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.     

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.     

The pharmacologic evaluation of locomotor activity versus inflammatory parameters in rat adjuvant arthritis

Adjuvant-induced arthritis (AA) is an experimental model of inflammatory joint disease in the rat which mimics rheumatoid arthritis. Although paw inflammation (e.g., swelling) is commonly used to monitor the efficacy of antiarthritic drugs, a reduction in locomotor function may provide a more sensitive evaluation of functional disability in AA rats. The purpose of the present study was to investigate the effect of dietary therapy with prednisolone or ibuprofen on locomotor activity as well as arthritic symptoms in established AA (days 20–42). AA rats demonstrated an increase in arthritis scores, spleen weights, fibrinogen, and WBC along with a reduction in locomotor function. Prednisolone (2 mg/kg/day) exhibited a positive therapeutic effect on all these parameters. Ibuprofen (50 mg/kg/day) consistently lowered arthritis scores and fibrinogen; however, locomotor function only improved on day 35. In conclusion, the measurement of locomotor activity in concert with other experimental parameters may provide a more meaningful evaluation of disease severity or improvement in AA.     

Differential effects of methotrexate and liposomally conjugated methotrexate in rat adjuvant-induced arthritis.

In this study we evaluated the comparative efficacy of free and liposomally conjugated methotrexate on both disease induction and suppression of acute inflammation in rat adjuvant-induced arthritis. Rats were given either empty liposomes (E-LIPO), free methotrexate (MTX) or the liposomally conjugated methotrexate (MTX-LIPO) at a dose of 100 micrograms/day for 7 consecutive days by the intravenous route. When MTX treatment was initiated on the day of arthritis induction the drug suppressed but did not abolish the development of joint inflammation. Free MTX had no significant anti-inflammatory effect upon an established arthritis when dosing was commenced on day 11 post-adjuvant induction. Conversely, MTX-LIPO did not affect the progression of the arthritis when dosing was started on day 0, but exerted a significant anti-inflammatory effect on an established arthritis. MTX-LIPO treatment was significantly less haematotoxic than free MTX.     

Immunosuppressive acidic protein (IAP) level used to monitor adjuvant arthritis in rats.

To determine if immunosuppressive acidic protein (IAP) responds to the degree of inflammation in adjuvant arthritis in rats (AA), we measured the serum IAP level of the rats by using the single immunodiffusion method, and the level of concanavalin A (Con A) binding protein by using nepherometry. Pharmacologic treatment with 0.3mg/kg of methotrexate (MTX) was done from day 5 to 14 postimmunization in rats with AA. The measured serum IAP level on day 21 indicated the most severe inflamed phase. IAP levels reflected the degree of primary and secondary inflammatory phases in AA, whereas ConA binding protein (CBP) levels did not. Our results suggest that IAP can be used to monitor the symptoms of inflammation and the efficacy of anti-inflammatory drugs.     

Efficacy of Royal Jelly on Methotrexate-Induced Systemic Oxidative Stress and Damage to Small Intestine in Rats

The aim of this present study is to investigate the mucositis caused by methotrexate (MTX), as well as whether the application of royal jelly (RJ) has a protective effect on oxidative stress. This present study included six groups each consisted of 12 Wistar rats. Distilled water (po: peroral) was given to the 1^st group as placebo for 10 days and MTX (20 mg/kg, intraperitoneal: ip) on the 7^th day. The 2^nd group received RJ (50mg/kg, po) for 10 days and normal saline (NS) instead of MTX. RJ (50mg/kg) was given to the 3^rd group for 10 days and MTX on the 7^th day. The 4^th group received RJ (100 mg/kg, po) for 10 days and NS was given intraperitoneally. RJ (100mg/kg) was given to the 5^th group for 10 days and a single dose of MTX. Distilled water was given to the 6^th (control) group for 10 days and intraperitoneal NS on the 7^th day. Malondialdehyde (MDA), glutathione peroxidase and superoxide dismutase were analyzed in blood samples on the 11^th day. Morphological and histopathological changes were examined in the intestinal tissue samples. Villus length and mucosal thickness, as well as the villus length/crypt ratio, were significantly decreased with MTX administration, and the semi-quantitative histological evaluation (SQHE) score was measured high (p<0.001). In addition, a decrease in the antioxidant parameters and an increase in the MDA levels were identified. The villus length and SQHE were significantly different in the groups receiving RJ (p<0.001) as compared to the MTX group. Although RJ addition had no effect on the decreased mucosal thickness and villus/crypt ratio in MTX groups, it caused an improvement in the antioxidant levels and a remarkable decrease in MDA levels. Adding RJ has a decreasing effect on the MTX-induced intestinal damage and it has a suppressive effect on MTX-induced oxidative stress by means of increasing antioxidant enzyme activity and decreasing lipid peroxidation.     

