlorodiamminepaltinum(II) (cis-PtII) suppressed adjuvant-induced arthritis in rats as assessed by paw volume, paw temperature, and microscopic appearance. Treated animals incurred lymphocytopenia and thymic atrophy. Paws from a number of rats with arthritis which were treated withcis-PtII showed focal bone marrow congestion and hemorrhages not found in rats with untreated arthritis.     

The effects of Enterococcus faecium and selenium on methotrexate treatment in rat adjuvant-induced arthritis

The effects of probiotic bacteria Enterococcus faecium (EF) and selenium were studied on methotrexate (MTX) treatment in rats with adjuvant arthritis (AA). Arthritic rats were preventive treated orally with the following substances: lyophilized EF (15mg/kg/day, 5 days a week); sodium selenite pentahydrate (SSe, 0.050mg/kg containing 0.015 mg/kg selenium, 5 days a week); MTX (0.6 mg/kg/week), and their combinations for the period of 50 days from adjuvant application. Levels of serum albumin, serum nitrite/nitrate concentrations, hind paw swelling, arthrogram scores, whole body bone mineral density (BMD), and bone erosions were evaluated as markers of inflammation and destructive changes associated with arthritis. Long-term preventive treatment with low-dose MTX significantly inhibited the markers of both inflammation and arthritis. EF or SSe when administered singly or in combination had no significant effect on given parameters in arthritic rats. EF but not SSe potentiated the beneficial effects of MTX, which resulted in a more significant reduction of hind paw swelling, arthrogram scores and whole body BMD decrease. EF had a tendency to improve also the effect of MTX on serum albumin and nitrite/nitrate concentrations. Our results indicate that EF may increase the preventive effect of MTX treatment in rat AA by improving its anti-inflammatory and anti-arthritic effects.     

PECAM-1 and leukosialin (CD43) expression correlate with heightened inflammation in rat adjuvant-induced arthritis.

A hallmark of both adjuvant-induced arthritis (AIA) and rheumatoid arthritis is chronic joint inflammation characterized by ingress of leukocytes into the inflamed synovial tissue. The timing of expression of adhesion molecules, which govern the ingress of leukocytes, is important in the orchestration of an inflammatory response. We examined the expression of vascular cell adhesion molecule-1 (VCAM-1), sialo adhesin, platelet and endothelial cell adhesion molecule-1 (PECAM-1), and leukosialin (CD43) in AIA, starting at adjuvant injection (day 0), through the peak of inflammation (day 18 postadjuvant injection), until day 54. VCAM-1 is constitutively expressed on the lining layer and ECs and its expression levels do not change throughout the progression of AIA. Sialoadhesin synovial tissue lining cell expression is decreased after adjuvant injection. In contrast, PECAM-1 expression is increased on synovial tissue lining cells on day 7 and is elevated through day 54 (peaking on day 54 with six-fold more cells expressing PECAM-1). PECAM-1 expression on endothelial cells peaks on day 7 with three-fold more cells expressing it, while on macrophages expression maximizes on day 25 with six-fold more cells expressing PECAM-1. CD43 expression is increased on synovial tissue lining cells, macrophages, neutrophils, and lymphocytes on days 18 and 25, before going back to basal levels. The increased expression of PECAM-1 and CD43 on leukocytes at the height of inflammation in AIA suggests important roles for these adhesion molecules in potentially binding their EC ligands resulting in leukocyte ingress into the synovial tissue.     

Effects of bisphosphonates on joint damage and bone loss in rat adjuvant-induced arthritis

Objective and design: Examination of the effects of bisphosphonates on joint damage and generalized bone loss.Materials: Adjuvant-arthritis was induced by injection of Mycobacterium butyricum into the footpad of the right hind paw of Lewis rats (8 animals/group) on day 0.Treatment: Arthritic rats were treated with the vehicle (saline), etidronate or alendronate (subcutaneously, daily 5 times a week for 3 weeks from day 1 to day 21). Experiment-1: Etidronate (0.1, 0.5, 2.5, 12.5 mg/kg) or alendronate (0.02, 0.1, 0.5, 2.5 mg/kg), Experiment-2: Etidronate (2.5, 5, 10mg/ kg) or alendronate (0.001, 0.01, 0.1 mg/kg).Methods: In the adjuvant-injected side of the hind limbs, paw swelling was evaluated at 1-week intervals, and bone mineral density (BMD) in the proximal tibia, histopathology and radiographical findings in the tibio-tarsal region were evaluated at the time of sacrifice (on day 21).Results: In all treatment schedules, both bisphosphonates significantly prevented paw swelling and bone loss. Alendronate reduced paw swelling at higher doses (over 0.1 mg/ kg) compared with its effect on BMD decrease (over 0.001 mg/kg). In contrast, etidronate reduced paw swelling and joint damage at doses similar to those (over 2.5 mg/kg) prevented BMD decrease.Conclusions: Both etidronate and alendronate are effective in reducing arthritic damage, but their effective dose ranges for inflammatory responses and BMD decrease clearly differ; i.e., the etidronate dose ranges for anti-inflammatory and anti-resorptive effects are similar, whereas the dose range for anti-inflammatory effects of alendronate is 100-fold higher than that for its anti-resorptive effects.Received 21 January 2003; returned for revision 14 July 2003; accepted by M. Katori 15 August 2003     

Chai-ling-tang (Japanese name: sairei-to) as an oral adjuvant.

