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Anti-inflammatory activity of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid in LPS-induced rat model
ProstaglandIns & Other Lipid Mediators ( IF 2.5 ) Pub Date : 2021-04-05 , DOI: 10.1016/j.prostaglandins.2021.106549
Yudy Tjahjono 1 , Srikanth Karnati 2 , Kuncoro Foe 1 , Efendi Anggara 1 , Yongky Novandi Gunawan 1 , Hendy Wijaya 1 , Steven 3 , Handi Suyono 3 , Senny Yesery Esar 1 , Wuryanto Hadinugroho 1 , Hevi Wihadmadyatami 4 , Süleyman Ergün 2 , Ratna Megawati Widharna 1 , Caroline 1
Affiliation  

Introduction

Salicylic acid derivate is very popular for its activity to suppress pain, fever, and inflammation. One of its derivatives is acetylsalicylic acid (ASA) which has been reported repeatedly that, as a non-steroidal anti-inflammatory drug (NSAID), it has a cardioprotective effect. Although ASA has various advantages, several studies have reported that it may induce severe peptic ulcer disease. We recently synthesized a new compound derived from salicylic acid, namely 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid (3-CH2Cl) which still has the benefit of acetylsalicylic acid as an analgesic and antiplatelet, but lacks its harmful side effects (Caroline et al., 2019). In addition, in silico studies of 3-CH2Cl showed a higher affinity towards protein receptor cyclooxygenase-2 (COX-2; PDB: 5F1A) than ASA. We hypothesized that 3-CH2Cl inhibits the COX-2 activity which could presumably decrease the inflammatory responses. However, no knowledge is available on the anti-inflammatory response and molecular signaling of this new compound. Hence, in this study, we investigated the potential functional relevance of 3-CH2Cl in regulating the inflammatory response in lipopolysaccharide (LPS)-induced rats. The results of this study show that this compound could significantly reduce the inflammatory parameter in LPS-induced rats.

Material and methods

Rats were induced with LPS of 0.5 mg/kg bw intravenously, prior oral administration with vehicle (3% Pulvis Gummi Arabicum / PGA), 500 mg/60 kg body weight (bw; rat dosage converted to human) of 3-CH2Cl and ASA. The inflammatory parameters such as changes in the temperature of septic shock, cardiac blood plasma concentrations of IL-1β and TNF-α (ELISA), blood inflammation parameters, white blood cell concentrations, and lung histopathology were observed. Meanwhile, the stability of 3-CH2Cl powder was evaluated.

Result

After the administration of 500 mg/60 kg bw of 3-CH2Cl (rat dosage converted to human) to LPS-induced rats, we observed a significant reduction of both TNF-α (5.70+/-1.04 × 103 pg/mL, p=<0.001) and IL-1β (2.32+/-0.28 × 103 pg/mL, p=<0.001) cardiac blood plasma concentrations. Besides, we found a reduction of white blood cell concentration and the severity of lung injury in the 3-CH2Cl group compared to the LPS-induced rat group. Additionally, this compound maintained the rat body temperature within normal limits during inflammation, preventing the rats to undergo septic shock, characterized by hypothermic (t = 120 min.) or hyperthermic (t = 360 min) conditions. Furthermore, 3-CH2Cl was found to be stable until 3 years at 25°C with a relative humidity of 75 ± 5%.

Conclusion

3-CH2Cl compound inhibited inflammation in the LPS-induced inflammation response model in rats, hypothetically through binding to COX-2, and presumably inhibited LPS-induced NF-κβ signaling pathways. This study could be used as a preliminary hint to investigate the target molecular pathways of 3-CH2Cl as a novel and less toxic therapeutical agent in alleviating the COX-related inflammatory diseases, and most importantly to support the planning and development of clinical trial.



中文翻译:


2-((3-(氯甲基)苯甲酰基)氧基)苯甲酸在LPS诱导的大鼠模型中的抗炎活性


 介绍


水杨酸衍生物因其抑制疼痛、发烧和炎症的活性而广受欢迎。其衍生物之一是乙酰水杨酸(ASA),多次报道其作为非甾体类抗炎药(NSAID)具有心脏保护作用。尽管 ASA 具有多种优点,但一些研究报道它可能诱发严重的消化性溃疡病。我们最近合成了一种由水杨酸衍生的新化合物,即2-((3-(氯甲基)苯甲酰基)氧基)苯甲酸(3-CH 2 Cl),它仍然具有乙酰水杨酸作为镇痛剂和抗血小板剂的优点,但缺乏其有害的副作用(Caroline et al., 2019)。此外,3-CH 2 Cl 的计算机模拟研究显示,与 ASA 相比,3-CH 2 Cl 对蛋白质受体环氧合酶-2 (COX-2;PDB:5F1A) 的亲和力更高。我们假设 3-CH 2 Cl 抑制 COX-2 活性,这可能会减少炎症反应。然而,目前尚不清楚这种新化合物的抗炎反应和分子信号传导。因此,在本研究中,我们研究了 3-CH 2 Cl 在调节脂多糖 (LPS) 诱导的大鼠炎症反应中的潜在功能相关性。本研究结果表明,该化合物可以显着降低 LPS 诱导的大鼠的炎症参数。

 材料与方法


大鼠用0.5mg/kg体重的LPS静脉注射诱导,之前口服赋形剂(3%阿拉伯胶粉剂/PGA)、500mg/60kg体重(体重;大鼠剂量换算为人)的3-CH 2 Cl和ASA。观察感染性休克时体温变化、心肌血浆IL-1β和TNF-α浓度(ELISA)、血液炎症参数、白细胞浓度、肺组织病理学等炎症参数。同时,对3-CH 2 Cl粉末的稳定性进行了评价。

 结果


给 LPS 诱导的大鼠施用 500 mg/60 kg bw 3-CH 2 Cl(大鼠剂量换算为人剂量)后,我们观察到 TNF-α 显着降低(5.70+/-1.04 × 10 3 pg/ mL, p=<0.001) 和 IL-1β (2.32+/-0.28 × 10 3 pg/mL, p=<0.001) 心脏血浆浓度。此外,我们发现与LPS诱导的大鼠组相比,3-CH 2 Cl组的白细胞浓度降低,肺损伤的严重程度降低。此外,该化合物在炎症期间将大鼠体温维持在正常范围内,防止大鼠遭受感染性休克,其特征是体温过低(t = 120 分钟)或体温过高(t = 360 分钟)条件。此外,发现 3-CH 2 Cl 在 25°C、相对湿度 75 ± 5% 的条件下可稳定保存 3 年。

 结论


3-CH 2 Cl 化合物假设通过与 COX-2 结合,抑制 LPS 诱导的大鼠炎症反应模型中的炎症,并可能抑制 LPS 诱导的 NF-κβ 信号通路。本研究可作为初步探讨3-CH 2 Cl作为一种新型低毒治疗剂减轻COX相关炎症性疾病的靶分子途径,最重要的是支持临床试验的规划和开展。

更新日期:2021-04-11
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