Effect of antiarthritic drugs on the enhanced interleukin-1 (IL-1) production by macrophages from adjuvant-induced arthritic (AA) rats

The effect of antiarthritic drugs on hindpaw edema and enhanced IL-1 production by macrophages from adjuvant arthritic (AA) rats was determined. Hindpaw edema was inhibited by indomethacin (INDO), methotrexate (MTX) or prednisolone (PRED) but not byd-penicillamine (d-PEN) or chloroquine (CQ). IL-1 production by splenic adherent cells was decreased by MTX and PRED; whereas, IL-1 production by peritoneal exudate cells was decreased by PRED, INDO andd-PEN. This normalization in IL-1 production is not caused by a direct inhibition of IL-1 production by the drugs but most likely reflects clinical improvement in the disease. Whether reduction in IL-1 levels provides a more meaningful parameter than paw edema for assessing clinical efficacy of disease-modifying drugs remains to be determined.Code:L-101     

Effects of methotrexate on collagen-induced arthritis in male Wistar rats

To evaluate the effect of methotrexate on collagen-induced arthritis, micro-computed tomography (micro-CT) and histopathological analyses were used in male Wistar rats. Rats were divided randomly into three groups. Group 1 was treated with 0.9% saline, and groups 2 and 3 were boosted with type Ⅱ collagen. From day 21 to 42, groups 1 and 2 were orally treated with 0.9% saline and group 3 was orally treated with 1.5 mg/kg methotrexate. All rats were sacrificed at day 42 after the first collagen treatment. Micro-CT analyses showed bony parameters, such as bone volume and trabecular number, were decreased in group 2 compared to group 1, and these parameters were recovered in group 3. Histopathological examination and pathological parameter scoring showed that the knee joints of rats in group 2 had severe joint destruction, showing cartilage and bone erosion, enlarged cavities with inflammatory cell infiltration and activation of synovial fibroblasts. By contrast, these changes were reduced in group 3. Taken together, methotrexate treatment showed therapeutic potential in male rat collagen-induced arthritis model, and micro-CT analysis and histopathological tools could be integrated to assess the quantification/qualification of arthritic lesions.     

Granisetron and carvedilol can protect experimental rats againstadjuvant-induced arthritis

Context: Rheumatoid arthritis (RA), a disabling autoimmune disorder of the joints as well as other organs, affects about 1% of population. Unfortunately, all current treatments of RA cause severe gastrointestinal, renal and other complications.

Objective: We aimed to evaluate the possible antiarthritic effects of a serotonin 5-HT₃ receptor blocker, granisetron, and a nonselective adrenergic receptor blocker, carvedilol, on complete Freund's adjuvant-induced RA in adult female albino rats.

Materials and methods: Rats were allocated into a normal control group, an arthritis control group, two reference treatment groups receiving dexamethasone (1.5?mg/kg/day) and methotrexate (1?mg/kg/day), and two treatment groups receiving granisetron (2.5?mg/kg/day) and carvedilol (10?mg/kg/day). Serum-specific rheumatoid, immunological, inflammatory and oxidative stress biomarkers were assessed. A confirmatory histopathological study on joints and spleens was performed.

