Protective effect of crocin on diazinon induced vascular toxicity in subchronic exposure in rat aorta ex-vivo

Abstract

Context: Diazinon (DZN) is a widely used organophosphate insecticide. Although mechanism of DZN cardiovascular toxicity is primarily mediated through inhibition of acetylcholinesterase, however, DZN causes remarkable atropine-insensitive hypotension in rats. It has been proved that oxidative stress is an important mechanism of DZN toxicity especially in chronic exposure. Crocin, an active ingredient of saffron, has been found to antagonize the hypotensive effects of DZN in rats, but do not reverse acetylcholinesterase inhibition. Objective: In this study the effects of DZN on contractile and relaxant responses in rat aorta as well as ex-vivo antioxidant actions of crocin have been investigated. Materials and methods: Rats were divided into 7 groups: corn oil (control), DZN (15?mg/kg/day, gavage), crocin (12.5, 25 and 50?mg/kg/day, i.p.) plus DZN, vitamin E (200?IU/kg, i.p., three days a week) plus DZN and crocin (50?mg/kg/day, i.p.) groups. Treatments were continued for 4 weeks. Contractile and relaxant responses were evaluated on the isolated aorta. Results: Our results showed that DZN not only decreased the contractile responses to KCl and Phenylephrine (PE) (p?<?0.001), but also attenuated the relaxant response to acetylcholine (ACh) (p?<?0.01). Crocin and vitamin E attenuated lipid peroxidation, improved the reduction of contractile responses by KCl and PE and restored the decrease in ACh relaxation in rat aorta. Conclusion: DZN induced vascular toxicity which may be due to oxidative stress and not to a cholinergic mechanism. Crocin improved toxic effects of DZN via reducing lipid peroxidation and restoring altered contractile and relaxant responses in rat aorta.     

Design,synthesis and preliminary evaluation of the anti-inflammatory of the specific selective targeting druggable enzymome cyclooxygenase-2 (COX-2) small molecule

Context: Development of a reliable and selective anti-inflammatory agent of cyclooxygenase-2 (COX-2), induced or up-regulated by inflammatory/injury stimulus such as IL-1β, TNF-α and LPS in the various types of organs, tissues and cells, with low side effects is a long-standing medicinal chemistry problem with significant social implications.

Objective: To target druggable enzymome COX-2 by exploiting NSAIDs and genipin (GEP) in anti-inflammatory infection.

Materials and methods: The compound aspirin GEP ester (AGE) was designed by computer-assisted screening, synthesized in the esterification of the acylate derivative and the methylate derivative with Et₃N, and evaluated with 20, 40 and 60?mg/kg from days 18 to 24 after immunization in collagen-induced arthritis (CIA) rats by the sequential enzymatic experiments, western-blot analysis and pathological observation methods.

Results: AGE exhibited higher binding affinity with COX-1 and displayed the lowest estimated free energy with COX-2 than other ligands built by hanging NSAIDs with GEP, and was characterized by ¹H NMR, ¹³C NMR and HRMS. AGE was competed against COX-2 with molecule-dependent potencies and selectivity (IC₅₀: 0.36?mM; selectivity index: 275) in the sequential enzymatic experiments and decreased the expression of COX-2 in peripheral blood lymphocytes of CIA rats. AGE (40 and 60?mg/kg) could significantly relieve the secondary hind paw swelling and arthritis index, along with observing AGE attenuated histopathological changes of fibroblast like synovial tissue (FLST) and mesenteric lymph node lymphocytes (MLNL) in CIA rats.

Discussion and conclusion: AGE pharmacophore reported herein may be an effective strategy to develop a novel anti-inflammatory agent and potential inhibitor of COX-2.     

Targeting inflammation and redox perturbations by lisinopril mitigates Freund’s adjuvant-induced arthritis in rats: role of JAK-2/STAT-3/RANKL axis,MMPs, and VEGF

Background

Cardiovascular disorders are major complications of rheumatoid arthritis (RA). Hence, finding effective agents that can target RA progression and its cardiovascular consequences is demanding. The present work aimed to explore the potential of lisinopril, an angiotensin-converting enzyme inhibitor, to mitigate adjuvant’s-induced arthritis with emphasis on the pro-inflammatory signals, articular degradation cues, and angiogenesis alongside JAK-2/STAT-3 and Nrf2/HO-1 pathways.