Immunomodulating and anti-tumor activities of orally administered Chai-Ling-Tang (Japanese name: sairei-to, ST) were investigated. The oral administration of ST into mice augmented the antibody response to intraperitoneally administered 2, 4, 6-trinitrophenyl-haptenated sheep red blood cells (TNP-SRBC). Orally administered ST showed also an enhancing effect on the antibody response to TNP-SRBC administered by the oral route. In addition, orally administered ST markedly activated the peritoneal macrophages to enhanced phagocytic and lysosomal enzyme activities. A significant inhibition of tumor growth was observed in a syngeneic tumor-mouse system when ST was administered orally. These results suggest that ST has an efficiency as an oral adjuvant or an oral biological response modifier (BRM).     

The local anti-inflammatory activity of rimexolone (Org 6216) in fibrin-induced monoarticular arthritis and adjuvant-induced arthritis

The effects of a number of steroids administered intra-articularly in a chronic model of fibrin-induced monoarticular arthritis in the rabbit have been investigated. Org 6216, hydrocortisone acetate, prednisolone tertiary butyl acetate and triamcinolone hexacetonide each suppressed the joint swelling produced 14 days after antigen challenge. These anti-inflammatory effects lasted for at least 7 days. Hydrocortisone semisuccinate was inactive in this model.In addition, the effects of the same compounds and several other anti-inflammatory steroids and indomethacin administered locally with adjuvant was assessed on the resultant paw oedema produced in the rat. The local anti-inflammatory activity, the duration of action and the systemic effects of these drugs varied considerably and only Org 6216, hydrocortisone acetate, prednisolone tertiary butyl acetate and indomethacin produced anti-inflammatory effects throughout the 4 days of the experiments and were devoid of significant adrenolytic and thymolytic activity.     

Meloxicam: A potent inhibitor of adjuvant arthritis in the Lewis rat

The effects of meloxicam, piroxicam, diclofenac and tenidap on the swelling of hind paws, radiologically-detectable bone and cartilage destruction of hind paws, increase in spleen weight, increase in erythrocyte sedimentation rate and changes in serum protein composition in male Lewis rats with adjuvant arthritis were studied following once-daily oral administration of these drugs for 21 days. All the drugs dose-dependently inhibited hind paw swelling. For equal activity against hind paw swelling caused by the secondary reaction, the required daily dose of piroxicam was about twice that of meloxicam; those of diclofenac and tenidap were about 3.5 and 60 times higher respectively. The bone and cartilage destruction induced by adjuvant arthritis were inhibited by meloxicam at low daily doses and by piroxicam at doses approximately four times those of meloxicam. Diclofenac and tenidap had only a weak effect on radiologically-detectable lesions when administered at doses sufficient to reduce paw swelling. Meloxicam also had a dose-dependent corrective effect on the systemic changes which occur in adjuvant arthritic rats, e.g. increase in spleen weight, increase in erythrocyte sedimentation rate and changes in serum protein composition. Piroxicam produced similar effects, at 3–4 times higher doses. Diclofenac and tenidap did not show comparable effects when administered at appropriate doses. These findings indicate that the action of meloxicam and piroxicam differs from that of diclofenac and tenidap in adjuvant arthritis in the Lewis rat. At oral doses which significantly reduce edema formation, only meloxicam and piroxicam showed a significant effect on systemic parameters of adjuvant disease in the Lewis rat.     

Effect of (+)-cyanidanol-3 (Catergen) in chronic active hepatitis. (Catergen plus prednisolone versus prednisolone in a controlled study)

