Anti-inflammatory and Antiplatelet effects of Leflunomide
| Autor: | Shiu-Jen Chen, 陳秀貞 |
|---|---|
| Rok vydání: | 2004 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 92 英文摘要 The isoxazole derivative leflunomide is a novel immunomodulating and anti-inflammatory agent currently being used for treatment of the transplant rejection immunosuppressive agent, rheumatoid arthritis, autoimmune diseases and transplant rejection. However, the true anti-inflammatory mechanism of leflunomide is still unclear. Therefore, the first aim of this study is to evaluate whether leflunomide has analgesic effect in a rat model of carrageenan-evoked theremal hyperalgesia and further investigates the possible mechanisms invoved. Our results show that the pre- or post-treatment with leflunomide significantly inhibits the carrageenan-evoked thermal hyperalgesia. The possible mechanisms may be associated with the decreased formation of nitric oxide and prostaglandin E2 due to the attenuation of inducible nitric oxide synthase and cyclooxygenase-2 protein expression in carrageenan-injected rat paws. Furthermore, leflunomide also suppresses the formation of tumor necrosis factor-alpha and increases the interleukin-10 production in the paw exudates. The myeloperoxidase activity in carrageenan-injected paws is also inhibited by leflunomide. The second aim of this study is to investigate whether leflunomide has antiplatelet effect and further explores the possible mechanisms involved. Preincubation of the rabbit washed platelet with leflunomide (10 ~ 100 µM) inhibits the dose-dependent platelet aggregation that is induced by arachidonic acid (100 µM) or collagen (10 µg/mL) with IC50 about 50 µM. Our data further indicate that the possible anti-aggregatory mechanisms may include (1) inhibition of thromboxane B2 formation through the suppressing of cyclooxygenase and thromboxane synthase activity of platelets (2) increase of platelat membrane fluidity (3) attenuation of the platelet surface glycoprotein Ⅱb/Ⅲa (GPⅡb/Ⅲa) expression (4) suppression of intraplatelet calcium mobilization. This study demonstrates that leflunomide is not only an effective anti-inflammatory and analgesic agent but also an antiplatelet aggregatory inhibitor. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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