Methods

Lisinopril (10 mg/kg/day) was administered by oral gavage for 3 weeks and the target signals were examined by biochemical assays, ELISA, histopathology, immunoblotting, and immunohistochemistry.

Results

Lisinopril attenuated the progression of arthritis as proven by lowering paw edema, arthritic index, and gait scores alongside diminishing the immune-cell infiltration/aberrant histopathology in the dorsal pouch lining. These favorable actions were associated with curtailing the production of inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-17) and the pro-inflammatory angiotensin II alongside upregulating the anti-inflammatory angiotensin-(1–7) in the hind paw of arthritic rats. At the molecular level, lisinopril inhibited the upstream JAK-2/STAT-3 pathway by downregulating the protein expression of p-JAK-2/total JAK-2 and p-STAT-3/total STAT-3 ratio and the nuclear levels of NF-κBp65. Meanwhile, lisinopril curbed the downstream cartilage degradation signals matrix metalloproteinases (MMP-3 and MMP-9) and the bone erosion cue RANKL. Equally important, the protein expression of the angiogenesis signal VEGF was downregulated in the hind paw/dorsal lining. With respect to oxidative stress, lisinopril suppressed the paw lipid peroxides and boosted GSH and Nrf-2/HO-1 pathway.

Conclusion

Lisinopril attenuated adjuvant-induced arthritis via inhibition of inflammation, articular degradation cues, and angiogenesis.

     

Amelioration of Collagen-Induced Arthritis in Mice by a Saponin Fraction from Gleditsia sinensis.

Abstract

In the current study, we investigated the therapeutic potential and underlying mechanisms of the saponin fraction from anomalous fruits of Gleditsia sinensis. Lam. (Leguminosae) (SFGS) on collagen II (CII)-induced arthritis (CIA) in DBA/1 mice. SFGS (50, 100, and 200 mg/kg), orally administered from the day of immunization, dose-dependently alleviated disease severity, postponed the onset and reduced the incidence rate of CIA. Histologic analysis revealed that joints of CIA mice treated with SFGS showed low inflammatory cell infiltration and slight synovium hyperplasia and focal bone erosion. Furthermore, SFGS treatments lowered the serum anti-CII autoantibody levels and suppressed the delayed-type hypersensitivity against CII in the ears of CIA mice. The findings indicated that SFGS ameliorated inflammation and joint destruction in CIA mice, which may be the consequence of suppression on CII-specific humoral and cellular immunity. SFGS should be a candidate novel therapeutic agent for rheumatoid arthritis.     

Comparison of the effects of crocin,safranal and diclofenac on local inflammation and inflammatory pain responses induced by carrageenan in rats

BackgroundCrocin and safranal are the active substances of saffron and have many biological properties. In the present study, we compared the effects of crocin, safranal and diclofenac on local inflammation and its induced pain in rats.MethodsLocal inflammation was induced by intraplantar (ipl) injection of carrageenan (100 μl, 2%). Paw thickness was measured before and after carrageenan injection. Inflammatory pain responses including cold allodynia, mechanical allodynia and hyperalgesia were assessed using acetone spray and von Frey filament tests, respectively. The number of neutrophils in inflammatory zone was counted 6.5 h after injection of carrageenan.ResultsCarrageenan produced edema, cold allodynia, mechanical allodynia and hyperalgesia and caused neutrophil infiltration in paw tissues. Crocin at doses of 25, 50 and 100 mg/kg, safranal at doses of 0.5, 1 and 2 mg/kg and diclofenac (as a reference drug) at a dose of 10 mg/kg attenuated edema, suppressed inflammatory pain responses and decreased the number of neutrophils.ConclusionThe present study showed anti-inflammatory and antinociceptive activities for crocin, safranal and diclofenac in carrageenan model of local inflammation and inflammatory pain.     

