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A triazole carboxamide class of drugs in a variety of models and some anti-inflammatory mechanism of action

Author: ZhengRu
Tutor: ZhangDeChang;YeCaiYing
School: Peking Union Medical College , China
Course: Pharmacology
Keywords: Triazole carboxamide Adjuvant arthritis Ulcerative colitis NF-κB Cytokines
CLC: R96
Type: PhD thesis
Year: 2010
Downloads: 300
Quote: 0
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Background rheumatoid arthritis, non-specific inflammatory bowel disease and other autoimmune diseases in our country showed an increasing trend in the incidence, but its etiology, pathogenesis remains unclear. Corticosteroids, non-steroidal anti-inflammatory drugs to treat such diseases commonly used drugs, but long-term use of these drugs toxic side effects, and for some patients is invalid, so the development of less toxic and can be effective in treating these diseases is important . Triazole carboxamide (carboxyamidotriazole, CAI) is a way to inhibit the influx of extracellular calcium compound, its in vitro and in vivo models were shown to inhibit tumor growth and metastasis, In addition, the compounds also inhibit angiogenesis, peanut arachidonic acid release and, in some cases, inhibition of NF-κB pathway activation effect. Our group by in vivo experiments have shown that the drug for acute, subacute and chronic inflammation were significant anti-inflammatory effect. In order to investigate the drug for certain inflammatory diseases of the potential therapeutic effect, we established adjuvant arthritis model and TNBS-induced colitis model, observe the efficacy of CAI, and from the tissue level, cellular and molecular level. explore the mechanism of anti-inflammatory effects of CAI, as a basis for further clinical studies. Research methodology established adjuvant arthritis model to paw volume, body weight, food consumption, and arthritis score for the evaluation visits CAI on rat primary lesions and secondary lesions effect. Venous blood and the rats were killed, HE staining of synovial tissue changes, measured by ELISA in serum and paw homogenate TNF-α and IL-1β levels. Homogenates of rat paw was measured PGE2 and NO levels. Established TNBS-induced colitis model to mortality, body weight, food consumption, clinical score, macroscopic and histological score evaluation score was investigated CAI on TNBS-induced colitis. Venous blood and the rats were killed, HE staining of histological changes in the colon for mucosal damage scores. Determination of the colon homogenate MPO activity. Measured by ELISA in serum and colon homogenates TNF-α and IL-6 levels. Observed by immunohistochemical methods in rat colon NF-κB and ICAM-1 activation or expression. Detect rat colon homogenate MDA content and SOD activity. Nitrate reduction assay using rat colon homogenates NO content. Using Masson's staining of rat colon tissue collagen deposition conditions were measured by ELISA colon homogenates TGF-β1 levels. In peritoneal macrophages as the object investigated the mechanism of CAI, MTT assay CAI in normal rats and rats with adjuvant arthritis peritoneal macrophage cell viability. Measured by ELISA in normal rats, rats with adjuvant arthritis and colitis rat peritoneal macrophages multiple cytokines levels. Determination of CAI PEG2 on macrophages and other inflammatory mediators NO. Determined by Western Blot using peritoneal macrophages in a variety of inflammation-related signaling protein expression and activation of the situation. Determined by immunocytochemistry the activation of NF-κB. Determined using the neutral red rat peritoneal macrophage phagocytosis. Through carbon clearance test, chicken erythrocytes induced hemolysin experiments and DNFB-induced delayed-type hypersensitivity in normal mice investigated CAI immune system. Results 1.CAI (10,20 and 40 mg / kg) to a dose-dependent improvement of primary rat adjuvant arthritis lesions and secondary lesions, CAI (20 and 40 mg / kg) can significantly improvement of laboratory animals paw swelling, weight, food consumption and joint score. CAI (20 mg / kg) on ??joint symptoms have occurred but did not occur completely irreversible lesions in animals have a certain effect. CAI (20 mg / kg) in combination with dexamethasone after the drug is more effective than either drug when used alone situations, and animal weight loss, and other adverse reactions and dexamethasone alone quite. 2. CAI (20 mg / kg) on ??rat paw tissue content of PGE2 had no significant effect. And dexamethasone is able to significantly reduce the adjuvant arthritis rat paw tissue content of PGE2 (p <0.001). CAI (20 mg / kg) and dexamethasone were able to significantly reduce the adjuvant arthritis rat paw in the NO content (p <0.01 and p <0.001). 3. CAI (20 mg / kg), respectively, can make the plantar tissue of TNF-α and IL-1β levels decreased 54.1% and 26.3% respectively (both p <0.05), and dexamethasone inhibition rather, serum TNF- α and IL-1β levels are also subject to CAI (both p <0.05) and dexamethasone significantly inhibited. 4 fumble modeling agent Experimental results show that the dose, 75 mg / kg TNBS / ethanol can successfully induced ulcerative colitis model in which intestinal pathological changes similar to human ulcerative colitis pathological changes. Ulcerative colitis mucosal congestion, edema, erosion or ulceration, mucosal inflammatory cell infiltration (mainly neutrophils) and crypt abscess formation. CAI (20,30 and 40 mg / kg) in a dose-dependent improvement in rats with experimental colitis symptoms of acute colitis and colonic fibrosis cases, CAI (30 and 40 mg / kg) can significantly improve the experimental animal's death rate, body weight, food consumption, clinical score, macroscopic and histological score score and so on. Generally see CAI (30 and 40 mg / kg) treatment group animals colon congestion, bowel wall thickening was significantly reduced mucosal defect small shallow; Histological see colon mucosal damage involving narrow, telangiectasia, follicular hyperplasia , submucosal edema and crypt structural damage is reduced significantly. 