Department of Clinical and Experimental Medicine, Pharmacology Section, University of Ferrara, Ferrara, Italy.
PLoS One. 2013;8(1):e54195. doi: 10.1371/journal.pone.0054195. Epub 2013 Jan 11.
A(2A) adenosine receptors (ARs) play a key role in the inhibition of the inflammatory process. The purpose of this study was to evaluate the modulation of A(2A)ARs in rheumatoid arthritis (RA) patients after different pharmacological treatments and to investigate the effect of A(2A)AR stimulation in a rat model of arthritis. We investigated A(2A)AR density and functionality in RA progression by using a longitudinal study in RA patients before and after methotrexate (MTX), anti-TNFα agents or rituximab treatments. A(2A)ARs were analyzed by saturation binding assays in lymphocytes from RA patients throughout the 24-month study timeframe. In an adjuvant-induced arthritis model in rats we showed the efficacy of the A(2A)AR agonist, CGS 21680 in comparison with standard therapies by means of paw volume assessment, radiographic and ultrasonographic imaging. Arthritic-associated pain was investigated in mechanical allodynia and thermal hyperalgesia tests. IL-10 release following A(2A)AR stimulation in lymphocytes from RA patients and in serum from arthritic rats was measured. In lymphocytes obtained from RA patients, the A(2A)AR up-regulation was gradually reduced in function of the treatment time and the stimulation of these receptors mediated a significant increase of IL-10 production. In the same cells, CGS 21680 did not affected cell viability and did not produced cytotoxic effects. The A(2A)AR agonist CGS 21680 was highly effective, as suggested by the marked reduction of clinical signs, in rat adjuvant-induced arthritis and associated pain. This study highlighted that A(2A)AR agonists represent a physiological-like therapeutic alternative for RA treatment as suggested by the anti-inflammatory role of A(2A)ARs in lymphocytes from RA patients. The effectiveness of A(2A)AR stimulation in a rat model of arthritis supported the role of A(2A)AR agonists as potential pharmacological treatment for RA.
A(2A) 腺苷受体 (ARs) 在抑制炎症过程中发挥着关键作用。本研究旨在评估不同药物治疗后类风湿关节炎 (RA) 患者 A(2A)AR 的调节作用,并研究 A(2A)AR 刺激在关节炎大鼠模型中的作用。我们通过对接受甲氨蝶呤 (MTX)、抗 TNFα 药物或利妥昔单抗治疗前后的 RA 患者进行纵向研究,来研究 A(2A)AR 在 RA 进展中的密度和功能。我们在 24 个月的研究时间内,通过饱和结合试验分析 RA 患者淋巴细胞中的 A(2A)AR。在大鼠佐剂诱导关节炎模型中,我们通过评估爪容积、放射学和超声成像,比较了 A(2A)AR 激动剂 CGS 21680 与标准疗法的疗效。在机械性痛觉过敏和热痛觉超敏试验中研究了关节炎相关疼痛。通过测量 RA 患者淋巴细胞和关节炎大鼠血清中 A(2A)AR 刺激后的 IL-10 释放来评估 IL-10 释放。在 RA 患者的淋巴细胞中,随着治疗时间的延长,A(2A)AR 的上调逐渐减少,而这些受体的刺激介导了 IL-10 产生的显著增加。在相同的细胞中,CGS 21680 不会影响细胞活力,也不会产生细胞毒性作用。A(2A)AR 激动剂 CGS 21680 非常有效,正如在大鼠佐剂诱导性关节炎和相关疼痛中明显减少临床症状所表明的那样。这项研究强调,A(2A)AR 激动剂代表了一种类似生理的 RA 治疗替代方案,因为 A(2A)AR 在 RA 患者的淋巴细胞中发挥抗炎作用。A(2A)AR 刺激在关节炎大鼠模型中的有效性支持了 A(2A)AR 激动剂作为 RA 潜在药物治疗的作用。