Guizhi-Shaoyao-Zhimu decoction attenuates bone erosion in rats that have collagen-induced arthritis via modulating NF‐κB signalling to suppress osteoclastogenesis

ContextGuizhi-Shaoyao-Zhimu decoction (GSZD) is commonly used to treat rheumatoid arthritis (RA), but its mechanism is unclear.ObjectiveTo investigate the effect of GSZD on bone erosion in type II collagen (CII)-induced arthritis (CIA) in rats and to identify the underlying mechanism.Materials and methodsThe CIA model was prepared in male Wistar rats by two subcutaneous injections of CII, 1 mg/mL. Fifty CIA rats were randomized equally into the control group given saline daily, the positive group given saline daily and methotrexate 0.75 mg/kg once a week, and three GSZD-treated groups gavaged daily with 800, 1600 and 3200 mg/kg of GSZD for 21 days. GSZD effects were assessed by paw volume, arthritic severity index and histopathology. Cytokine levels were determined by ELISA. The effects of GSZD on RAW264.7 cells were evaluated by receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and bone resorption assay. Expression of IκB-α and p65 was measured by Western blotting. Major components of GSZD were identified by HPLC.ResultsArthritis index score, paw volume and bone destruction score showed that GSZD improved inflammatory symptoms and reduced joint tissue erosion (p < 0.01). GSZD decreased RANKL, and the number of osteoclasts (OCs) in joint tissues (p < 0.01) and increased osteoprotegerin levels (p < 0.01). GSZD inhibited RANKL-induced RAW264.7 differentiation and reduced bone resorption by OCs. GSZD upregulated IκB (p < 0.01) and p65 (p < 0.01) in the cytoplasm and downregulated p65 (p < 0.01) in the cell nucleus.ConclusionsGuizhi-Shaoyao-Zhimu decoction has an anti-RA effect, suggesting its possible use as a supplement and alternative drug therapy for RA.     

Alantolactone alleviates collagen-induced arthritis and inhibits Th17 cell differentiation through modulation of STAT3 signalling

Context Alantolactone, the bioactive component in Inula helenium L. (Asteraceae), exhibits multiple biological effects.Objective We aimed to determine the anti-inflammatory effect of alantolactone in a collagen-induced arthritis (CIA) mouse model and its immunomodulatory effects on Th17 differentiation.Materials and methods A CIA mouse model was established with DBA/1 mice randomly divided into four groups (n = 6): healthy, vehicle and two alantolactone-treated groups (25 or 50 mg/kg), followed by oral administration of alantolactone to mice for 21 consecutive days after arthritis onset. The severity of CIA was evaluated by an arthritic scoring system and histopathological examination. Levels of cytokines and anti-CII antibodies as well as percentages of splenic Th17 and Th17 differentiation with or without alantolactone treatments (0.62, 1.2 or 2.5 μM) were detected with ELISA and flow cytometry, respectively. Western blot analysis was used to evaluate intracellular signalling in alantolactone-treated spleen cells.Results In CIA mice, alantolactone at 50 mg/kg attenuated RA symptoms, including high arthritis scores, infiltrating inflammatory cells, synovial hyperplasia, bone erosion and levels of the proinflammatory cytokines TNF-α, IL-6 and IL-17A, but not IL-10 in paw tissues. Alantolactone also reduced the number of splenic Th17 cells and the capability of naïve CD4⁺ T cells to differentiate into the Th17 subset by downregulating STAT3/RORγt signalling by as early as 24 h of treatment.Discussion and conclusions Alantolactone possesses an anti-inflammatory effect that suppresses murine CIA by inhibiting Th17 cell differentiation, suggesting alantolactone is an adjunctive therapeutic candidate to treat rheumatoid arthritis.     

Effects of rosmarinic acid on acetaminophen-induced hepatotoxicity in male Wistar rats

Context: Drug-induced liver injury is a significant worldwide clinical problem. Rosmarinic acid (RA), a natural phenol, has antioxidant effects.

