Ahmad Sheikh Fayaz, Zoheir Khairy M A, Bakheet Saleh A, Ashour Abdelkader E, Attia Sabry M
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, PO Box 11451, Riyadh, Saudi Arabia; Department of Cell Biology, National Research Centre, Cario, Egypt.
Cytokine. 2014 Aug;68(2):76-85. doi: 10.1016/j.cyto.2014.04.006. Epub 2014 May 4.
Rheumatoid arthritis (RA) is one of the major autoimmune diseases of global prevalence. Irrespective of much research in RA disease, no drugs with capable safety profiles are yet available. Poly(ADP-ribose) polymerase-1 (PARP-1) synthesizes and transfers ADP ribose polymers to target proteins, and regulates DNA repair and genomic integrity maintenance. PARP-1 also plays a crucial role in the progression of the inflammatory response, and its inhibition confers protection in several models of inflammatory disorders. We investigated the possible anti-arthritic effects of the PARP-1 inhibitor 5-aminoisoquinolinone (5-AIQ) in a mouse model of adjuvant induced arthritis (AIA). In this study, we examined the effects of 5-AIQ on the key mediators of arthritic inflammation, namely, edema and arthritic score, T cell subsets, regulatory T (Treg) cells, IL-17A, GITR expressing cells, NF-kB p65, IkB-α and pro and anti-inflammatory mediators mRNA expression levels. PARP-1 inhibition 5-AIQ treatment significantly attenuated the severity of AIA, reduced the arthritis scores, a substantial reduction in the levels of T cell subsets, IL-17A, NF-kB p65, GITR expressing cells, and as well as the pro-inflammatory mediators. However, 5-AIQ significantly up-regulated the number of Tregs cells, IkB-α levels and mRNA expression of anti-inflammatory mediators. Our results suggest that treatment with 5-AIQ attenuated AIA in mice might offer a promising alternative/adjunct treatment for RA.
类风湿性关节炎（RA）是全球流行的主要自身免疫性疾病之一。尽管对RA疾病进行了大量研究，但尚无具有可靠安全性的药物。聚（ADP - 核糖）聚合酶 - 1（PARP - 1）合成并将ADP核糖聚合物转移到靶蛋白上，并调节DNA修复和基因组完整性维持。PARP - 1在炎症反应的进展中也起着关键作用，其抑制作用在几种炎症性疾病模型中具有保护作用。我们在佐剂诱导性关节炎（AIA）小鼠模型中研究了PARP - 1抑制剂5 - 氨基异喹啉酮（5 - AIQ）可能的抗关节炎作用。在本研究中，我们检测了5 - AIQ对关节炎炎症关键介质的影响，即水肿和关节炎评分、T细胞亚群、调节性T（Treg）细胞、IL - 17A、表达糖皮质激素诱导肿瘤坏死因子受体（GITR）的细胞、NF - kB p65、IkB - α以及促炎和抗炎介质mRNA表达水平。PARP - 1抑制性5 - AIQ治疗显著减轻了AIA的严重程度，降低了关节炎评分，大量减少了T细胞亚群、IL - 17A、NF - kB p65、表达GITR的细胞以及促炎介质的水平。然而，5 - AIQ显著上调了Tregs细胞数量、IkB - α水平和抗炎介质的mRNA表达。我们的结果表明，用5 - AIQ治疗减轻小鼠AIA可能为RA提供一种有前景的替代/辅助治疗方法。