Thirty-six patients with biopsy-proved chronic active hepatitis (CAH) were randomized. Of these 18 patients, 15 of them HBsAg and/or anti-HBc positive, received (+)-cyanidanol-3 (Catergen, Zyma) in doses of 1.5 g daily for 6 months in addition to the previously started low dose (10-15 mg/day) prednisolone. The other 18 patients, 16 of them HBsAg and/or anti-HBc positive, continued on the former corticosteroid treatment exclusively. After 6 months an overall clinical-biochemical improvement was noted in 10 cyanidanol-treated and in 6 control patients, while the condition deteriorated in 4 drug-treated and 8 control subjects. Serum GPT activity decreased to less than twice the normal in 12/16 drug-treated and in 7/13 control subjects, gamma-GT fell to normal in 7/16 cyanidanol-treated and in 1/10 control patients, IgG fell to normal in 4/8 drug-treated and in 1/9 control patients who all had initially elevated values. The percentage of "active" E-rosette forming cells fell in both groups but the decrease was significant only in the control cases, i.e. cyanidanol inhibited the progressive fall in circulating T cells during the course of the disease. Lymphocyte proliferative response to phytohaemagglutinin stimulation, as measured by 3H-thymidine incorporation, significantly increased in the cyanidanol group. Anti-HBs titres were markedly raised in 7/15 drug-treated and in 2/16 control patients. Thus, cyanidanol had some slight beneficial effect on biochemical liver function tests and the immunological activity in CAH patients. Its use may be recommended as an adjuvant constituent of the complex therapy of the disease.     

Effect of antiserotonin antibodies on pain sensitivity in rats with adjuvant-induced arthritis

Active immunization with a serotonin—protein conjugate inducing the formation of antiserotonin antibodies exerts an analgesic effect in rats with adjuvant-induced arthritis and inhibits the development of arthritis in early stages after injection of Freund's complete adjuvant. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 9, pp. 292–295, September, 1997     

Effects of a protein kinase C inhibitor (PKCI) on the development of adjuvant-induced arthritis (AA) in rats

Inflammation Research -     

FK506 is superior to methotrexate in therapeutic effects on advanced stage of rat adjuvant-induced arthritis

OBJECTIVE AND DESIGN: The anti-arthritic properties of FK506 were compared with methotrexate (MTX) in established adjuvant-induced arthritis (AIA) in rats. MATERIAL: Female Lewis rats. TREATMENT: Arthritic rats were orally administered with FK506 (1-5.6 mg/kg) and MTX (0.1-1 mg/kg) from days 15-24. METHODS: Arthritis was induced by injection of Mycobacterium tuberculosis into the right hind footpad on day 0. Efficacy was determined on the basis of paw inflammation measured by paw volume and histological change, hyperalgesia and grip strength. Grip strength measurement was employed as an indication of function of paws in arthritic rats. Peripheral white blood cell (WBC) counts and thymus weights were measured, mainly as indicators of toxic side effects. RESULTS: FK506 suppressed paw inflammation and hyperalgesia without toxic effects on WBC and thymus in established AIA. MTX slightly suppressed paw inflammation and hyperalgesia at the highest dose (1 mg/kg). Toxic effects were observed at lower doses than the effective treatment dose with MTX. Grip strength was found to decrease during development of AIA. FK506, but not MTX, treated rats recovered grip strength loss. CONCLUSIONS: The results show that FK506 is more effective and less toxic than MTX in treating established AIA in rats.     

Effects of acute and chronic prednisolone treatment on serum zinc levels in rats with adjuvant arthritis

Several studies in animals and humans have independently demonstrated that zinc metabolism is significantly affected either by inflammation or by glucocorticoid administration. The relative importance of these two factors was assessed in this study by the investigation of the effects on serum zinc concentrations of acute and chronic prednisolone treatments in adjuvant arthritis rats and in healthy controls animals. Acute steroid administration (3 mg/kg, i.p.) caused a rapid drop in serum zinc followed by a quick recovery, regardless to the fact that these concentrations were normal (healthy animals) or already reduced by the inflammatory process. However, the modification occurred faster in inflamed animals. Chronic steroid administration (0.58 to 0.78 mg/kg/day during 1 to 4 weeks) had a more complex effect. A previous experiment in healthy rats demonstrated that such a treatment only induced a slight decrease in serum zinc. In adjuvant arthritis animals, the early steroid treatment of the induced process promoted a further decrease in serum zinc level while a delayed treatment did not result in additional changes.     

Anti-inflammatory and immuno-modulatory effects of novel retinoidlike 2,4,6,8-nonatetraenoic acids (NTA) in adjuvant-induced arthritis

Prophylactic treatment (p.o.) of rats with adjuvant-induced arthritis (AA) with two retinoid-like 2,4,6,8-nonatetraenoic acids (NTA), Ro 23-6457 and Ro 23-2895, significantly reduced hind paw swelling between days 10–23 and the level of plasma fibrinogen (MED 25 moles/kg). When given therapeutically (75 moles/kg between day 21 and 28) either NTA arrested the progression of the disease (MED, 25–75 moles/kg).Unseparated and adherent cell (AC) depleted spleen cells from rats with AA (day 12–15) responded poorly to the T cell mitogen, Con A (2.5 g/ml) and the B cell mitogen, LPS (10 g/ml). The responses were partially restored (30% of normal responses) in AC-depleted (but not unseparated) spleen cells from Ro 23-6457 treated rats (75 and 250 moles/kg/day). These data demonstrate an immunomodulatory effect of Ro 23-6457 in the adjuvant rat which may contribute to its anti-inflammatory activity in AA.