Objective: The effects of RA against acetaminophen (N-acetyl-p-amino-phenol (APAP))-induced oxidative damage and hepatotoxicity in rats were investigated.

Materials and methods: Male Wistar rats were pretreated with RA (10, 50 and 100?mg/kg, i.g.) for one week. On day 7, rats received APAP (500?mg/kg, i.p.). Then aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein, malondialdehyde (MDA), glutathione (GSH), total antioxidant capacity (TAC), glutathione S-transferase (GST), cytochrome CYP450 and histopathological changes were determined.

Results: APAP-induced oxidative stress in liver by a significant increase in the level of MDA (7.6?±?0.21?nmol/mg) as well as a decrease in the contents of TAC (1.75?±?0.14?μmol/g), GSH (1.9?±?0.22?μmol/g) and GST) 3.2?±?0.28?U/mg). RA treatment decreased MDA (4.32?±?0.35?nmol/mg) but increased the contents of TAC (3.51?±?0.34?μmol/g), GSH (3.42?±?0.16?μmol/g) and GST (5.71?±?0.71?μmol/g) in APAP group. RA 100?mg/kg decreased ALT (91.5?±?1.5?U/L), AST (169?±?8.8?U/L) and CYP450 (3?±?0.2?nmol/min/mg) in APAP group. Histologically RA attenuated hepatic damage by decreasing necrosis, inflammation, and haemorrhage in liver sections of APAP group.

Discussion and conclusions: This is the first report that oral administration of RA dose-dependently elicited significant hepatoprotective effects in rats through inhibition of hepatic CYP2E1 activity and lipid peroxidation. RA-protected hepatic GSH and GST reserves and total tissue antioxidant capacity.     

A combination of Sinomenine and Methotrexate reduces joint damage of collagen induced arthritis in rats by modulating osteoclast-related cytokines

ObjectiveTo analyze the combination therapy of Sinomenine (SIN) and Methotrexate (MTX) in rheumatoid arthritis (RA), we herein demonstrated the combination effect of SIN and MTX on collagen-induced arthritis (CIA) in rats through their modulation on osteoclast-related cytokines.MethodsCIA was induced by the immunization of type II collagen (CII) in SD rats. SIN and MTX were administrated alone or in combination after the onset of arthritis. Arthritis index and histological analysis were used to evaluate the effect of treatments. Effects of SIN and MTX on expression of receptor activator of NF-κB ligand (RANKL) and osteopontin (OPN) in synovial tissues were assayed by immunohistochemistry. RANKL, osteoprotegerin (OPG), IL-6, IL-17 and matrix metalloproteinases (MMPs) in rat serum were measured by ELISA. The expression of osteoclast-related cytokines in fibroblast-like synoviocytes (FLS) from RA patients was assayed by RT-PCR.ResultsSIN and MTX combination additively reduced the inflammatory symptoms and joint damage in CIA. Combination of SIN and MTX significantly repressed synovial RANKL and OPN production. SIN and MTX exhibited complementary and synergistic effect upon down-regulating RANKL, IL-6, IL-17 and MMPs in rat serum. SIN and MTX also modulated the expression of RANKL and OPG in RA-FLS.ConclusionSIN and MTX have additive effects, decreasing inflammation and joint damage in CIA rats by modulating osteoclast-related cytokines. These results are indicative of the combined effect of SIN and MTX for anti-arthritic treatment in RA.     

Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is a chronic inflammatory disease. Histone deacetylase inhibitors (HDACi), a new class of anti-cancer agents, have recently been reported to exhibit potent anti-inflammatory activities. A proof of concept study was carried out with suberoylanilide hydroxamic acid (SAHA) and MS-275, two HDACi currently undergoing clinical investigations for various oncological indications. EXPERIMENTAL APPROACH: The anti-rheumatic effects of SAHA and MS-275 were assessed in both mouse and rat collagen induced arthritis (CIA) models. KEY RESULTS: SAHA exhibited moderate prophylactic efficacy. It attenuated paw swelling due to inflammation, decreased bone erosion in both mice and rats and reduced slightly the RA-induced bone resorption in rats. However, SAHA could not inhibit the onset of arthritis. In contrast, MS-275 displayed dramatic anti-rheumatic activities. In prophylactic intervention, high doses of MS-275 prevented bone erosion and markedly delayed the onset of arthritis; at low doses, MS-275 strongly attenuated paw swelling, bone erosion, and bone resorption associated with RA. Furthermore, the therapeutic efficacy of MS-275 was also documented. After the onset of arthritis, it could stop the disease progression and joint destruction. An anti inflammatory effect of MS-275 was also confirmed through its capacity to decrease serum IL-6 and IL-1beta levels in the CIA induced mouse model. The anti-rheumatic activity of MS-275 was also confirmed through histological observation. No synovial hyperplasia, pannus formation, cartilage or bone destruction were observed in the high dose prophylactic intervention in mice. CONCLUSION AND IMPLICATION: This study strongly supported HDACi as an innovative therapeutic strategy for RA.     

The anti-arthritic activity of total glycosides from Pterocephalus hookeri,a traditional Tibetan herbal medicine

Context: Pterocephalus hookeri (C. B. Clarke) Hock., a traditional Tibetan herbal medicine rich in glycosides, has been used to treat several diseases including rheumatoid arthritis.

Objective: To evaluate the anti-arthritic activity of total glycosides from P. hookeri, and its possible mechanisms of action.

Materials and methods: Anti-arthritic activity of total glycosides from P. hookeri (oral administration for 30 days at 14–56?mg/kg) was evaluated using paw swelling, arthritis scores and histopathological measurement in adjuvant-induced arthritis (AA) Sprague-Dawley rats. The NF-κB p65 expression in synovial tissues, and serum superoxide dismutase (SOD) activity, malondialdehyde (MDA) and nitric oxide (NO) levels was measured in AA rats, respectively. Further assessment of anti-inflammatory and analgesic activities of these glycosides were carried out using inflammation and hyperalgesia models induced by xylene, carrageenan, agar and acetic acid, respectively.

Results: Total glycosides (56?mg/kg) decreased the paw swelling (38.0%, p?p?p?p?p?p?p?Discussion and conclusion: Our findings confirmed the anti-arthritic property of the total glycosides from P. hookeri, which may be attributed to its inhibition on NF-κB signalling and oxidative stress.     

Naltrexone (NTX) relieves inflammation in the collagen-induced- arthritis (CIA) rat models through regulating TLR4/NFκB signaling pathway

ObjectiveOur aim was to study the efficacy and mechanism by which NTX alleviate arthritis in CIA rat models in vivo.MethodsFemale Wistar rats were randomly divided into 6 groups, their weights were observed and the severity of arthritis and pathological changes were evaluated by HE staining. T lymphocyte subsets were detected by flow cytometry. The expression of cytokines was detected in peripheral serum by ELISA. Real time PCR, immunohistochemical staining and western blot analysis were utilized to detect the mRNA and protein expression of opioid receptors, TLR4, RANKL and /NF-κB in synovial tissue and the spleen.ResultsThe weight of the rats in the 10 mg/kg NTX group decreased the least, and had the least severe arthritis. CD4⁺ T cells, Th1 cells and Treg cells increased, and CD8⁺T cells, Th1 cells and Th17 cells decreased in the splenic lymphocytes. The expression of proinflammatory cytokines decreased, and the expression of anti-inflammatory cytokines increased. MOR and DOR were strongly expressed in the spleen, whereas KOR and DOR were strongly expressed in synovial tissue. The expression of TLR4, NF-κB and RANKL was reduced in the spleen and synovium in the NTX group.ConclusionsNTX relieved the severity of arthritis in the CIA rat models at a concentration of 10 mg/kg by regulating T lymphocyte subsets and the expression of cytokines. NTX affected opioid receptors to inhibit the TLR4/NF-κB signaling pathway, regulating the systemic immune response and decreasing osteoclast differentiation, thereby alleviating inflammation and the erosion of articular cartilage along with bone tissue.     