Results: Granisetron administration significantly improved all the measured biomarkers, with the values of rheumatoid factor, matrix metalloproteinase-3, cartilage oligomeric matrix protein, immunoglobulin G, antinuclear antibody and myeloperoxidase being restored back to normal levels. Carvedilol administration significantly improved all biomarkers, with serum MPO value restored back to normal levels.

Discussion and conclusions: Serotonin 5-HT₃ receptor blockers and adrenergic receptor blockers, represented by granisetron and carvedilol, may represent new promising protective strategies against RA, at least owing to immune-modulator, anti-inflammatory and antioxidant potentials.     

Hypoglycemic and hypolipidemic effect and antioxidant activity of chronic epigallocatechin-gallate in streptozotocin-diabetic rats

Background and objective: Green tea catechins including epigallocatechin-3-gallate (EGCG) could exert beneficial health effects to ameliorate metabolic diseases. The effect of chronic administration of EGCG was evaluated on serum glucose and lipid profile and hepatic lipid peroxidation in streptozotocin (STZ)-diabetic rats. Materials and methods: Rats received EGCG 25 mg/kg/day for 8 weeks 1 week after diabetes induction. Serum glucose, triglyceride, total cholesterol, HDL- and LDL-cholesterol levels and MDA level and SOD activity in hepatic tissue were spectrophotometrically measured. Results: Treatment of diabetic rats with EGCG produced a hypoglycemic effect and there were appropriate changes regarding serum lipids in treated diabetic group. Meanwhile, EGCG treatment attenuated the increased MDA content and reduced activity of SOD in liver. Conclusion: Chronic treatment of diabetic rats with EGCG could prevent abnormal changes in blood glucose and lipid profile and attenuat hepatic lipid peroxidation.     

Alteration of interleukin-1 production and the acute phase response following medication of adjuvant arthritic rats with cyclosporin-A or methotrexate

The purpose of the paper was to determine whether two clinically active antirheumatic compounds, cyclosporin-A (CS-A) and methotrexate (MTX) were efficacious in the treatment of adjuvant arthritis (AA) in rats, as measured by reduction of paw inflammation, lymphocyte activating factor (LAF) activity and the acute phase response. Parameters of the acute phase response consisted of plasma fibronectin (Fn), C-reactive protein (CRP), albumin and iron. Rats injected with Freund's complete adjuvant on day 1, developed systemic arthritis, which was quantitated by measuring non-injected paw swelling on day 17. When compared to normal animals, AA rats had significantly (P less than or equal to 0.01) increased: (1) splenic LAF activity (100% increase), (2) plasma Fn (58%), and (3) CRP (122%), as well as abnormally reduced levels of: (1) plasma albumin (53% reduction), and (2) iron (54%). Orally dosing AA rats from days 3 to 17 with the immunoregulatory drugs, CS-A (3 and 5 mg/kg) or MTX (0.5 and 1 mg/kg), significantly (P less than or equal to 0.01) reduced paw inflammation (100% reduction), increased final body wt 40-50 g over arthritic controls and decreased LAF activity from splenic leukocytes. The acute phase response, often associated with a high degree of LAF activity, was significantly (P less than or equal to 0.01) decreased by dosing with CS-A (3 and 5 mg/kg) and MTX (0.5 and 1 mg/kg). The inhibition of the acute phase response was measured by reduction of high plasma Fn levels (42-79% decrease) and CRP levels (57-100% decrease) as well as elevation of subnormal levels of plasma albumin (57-101% increase) and iron (40-114% increase). Dosing with the nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin (50 and 100 mg/kg) or phenylbutazone (10 and 30 mg/kg), significantly inhibited paw inflammation (29-85%), but did not decrease the high rate of splenic LAF activity, nor did aspirin (55, 100 and 200 mg/kg) or phenylbutazone (1, 10 and 30 mg/kg) alter the acute phase response in AA rats, as measured by levels of plasma Fn, CRP, albumin and iron. Since CS-A and MTX have been reported to be effective in the treatment of RA, their activity in the LAF, Fn, CRP, albumin and iron assays of the AA rat suggests that these immunological and serological parameters may be useful in identifying potential antirheumatic drugs and distinguishing them from standard NSAIDs.     

