Potent antiarthritic properties of a glucocorticoid derivative, NCX-1015, in an experimental model of arthritis

Here, we describe the improved antiarthritic properties of a nitric oxide-releasing derivative of prednisolone that includes a sparing of the effects on bone. Glucocorticoids are widely used in the treatment of chronic inflammatory pathologies, but their use is often accompanied by side effects, including osteoporosis. Recently, a new steroid able to release low levels of nitric oxide showed potent inhibition of leukocyte trafficking and chemokine generation in models of acute inflammation. The objective of this study was to assess the anti-inflammatory activity of this nitric-oxide releasing glucocorticoid, nitro-prednisolone (NCX-1015), in parallel with the parent compound prednisolone and a control molecule lacking an NO group, (NCX-1016), in a model of rat collagen-induced arthritis. Dosing of rats with NCX-1015 (0.4–4 μmol/kg, i.p.) greatly reduced all parameters of inflammation. A significant but inferior anti-inflammatory effect also was obtained with prednisolone. Collagen-induced arthritic rats had elevated pyridinoline values (>60% over naïve rats), indicating bone and cartilage erosion; this increase was prevented by NCX-1015 but not by prednisolone or NCX-1016 treatment. In vitro, prednisolone (1 nM), but not NCX-1015, elevated bone resorbing activity of rat primary osteoclasts. In conclusion, NCX-1015 is a steroid derivative with a potential for the treatment of chronic inflammatory pathologies and that has milder side effects anticipated on the bone compartment.

本研究阐述了一氧化氮（nitric oxide）释放型泼尼松龙（prednisolone）衍生物的改良抗关节炎特性，该衍生物可减轻对骨骼的不良影响。糖皮质激素（Glucocorticoids）被广泛应用于慢性炎症性疾病的临床治疗，但其使用常伴随包括骨质疏松症（osteoporosis）在内的多种副作用。近期研究发现，一种可释放低水平一氧化氮的新型甾体类化合物，在急性炎症模型中可强效抑制白细胞迁移与趋化因子生成。本研究旨在评估该一氧化氮释放型糖皮质激素——硝基泼尼松龙（nitro-prednisolone, NCX-1015）的抗炎活性，并将其与母体化合物泼尼松龙以及不含一氧化氮基团的对照分子NCX-1016进行对比，实验采用大鼠胶原诱导性关节炎（collagen-induced arthritis, CIA）模型。以0.4~4 μmol/kg的剂量对大鼠腹腔注射NCX-1015，可显著降低所有炎症相关参数；泼尼松龙也可产生显著但稍弱的抗炎效果。胶原诱导性关节炎模型大鼠的吡啶啉（pyridinoline）水平较未造模正常大鼠升高60%以上，提示存在骨与软骨侵蚀；该水平升高可被NCX-1015阻断，但泼尼松龙与NCX-1016均无此保护作用。体外实验显示，1 nM浓度的泼尼松龙可增强大鼠原代破骨细胞（osteoclasts）的骨吸收活性，而NCX-1015无此作用。综上，NCX-1015是一种甾体类衍生物，有望用于慢性炎症性疾病的治疗，且预期对骨骼系统的副作用更为温和。