Improvement of cytotoxic and apoptogenic properties of crocin in cancer cell lines by its nanoliposomal form

Objective: Saffron Crocus sativus L. (Iridaceae) is known for anticancer properties. However, limited effort has been made to correlate these effects to the active ingredients of saffron. In the present study, cytotoxic effects of crocin, the major coloring compound in saffron, and its nanoliposomal form for better cellular delivery are investigated.

Methods: HeLa and MCF-7 cells were cultured and exposed to crocin (1, 2, and 4?mM) and liposomal crocin (0.5 and 1?mM). The 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was performed to assess cytotoxicity. Apoptotic cells were determined using propidium iodide (PI) staining of DNA fragmentation by flow cytometry.

Results: MTT assay revealed a remarkable and concentration-dependent cytotoxic effect of crocin on HeLa and MCF-7 cells in comparison with non-malignant cell line (L929). Crocin liposomal forms (IC₅₀ values after 48 h: 0.61, 0.64, and 1.2?mM) showed enhanced cytotoxic effect compared with the crocin (IC₅₀ after 48 h: 1.603?mM) in HeLa cells. Crocin and its liposomal form induced a sub-G1 peak in flow cytometry histogram of treated cells indicating apoptosis is involved in this toxicity. Liposomal encapsulation enhances apoptogenic effects of crocin on cancerous cells.

Conclusion: It might be concluded that crocin and its liposomes could cause cell death in HeLa and MCF-7 cells, in which liposomal encapsulation improved cytotoxic effects. They could be also considered as a promising chemotherapeutic agent in cancer treatment in future.     

SND-117, a sinomenine bivalent alleviates type II collagen-induced arthritis in mice

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that affects about 1% of the population worldwide. RA is mainly manifested by persistent synovitis and progressive joint destruction. The aim of the present study was to examine the anti-arthritis effects of SND-117, a sinomenine bivalent that is obtained from the structure modification of a clinically available anti-RA drug, sinomenine. The arthritis model (CIA) was established by immunizing DBA/1 mice with type II collagen, and the arthritis scores including inflammation, joint destruction and bone erosion were assessed after booster immunization for 3 weeks. The levels of cytokines such as IL-1β, IL-6 and TNF-α were analyzed by quantitative PCR and ELISA. The TNF-α induced NF-κB activation in fibroblast-like synovial cells (FLSCs) was analyzed by Western blot. SND-117 significantly relieved the inflammatory symptoms of collagen-induced arthritis, reduced bone erosion and joint destruction in CIA mice. The serum levels of IL-1β, IL-6 and TNF-α of CIA mice were markedly decreased by SND-117. SND-117 also strongly inhibited the phosphorylation and nuclear translocation of NF-κB p65 in FLSCs upon TNF-α stimulation. These data demonstrated that SND-117 could effectively block the pathogenesis of collagen-induced arthritis in CIA mice via inhibition of NF-κB signaling, and might provide potential clinic benefits in rheumatoid arthritis management.     

The expanding role of IL-7 and thymic stromal lymphopoietin as therapeutic target for rheumatoid arthritis

Introduction: The discovery of IL-7 and thymic stromal lymphopoietin (TSLP) has been a major step in the understanding of arthritis. IL-7 amplifies the inflammation induced by other cytokines, primarily TNF. In animal models of arthritis, inhibition of IL-7 limits inflammation and joint erosion. TSLP is an IL-7-like cytokine that triggers dendritic cell-mediated Th2-type inflammatory responses and is considered as a master switch for allergic inflammation. TSLP is a downstream molecule of TNF-α and as such may be involved in the pathophysiology of inflammatory arthritis.

Areas covered: This review summarizes current knowledge of the role of IL-7 and TSLP derived from both animal models and studies in patients with rheumatoid arthritis (RA). The emergence of IL-7 blockade as a future therapy in RA is highlighted, along with the potential goals and limitations of this therapeutic approach. The write-up also highlights the functional capacities of TSLP in arthritis.

