Mei Wen-Yi, Yu Ming-Jun, Yao Sen, Wang Kui-Ling, Yao Ri-Sheng
School of Biological and Medical Engineering, Hefei University of Technology.
School of Pharmacy, Anhui University of Chinese Medicine.
Chem Pharm Bull (Tokyo). 2018 Apr 1;66(4):410-415. doi: 10.1248/cpb.c17-00887. Epub 2018 Feb 8.
The anti-inflammatory effects of (R)-2-(1H-Imidazol-1-yl) ethyl-3-(1H-indol-3-yl)-2-(2-p-tolylacetamido)propanamide (RH-1402), a previous designed small molecule Gastrin releasing peptide (GRP) antagonist were evaluated in adjuvant-induced arthritic model of rats, and the inhibitory effect on neutrophil migration induced by GRP was determined by a transwell system experiment in vitro. The arthritis was induced by injection of Complete Freund's Adjuvant (CFA) containing 10 mg/mL of heat killed mycobacterium into the left hind footpad. Experimental rats were randomly divided into 6 groups, including control, placebo, positive control group, RH-1402 of low/middle/high dose group. Disease incidence and severity was evaluated through scoring of the paw edema and histologic features of joint synovial. Blood of all experimental rats was collected for interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) cytokine levels. A transwell system was used to investigate whether RH-1402 would inhibit neutrophils migrating up a gradient of GRP in vitro. RH-1402 (5 and 10 mg/kg) significantly decreased adjuvant induced increased arthritis index during the administration period (days 14-20). Significant inhibition of joint synovial histological features can be found in the RH-1402 treated group, including alleviated Hyperplasia, Inflammatory of infiltration and activation of pannus formation. It also suppressed TNF-α and IL-1β level. Five and 10 mg/kg of RH-1402 significantly inhibited the effect of GRP on neutrophil migration with a dose dependent relationship. These findings indicate that RH-1402 have potential protective anti-inflammatory effects on experimental models of arthritis.
(R)-2-(1H-咪唑-1-基)乙基-3-(1H-吲哚-3-基)-2-(2-对甲苯基乙酰胺基)丙酰胺(RH-1402)是一种先前设计的小分子胃泌素释放肽(GRP)拮抗剂，在佐剂诱导的大鼠关节炎模型中评估了其抗炎作用，并通过体外Transwell系统实验确定了其对GRP诱导的中性粒细胞迁移的抑制作用。通过向左后足垫注射含10mg/mL热灭活分枝杆菌的完全弗氏佐剂(CFA)诱导关节炎。实验大鼠随机分为6组，包括对照组、安慰剂组、阳性对照组、低/中/高剂量RH-1402组。通过爪肿胀评分和关节滑膜组织学特征评估疾病发病率和严重程度。采集所有实验大鼠的血液检测白细胞介素1β(IL-1β)和肿瘤坏死因子α(TNF-α)细胞因子水平。使用Transwell系统研究RH-1402在体外是否会抑制中性粒细胞向GRP梯度迁移。RH-1402(5和10mg/kg)在给药期(第14 - 20天)显著降低佐剂诱导的关节炎指数升高。在RH-1402治疗组可发现对关节滑膜组织学特征有显著抑制作用，包括增生减轻、炎性浸润减轻和血管翳形成激活减轻。它还抑制了TNF-α和IL-1β水平。5和10mg/kg的RH-1402显著抑制GRP对中性粒细胞迁移的作用，呈剂量依赖性关系。这些发现表明，RH-1402对关节炎实验模型具有潜在的保护性抗炎作用。
