Departments of Pharmacy, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Drug Des Devel Ther. 2020 Oct 5;14:4101-4113. doi: 10.2147/DDDT.S256850. eCollection 2020.
To overcome negative adverse effects and improve therapeutic index of dexamethasone (Dex) in rheumatoid arthritis (RA), we developed a novel sustained release formulation-intra-articular injectable dexamethasone-loaded thermosensitive hydrogel (DLTH) with chitosan-glycerin-borax as carrier for the remission of inflammation and pain. The focus of this article is to explore both anti-inflammatory and pain-relieving effects of DLTH joint injection in bovine type-II collagen-induced arthritis (CIA) rats.
Wistar rats were randomized into three groups, including the normal group (n=6), the model group (n=6) and the DLTH group (n=10). Joint injection of DLTH (1mg/kg Dex per rat) was injected on day 12 in the DLTH group twice a week for three weeks. Clinical signs of body weight, paw swelling and arthritis scores, histologic analysis, hind paw mechanical withdrawal threshold (MWT), plantar pressure pain threshold (PPT) were taken into consideration. Serum contents of IL-17A, prostaglandin E2 (PGE2), prostacyclin 2 (PGI2) and prostaglandin D2 (PGD2), real-time polymerase chain reaction (PCR) analysis of inflammatory factors and pain-related mediators in synovium and dorsal root ganglia (DRG), Western blotting of NF-κB in synovium were all evaluated.
Paw swelling, arthritis scores and joint inflammation destruction were all attenuated in the DLTH-treated group. Results showed that DLTH not only down-regulated serum IL-17A, but also mRNA levels of inflammatory factors and NGF, and key proteins contents of the NF-κB pathway in synovium. Increases of MWT and PPT in DLTH-treated rats elucidated pain-reducing effects of DLTH. Elevated serum PGD2 levels and declines of serum PGE2 and PGI2, and inflammatory and pain-related genes in DRGs in the DLTH group were also recorded.
These data elucidated that DLTH joint injection impeded synovial inflammation processes through down-regulating transcription activity of NF-κB pathway, and intra-articular DLTH may aid in the regulation of RA pain through regulating inflammation and pain conduction process.
为了克服地塞米松（Dex）在类风湿关节炎（RA）中的负面不良反应并提高其治疗指数，我们开发了一种新型的持续释放制剂——壳聚糖-甘油-硼砂作为载体的关节内注射地塞米松负载温敏水凝胶（DLTH），用于缓解炎症和疼痛。本文的重点是探讨 DLTH 关节内注射在牛型 II 型胶原诱导关节炎（CIA）大鼠中的抗炎和止痛作用。
Wistar 大鼠随机分为三组，包括正常组（n=6）、模型组（n=6）和 DLTH 组（n=10）。DLTH 组于第 12 天开始每周两次关节内注射 DLTH（每只大鼠 1mg/kg Dex），共 3 周。观察体重、爪肿胀和关节炎评分、组织学分析、后爪机械撤回阈值（MWT）、足底压痛阈值（PPT）等临床症状。检测血清白细胞介素 17A（IL-17A）、前列腺素 E2（PGE2）、前列环素 2（PGI2）和前列腺素 D2（PGD2）含量，实时聚合酶链反应（PCR）分析滑膜和背根神经节（DRG）中炎症因子和痛觉相关介质，Western blot 检测滑膜中 NF-κB 的表达。
DLTH 治疗组大鼠爪肿胀、关节炎评分和关节炎症破坏均减轻。结果表明，DLTH 不仅下调了血清 IL-17A，还下调了滑膜中炎症因子和 NGF 的 mRNA 水平，以及 NF-κB 通路的关键蛋白含量。DLTH 治疗大鼠的 MWT 和 PPT 增加表明 DLTH 具有止痛作用。DLTH 组血清 PGD2 水平升高，血清 PGE2 和 PGI2 水平降低，DRG 中炎症和痛觉相关基因表达下调。
这些数据表明，DLTH 关节内注射通过下调 NF-κB 通路的转录活性，抑制滑膜炎症过程，关节内注射 DLTH 可能通过调节炎症和疼痛传导过程来辅助调节 RA 疼痛。