Expert opinion: Evidences suggest important roles for IL-7 and TSLP in the pathogenesis of RA and can be viewed as potential therapeutic targets. Regulation of these at genetic level is a promising investigational area. Given the difficulty in reconstituting T cells in patients with RA, therapeutic approaches that minimize the elimination of T cells are likely to be more desirable.     

Ameliorating effect of Celastrus paniculatus standardized extract and its fractions on 3-nitropropionic acid induced neuronal damage in rats: possible antioxidant mechanism

Context: Celastrus paniculatus Wild. (Celasteraceae) (CP) is a well-known Ayurvedic ‘Medhya Rasayana’ (nervine tonic), used extensively as a neuro-protective and memory enhancer, and in different central nervous system disorders.

Objective: To evaluate the effect of CP against 3-nitropropionic acid (3-NP) induced Huntington's disease (HD) like symptoms in Wistar male rats.

Materials and methods: The ethanol extract of CP seeds (CPEE), prepared by maceration, was standardized on the basis of linoleic acid content (6.42%) using thin layer chromatography densitometric analysis. Protective effect of CPEE (100 and 200?mg/kg) and its various fractions, viz., petroleum ether (40?mg/kg), ethyl acetate (2.5?mg/kg), n-butanol (7?mg/kg) and aqueous (18?mg/kg), administered orally for 20 days, against 3-NP (10?mg/kg, i.p. for 14 days) was assessed by their effect on body weight, locomotor activity, grip strength, gait pattern and cognitive dysfunction and biochemical parameters for oxidative damage in the striatum and cortex regions of the brain.

Results: CPEE (100 and 200?mg/kg) treated animals exhibited a significant (p?p?Conclusions: CPEE has a protective action against 3-NP induced HD like symptoms due to its strong antioxidant effect.     

Suramin ameliorates collagen induced arthritis

Suramin, a polysulfonated polyaromatic symmetrical urea is known for multiple therapeutic effects including antineoplastic activity. It is known as an antagonist of ATP at P2X purinergic receptors. Suramin is also found to inhibit protein synthesis affecting both initiation and elongation of the polypeptide chain. As a growth factor blocker, it is reported to suppress experimental myocardial inflammation. Here, we describe the anti-arthritic property of suramin in the collagen induced arthritic (CIA) rat, a model of human rheumatoid arthritis (RA). Intraperitoneal (i.p) injection of suramin (10 mg/kg/day) for 3 weeks was found to reduce inflammation and repair joint destruction in CIA rats. Recovery of body weight (p<0.0001), reduction in splenic (p<0.05) and arthritic indices (p<0.0001) and reappearance of smooth synovial lining after suramin treatment to CIA rats were found to be significant. Levels of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6 in plasma and joint extracts were reduced (p<0.0001) significantly in response to suramin treatment. Several acute phase proteins were normalized after suramin administration.     

A pH-triggered delayed-release chronotherapeutic drug delivery system of aceclofenac for effective management of early morning symptoms of rheumatoid arthritis

Abstract

Context: Rheumatoid arthritis (RA) is differentiated as an early morning exacerbation of the core arthritis condition associated with increase in pain and stiffness in joints and necessitate for medication. Objective: The aim of the present work was to develop and optimise a pH-triggered delayed-release colon-specific aceclofenac microspheres and to accomplish chronotherapy of RA. Methods: A 3-factor, 3-level Box–Behnken design (BBD) was used to optimise selected variables. Developed formulation was evaluated for in vivo delayed response and anti-arthritis activity in rats. Results: The particle size and encapsulation efficacy of these microspheres were 117.36?±?10.54?µm and 85.06?±?5.85%, respectively. Optimised formulation was analysed by SEM, DSC, X-RPD and FTIR. The in vivo evaluation reveled delayed anti-inflammatory activity in carrageenan-induced rats and anti-arthritic activity in freund’s adjuvant-induced arthritis rats. Conclusion: The optimised aceclofenac microspheres formulation is potential for the chronotherapy of early morning symptoms of RA.     