<Emphasis Type="Italic">Lactobacillus casei</Emphasis> reduces the Inflammatory Joint Damage Associated with Collagen-Induced Arthritis (CIA) by Reducing the Pro-Inflammatory Cytokines

This study evaluated the therapeutic efficacy of Lactobacillus casei in treating rheumatoid arthritis using collagen-induced arthritis (CIA) animal model. Healthy female Wistar rats (weight—180–200 g) were included in this study. Oral administration of L. casei was started on the same day. Indomethacin was used as standard reference drug. Serum level of IL-6, α-TNF, and IL-10 were observed. Four-point arthritis indexes were also assessed at the end of week for 28th day. L. casei-treated rats had shown normal histopathology without any synovial infiltration, pannus formation, cartilage, and bone destruction. Arthritis score was also lower for the group treated with L. casei. Oral administration of L. casei significantly decreased the pro-inflammatory cytokines. Present study suggests that L. casei has potent antiarthritic effect in CIA model. Inhibition of COX-2 via inhibiting the pro-inflammatory cytokines is an understanding of the complex interactions involved in these pathways.     

Hedgehog信号通路阻断剂环巴胺体外对佐剂性关节炎大鼠的关节软骨细胞增殖的影响

目的探讨Hedgehog(Hh)信号通路抑制剂环巴胺体外对佐剂性关节炎大鼠(AA)模型的关节软骨细胞增殖的影响和部分机制。方法弗氏完全佐剂诱导AA大鼠,测量关节炎指数和继发性足肿胀度,HE染色观察两组软骨组织生长情况;取AA大鼠踝关节软骨组织,采用胰蛋白酶-胶原酶法分离、培养、鉴定,环巴胺(0、0.05、0.5、5、20μmol/L)体外给药,MTT法检测AA大鼠踝关节软骨细胞增殖,Annexin V-FITC/PI双染检测AA大鼠踝关节软骨细胞凋亡,Western blotting检测AA大鼠踝关节软骨细胞Shh、Ptch1、Gli1的蛋白表达。结果弗氏完全佐剂诱导后,与正常大鼠相比,AA大鼠关节炎指数和继发性足肿胀度明显升高,HE染色显示,AA大鼠踝关节软骨组织有破坏;甲苯胺蓝和Ⅱ型胶原鉴定体外成功培养AA大鼠踝关节软骨细胞;体外给药环巴胺(0.05、0.5、5、20μmol/L)可升高AA模型关节软骨细胞增殖,流式细胞检测结果显示,环巴胺能降低AA模型软骨细胞凋亡率;与未用环巴胺组相比,环巴胺(0.5、5、20μmol/L)给药对AA软骨细胞中Hh信号通路相关蛋白(Shh、Ptch1、Gli1)表达显著下降。结论弗氏完全佐剂诱导建立AA大鼠模型成立,体外给药环巴胺可抑制AA大鼠软骨细胞的增殖,抑制软骨细胞的凋亡,该作用与抑制AA大鼠软骨细胞Hh信号有关。     

Methotrexate,combined with cyclophosphamide attenuates murine collagen induced arthritis by modulating the expression level of Breg and DCs

To explore the mechanism of methotrexate (MTX) and its combination with cyclophosphamide (CTX) in collagen-induced arthritis (CIA), we investigated the levels of several immune cells and cytokines in mice with different treatments. CIA was induced in DBA/1 mice at the age of 7 weeks by primary immunization with 100 μl emulsion containing 2 mg/ml bovine type II collagen which was mixed with complete Freund's adjuvant (CFA). The booster immunization was performed with 50–100 μl emulsion containing 2 mg/ml bovine type II collagen (CII) mixed with incomplete Freund's adjuvant (IFA). MTX, CTX or both were administrated after the booster immunization. Therapeutic effect was evaluated by arthritic scores, X-rays and assessment of histopathological joint destruction. The expression of TNF-α, IL-6, IL-23, IL-10 were also measured. The frequencies of different immune cell subsets in the lymph node, spleen and bone marrow were determined by flow cytometry analysis. Our results showed that CTX and MTX treatment attenuated the severity of arthritis of CIA mice and reduced the levels of several cytokines. CTX and MTX treated mice showed a lower frequency of B cells in bone marrow. Also, when treated the CIA mice with MTX, alone or together with CTX, the lymph nodes and spleen exhibited a decrease in regulatory B cells (Breg) and dendritic cells (DCs). Notably, the combination of MTX and CTX had a more pronounced effect. By measuring the levels of different immune cells those participated in the development of rheumatoid arthritis (RA), our experiment may help to evaluate the therapeutic effects and prognosis of arthritic diseases.     

