Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvant-induced arthritis
Spinal adenosine receptor activation inhibits inflammation and joint destruction in rat adjuvant-induced arthritis
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DOI：
10.1002/art.10595
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发表时间：
2002-11-01
影响因子：
--
通讯作者：
Firestein, GS
中科院分区：
文献类型：
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作者：
Boyle, DL;Moore, J;Firestein, GS
Objective.观察脊髓腺苷（Ado）受体激动对大鼠佐剂性关节炎（AIA）的影响。将长期鞘内（IT）导管植入大鼠体内，为药物输送提供脊髓通路。在尾基部用完全弗氏佐剂免疫动物。8天后和此后每隔一天直至第20天，用选择性Ado A1受体激动剂环己基腺苷（CHA）或溶媒IT处理大鼠。在一些实验中，动物接受额外的非选择性Ado拮抗剂茶碱的每日腹膜内注射。通过水置换体积描记法测量爪肿胀。采用电迁移率变动分析法测定IT CHA对激活蛋白I（AP-1）活化的影响。免疫组化法检测脊髓c-Fos表达。脊柱CHA显著抑制AIA中的炎症，IT CHA组的爪肿胀平均增加+/- SEM 20.9 +/- 16.9%，而生理盐水组为81.3 +/- 10.6%。CHA的抗心律失常作用是通过Ado受体介导的，因为该作用可被全身性茶碱联合给药逆转。此外，X光片显示，在CRA治疗的动物中，骨和软骨破坏显著减少。AP-1是金属蛋白酶表达的关键调节因子，其滑膜表达在IT CRA处理的动物中较低。C-Fos表达定位于脊髓I-VI层，ITCHA治疗组浅层C-Fos表达轻度降低。这些数据表明，脊髓可以调节外周炎症。针对中枢神经系统的治疗策略可能对关节炎有用。
Objective. To examine the effect of spinal cord adenosine (Ado) receptor stimulation on rat adjuvant-induced arthritis (AIA).Methods. Long-term intrathecal (IT) catheters were implanted into rats to provide spinal access for drug delivery. Animals were immunized with complete Freund's adjuvant at the tail base. Eight days later and every other day thereafter until day 20, rats were treated IT with the selective Ado A1 receptor agonist cyclohexyladenosine (CHA) or vehicle. In some experiments, animals received an additional daily intraperitoneal injection of the nonselective Ado antagonist theophylline. Paw swelling was measured by water displacement plethysmometry. The effect of IT CHA on the activation of activator protein I (AP-1) was determined by electro-mobility shift assay. Spinal cord c-Fos expression was determined by immunohistochemistry.Results. Spinal CHA significantly inhibited inflammation in AIA, with a mean +/- SEM 20.9 +/- 16.9% increase in paw swelling in the IT CHA group compared with 81.3 +/- 10.6% in the saline group. The antiinflammatory effect of CHA was mediated through Ado receptors since the effect was reversed by coadministration of systemic theophylline. In addition, radiographs showed significantly less bone and cartilage destruction in the CRA-treated animals. Synovial expression of AP-1, which is a key regulator of metalloproteinase expression, was lower in IT CRA-treated animals. C-Fos expression was localized to spinal laminae I-VI, with a modest decrease observed in the superficial laminae in IT CHA-treated rats.Conclusion. These data demonstrate that the spinal cord can regulate peripheral inflammation. Therapeutic strategies that target the central nervous system might be useful in arthritis.