Anti-inflammatory activity of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid in LPS-induced rat model

Tjahjono, Yudy and Karnati, Srikanth and Foe, Kuncoro and Anggara, Efendi and Gunawan, Yongky Novandi and Wijaya, Hendy and Steven, Steven and Suyono, Handi and Esar, Senny Yesery and Hadinugroho, Wuryanto and Wihadmadyatami, Hevi and Ergun, Suleyman and Widharna, Ratna Megawati and Caroline, Caroline (2021) Anti-inflammatory activity of 2-((3-(chloromethyl)benzoyl)oxy)benzoic acid in LPS-induced rat model. PROSTAGLANDINS & OTHER LIPID MEDIATORS, 154. ISSN 1098-8823

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Abstract

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 antiinflammatory 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 cyclooxygenase2 (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-1 beta and TNF-alpha (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-alpha (5.70+/-1.04 x 10(3) pg/mL, p=<0.001) and IL-1 beta (2.32+/-0.28 x 10(3) 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 degrees 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-kappa beta 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.

Item Type: Article
Uncontrolled Keywords: Anti-inflammatory activity; 2-((3-(Chloromethyl)benzoyl)oxy)benzoic acid; COX; LPS; Rat
Subjects: Veterinary Medicine
Divisions: Faculty of Veterinary Medicine
Depositing User: Sri JUNANDI
Date Deposited: 19 Oct 2024 08:50
Last Modified: 19 Oct 2024 08:50
URI: https://ir.lib.ugm.ac.id/id/eprint/9172

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