Alleviation of rheumatoid arthritis by cell-transducible methotrexate upon transcutaneous delivery

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is initiated and maintained by various inflammatory/immune cells and their cytokines, leading to cartilage degradation and bone erosion. Despite its potent therapeutic efficacy on RA, the oral administration of methotrexate (MTX) provokes serious adverse systemic complications, thus necessitating the local application of MTX. Here, we show that transcutaneous MTX (TC-MTX) can efficiently penetrate joint skin ex vivo and in vivo, and that TC-MTX can significantly improve the various inflammatory symptoms associated with RA. Further, TC-MTX preserved the joint-structures in mice with collagen-induced arthritis (CIA), which was also confirmed by three-dimensional micro-computed tomography scan. TC-MTX markedly decreased the secretion of inflammatory cytokines both in the serum and in inflamed joints of CIA mice. Further, its therapeutic potential is comparable to that of etanercept, a biological agent that block tumor necrosis factor (TNF)-α. Importantly, the systemic cytotoxicity of TC-MTX was not detected. Thus, TC-MTX can be a new therapeutic modality for RA patients without systemic complications.     

Effects of alpha-linked galactooligosaccharide on adjuvant-induced arthritis in Wistar rats and type II collagen-induced arthritis in DBA/1J mice

alpha-Linked galactooligosaccharide (alpha-GOS) has been reported to change the composition of enteric microflora. In the present study, the antiarthritic effect of alpha-GOS was evaluated by employing adjuvant-induced arthritis (AIA) in Wistar rats and type II collagen-induced arthritis (CIA) in DBA/1J mice. The animals were given alpha-GOS orally. This substance had beneficial effects on both clinical signs, such as erythema and swelling of the limbs, and histopathological findings in the hind paw joints in a dose-dependent manner. alpha-GOS reduced the plasma nitrite/nitrate (NOx) level in rats with AIA. In the cell culture system employing peritoneal macrophages from rats with AIA, alpha-GOS enhanced interleukin-1 production without lipopolysaccharide stimulation in a dose-dependent manner, suggesting that alpha-GOS stimulates peritoneal macrophages through modulation of enteric microflora. Since alpha-GOS modulates the composition of the enteric microflora, the antiarthritic effects of alpha-GOS could be partly attributable to its immunomodulating activity. Thus, alpha-GOS is a potential functional food for the treatment of human rheumatoid arthritis.     

Effects of epigallocatechin-3-gallate on pentylenetetrazole-induced kindling, cognitive impairment and oxidative stress in rats

Cognitive dysfunction is commonly observed in epileptic patients. It has been shown that not only epilepsy but also antiepileptic drugs could induce cognitive impairment. Thus, there is an urgent need for drugs that can suppress seizures without causing cognitive deficit. Recent studies have shown that oxidative stress is involved in the pathophysiology of epilepsy, and many antioxidants have an antiepileptic property. Epigallocatechin-3-gallate (EGCG), a catechin polyphenols component, is found to be an effective antioxidant. The purpose of this study was to assess the effect of EGCG against seizures, seizure-induced oxidative stress and cognitive impairment in pentylenetetrazole-induced kindling. Male Sprague-Dawley rats were injected intraperitoneally with a dose of 35 mg/kg of pentylenetetrazole (PTZ) once every alternate day for 13 injections. EGCG was administered daily in two doses (25mg/kg and 50mg/kg) intraperitoneally along with alternate-day PTZ. Morris water maze test was carried out 24h after the last injection of PTZ, and the oxidative stress parameters (malondialdehyde and glutathione) were assessed after the completion of the behavioral test. The results showed that EGCG dose-dependently suppressed the progression of kindling. EGCG also ameliorated the cognitive impairment and oxidative stress induced by PTZ kindling. These observations suggest that EGCG may be a potential agent for the treatment of epilepsy as well as a preventive agent against cognitive impairment induced by seizure.     