5 compared with the control group, TNBS-induced colitis rat colon homogenates of MPO activity increased, giving experimental animals CAI (40 mg / kg) after, MPO activity was significantly lower (p <0.05). 6. CAI (40 mg / kg), respectively, can make the colon tissue TNF-α and IL-6 levels decreased 52.68% (p <0.01) and 57.15% (p <0.01), its inhibitory effect on TNF-α is stronger than SASP, but slightly lower than Infliximab, but CAI for the inhibition of IL-6 is stronger than SASP and Infliximab. Serum TNF-α and IL-6 levels are also subject to CAI (inhibition rates were 75.35% [p <0.001] and 32.57% [p <0.01]) a significant inhibition. 7 gives experimental animals CAI (40 mg / kg) after colitis colon tissue MDA and NO were significantly decreased, while SOD activity was significantly increased. Compared with PEG400, MDA and NO levels were reduced by 25.97% and 41.58% (both p <0.05), SOD activity increased 49.23% (p <0.01). 8 Immunohistochemical detection showed that rats with ulcerative colitis colon tissue NF-κB p65 nuclear translocation and ICAM-1 expression was significantly increased by CAI treatment, rat colon tissue NF-κB p65 nuclear translocation and ICAM-1 expression was significantly decreased. 9 ulcerative colitis rat CAI (40mg/kg) treatment, colon homogenates TGF-β1 levels were significantly decreased (p <0.01). Masson's trichrome staining results showed, CAI can significantly reduce the rat colon tissue deposition of collagen fibers. 10.CAI of normal rats and rats with adjuvant arthritis peritoneal macrophage activity were not affected, CAI in normal rats and rats with adjuvant arthritis peritoneal macrophage phagocytosis was not affected. 11 For normal rat peritoneal macrophages concerned, CAI effect after 18 h, CAI (20 and 40μmol / L) could inhibit the generation amount of TNF-α (p <0.05 and p <0.01). CAI (10,20 and 40μmol / L) could inhibit the generation amount of IL-6 (p <0.05, p <0.01 and p <0.001). CAI (10,20 and 40μmol / L) could inhibit the generation amount of INF-γ (p <0.05, p <0.01 and p <0.01). For the adjuvant arthritis rat peritoneal macrophages concerned, CAI (20 mg / kg) can make the adjuvant arthritis rat peritoneal macrophages TNF-α, IL-6 and INF-γ levels were decreased 63.56% (p <0.01), 14.52% (p <0.05) and 80.81% (p <0.01), CAI while the IL-10 can be increased, but the results compared with the PEG400 was no significant difference. For colitis rat peritoneal macrophages concerned, CAI (40mg/kg) can significantly reduce TNBS-induced colitis rat peritoneal macrophages TNF-α and IL-6 generation capacity (p <0.001), inhibition rate respectively, 77.05% and 56.66%. 12 For normal rat peritoneal macrophages, respectively, of the concentrations of 10, 20 and 40μmol / L of CAI and rat peritoneal macrophages together 18 h (while adding LPS stimulation) after a dose dependent inhibits the generation of NO. CAI able to produce significant expression of iNOS inhibition, and with CAI formation of NO inhibition same trend. For the adjuvant arthritis rat peritoneal macrophages concerned, compared with PEG400, CAI (20mg/kg) on ??rat peritoneal macrophage supernatants did not affect the amount of PGE2. CAI (20 mg / kg) can significantly reduce the adjuvant arthritis rat peritoneal macrophages supernatant NO content (p <0.01). CAI (20 mg / kg) for COX-2 and iNOS protein expression consistent with the above results. 13 For normal rat peritoneal macrophages concerned, DMSO group macrophage nuclei and cytoplasm NF-κB p65 staining were darker, and CAI (20μmol / L) group macrophage nuclei almost no staining cytoplasm staining is also lighter, suggesting that CAI can inhibit p65 into the nucleus. 10 and 20, respectively, and a concentration of 40μmol / L of CAI and rat peritoneal macrophages together 18 h (while adding LPS stimulation), the LPS-induced IκBα degradation will produce significant blocking effect, CAI can reduced LPS-induced IκBα phosphorylation, these effects were shown a dose-dependent manner. For the adjuvant arthritis rat peritoneal macrophages concerned, CAI (20 mg / kg) capable of p65 nuclear translocation and degradation of IκB-α and phosphorylated produce significant blocking effect. CAI (20mg/kg) can inhibit adjuvant arthritis in rat peritoneal macrophages JNK and p38 MAPK phosphorylation. However, the drugs on the non-phosphorylated JNK and p38 expression has no effect. 14. CAI (20 mg / kg) in normal mice did not affect the ability of carbon clearance, CAI (20 mg / kg) of chicken erythrocytes induced formation of hemolysin no inhibitory effect, CAI (20 mg / kg) on DNFB-induced delayed-type hypersensitivity in mice without inhibition. Conclusion CAI adjuvant arthritis in rats and TNBS induced colitis have a better therapeutic effect. Various animal models and cell levels were prompted studies, CAI to inhibit NF-κB pathway activation associated and by scavenging reactive oxygen species, inhibition of TNF-α, IL-6 and NF-κB activation, blocking each activation Positive feedback path, blocking IL-6, IL-1β and other cytokines, the final performance of a variety of pro-inflammatory cytokine levels decreased, thereby improving a variety of inflammatory symptoms. In addition, CAI on the role of macrophages mainly in the inhibition of cytokine secretion, and macrophage phagocytic function has no effect, CAI not by suppressing the immune system play a role in inflammation. In summary, our findings can be speculated, CAI as an orally active, with fewer side effects and affordable drugs for the clinical treatment of autoimmune diseases with high potential value.

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