Protective effects of fenofibrate and resveratrol in an aggressive model of rheumatoid arthritis in rats

Context Fibrates were reported to have anti-inflammatory effects while the naturally occurring polyphenol resveratrol was traditionally known as a potent antioxidant agent.

Objective The effects of fenofibrate and resveratrol were investigated on complete Freund’s adjuvant (CFA)-induced rheumatoid arthritis (RA) in adult female albino rats.

Materials and methods Rats were divided into a normal control group, an arthritis control group receiving CFA, two reference treatment groups receiving dexamesathone (1.5?mg/kg/day) and methotrexate (1?mg/kg/day), and two treatment groups receiving fenofibrate (100?mg/kg/day) and resveratrol (10?mg/kg/day) for seven consecutive days. Assessment of RA was performed by measuring serum rheumatoid factor (RF), matrix metalloprotinease-3 (MMP-3) and cartilage oligomeric matrix protein (COMP) as specific rheumatoid biomarkers, immunoglobulin G (IgG) and antinuclear antibody (ANA) as immunological biomarkers, tumour necrosis factor-alpha (TNF-α) and interleukin-10 (IL-10) as immunomodulatory cytokines, myeloperoxidase (MPO) and C-reactive protein (CRP) as inflammatory biomarkers and malondialdehyde (MDA) and glutathione (GSH) as oxidative stress biomarkers, supported by a histopathological study on joints and spleens.

Results Serum RF, MMP-3, COMP, IgG, ANA, TNF-α, MPO, CRP and MDA were decreased to about 36, 56, 66, 65, 9, 35, 24, 44 and 31% by fenofibrate, and to about 37, 59, 44, 70, 5, 30, 23, 33 and 28% by resveratrol treatments, respectively. Alternatively, serum IL-10 and GSH were significantly increased to about 215 and 251% by fenofibrate and to about 225 and 273% by resveratrol treatments, respectively.

Discussion and conclusion Fenofibrate and resveratrol protect against RA, possibly through their immunomodulatory, anti-inflammatory and antioxidant potential.     

Anti-rheumatic activity of Ananas comosus fruit peel extract in a complete Freund’s adjuvant rat model

Context: Rheumatoid arthritis is a chronic, autoimmune and systemic inflammatory disease, which targets synovial joints leading to joint destruction mediated in part by migration of inflammatory cells into the synovial tissue.

Objective: The present study evaluates the anti-rheumatic effect of a methanol extract of Ananas comosus (L.) Merr. (Bromeliaceae) peel in rats.

Materials and methods: Anti-rheumatic activity of crude extract of peels of A. comosus in complete Freund’s induced arthritis model in rats was studied at doses of 50, 100, 250 and 500?mg/kg b.w. for 21 days. Parameters such as paw size, levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), C-reactive proteins (CRP) and prostaglandins (PGE₂) were analysed.

Results: Oral administration of the extract significantly reduced the swelling in the paw of rats (EC₅₀ 65.1?±?2.95?mg/kg b.w.) with a maximal inhibition of 77.01?±?10.53% on 21st day at 500?mg/kg b.w. The extract also significantly reduced the levels of SOD, CAT and GPx in liver (EC₅₀ 26.84?±?16.37, 68.37?±?19.22, 106.54?±?34.81?mg/kg b.w., respectively), kidney (EC₅₀ 261.75?±?81.5, 176.38?±?8.08, 14.32?±?6.64, mg/kg b.w., respectively) and spleen (EC₅₀ 152.14?±?39.57, 83.97?±?14.6, 47.1?±?10.45?mg/kg b.w., respectively); and CRP (EC₅₀ 36.37?±?12.4?mg/kg b.w.) and PGE₂ (EC₅₀ 191.06?±?71.54?mg/kg b.w.) in tissue homogenate and serum, respectively, at 500?mg/kg b.w. as compared to arthritic control group.

Discussion and conclusion: These results suggest that A. comosus fruit peel extract exerts anti-rheumatic activity.