Impact of ellagic acid on adriamycin-induced testicular histopathological lesions,apoptosis, lipid peroxidation and sperm damages

The aim of the present study was to investigate whether ellagic acid (EA) has protective effect on adriamycin (ADR)-induced testicular and spermatozoal toxicity associated with the oxidative stress in male rats. Thirthy-two healthy 8-week-old male Sprague–Dawley rats were equally divided into four groups. The first (EA) group was treated with EA (2 mg/kg/every other day) by gavage. The second (ADR) group received ADR (2 mg/kg/once a week) intraperitoneally, while the combination of ADR and EA was given to the third (ADR + EA) group. The forth (control) group was treated with placebo. At the end of the 8-week treatment period, reproductive organ weights, epididymal sperm parameters, histopathological changes and apoptosis via Bax and Bcl-2 proteins, testicular tissue lipid peroxidation, and antioxidant enzyme activities, were investigated. ADR administration was determined to cause significant decreases in reproductive organ weights, epididymal sperm concentration and motility, plasma testosterone concentration, diameter of seminiferous tubules, germinal cell layer thickness, Johnsen's testicular score and Bcl-2 positive antiapoptotic cell rate, wherease it caused significant increases in level of lipid peroxidation and glutathione, catalase activity, abnormal sperm rates and Bax positive apoptotic cell rates along with degeneration, necrosis, immature germ cells, congestion and atrophy in testicular tissue when compared with the control group. EA administration to ADR-treated rats provided significant improvements in ADR-induced disturbed oxidant/antioxidant balance, decreased testosterone concentration, testicular apoptosis and mild improvements in the histopathological view of the testicular tissue. However, EA failed to improve decreased reproductive organ weights and deteriorated sperm parameters due to ADR administration. It is concluded that while ADR has direct or indirect (lipid peroxidation) negative effects on sperm structure and testicular apoptosis in rats, EA has protective effects on ADR-induced testicular lipid peroxidation and apoptosis.     

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.     

Design of a new line in treatment of experimental rheumatoid arthritis by artesunate

This study was aimed to evaluate the therapeutic potency of a new antimalarial drug, artesunate, in an experimental model of rheumatoid arthritis. Collagen-induced arthritis (CIA) was induced in Lewis rats.The intraperitoneally administration of artesunate (ARS) and methotrexate (MTX) were started on day 25 postimmunization and continued until final assessment on day 35. During this period, clinical examination was intermittent. The anticollagen type II antibody (CII Ab) and nitric oxide synthesis were measured. The paws and kness were then removed for histopathology and radiography assay. The biocompatibility of ARS and MTX were assessed using fibrosarcoma cell line. Our results showed that i.p. injection of artesunate to arthritic rats induced a significant reduction in paw edema. This beneficial effect was associated with a significant decrease in anti-CII antibody response compared with untreated rats. Histopathological assessment showed reduced inflammatory cells infiltrate in joints of treated rats, and tissue edema and bone erosion in the paws were markedly reduced following ARS therapy. Moreover, our radiographic results paralleled histological findings. Cytotoxicity analysis of ARS showed greater tolerability compared with MTX. Treatment with ARS significantly diminished nitric oxide formation in treated rats compared with untreated controls. Our findings revealed the therapeutic efficacy of artesunate in experimental rheumatoid arthritis compared with a choice drug (methotrexate). This result may recommend it as a second-line drug in the treatment of rheumatoid arthritis.