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

Autor: Tjahjono Y; Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Karnati S; Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany., Foe K; Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Anggara E; Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Gunawan YN; Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Wijaya H; Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Steven; Faculty of Medicine, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Suyono H; Faculty of Medicine, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Esar SY; Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Hadinugroho W; Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Wihadmadyatami H; Faculty of Veterinary Medicine, Universitas Gadjah Mada, Jalan Fauna 2, Sleman, 55281, Yogyakarta, Indonesia., Ergün S; Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany., Widharna RM; Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia., Caroline; Faculty of Pharmacy, Widya Mandala Catholic University Surabaya, Jalan Kalisari Selatan 1, Surabaya, 60237, East Java, Indonesia. Electronic address: caroline@ukwms.ac.id.
Jazyk: angličtina
Zdroj: Prostaglandins & other lipid mediators [Prostaglandins Other Lipid Mediat] 2021 Jun; Vol. 154, pp. 106549. Date of Electronic Publication: 2021 Apr 05.
DOI: 10.1016/j.prostaglandins.2021.106549
Abstrakt: 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-CH 2 Cl) 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-CH 2 Cl showed a higher affinity towards protein receptor cyclooxygenase-2 (COX-2; PDB: 5F1A) than ASA. We hypothesized that 3-CH 2 Cl 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-CH 2 Cl 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-CH 2 Cl 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-CH 2 Cl powder was evaluated.
Result: After the administration of 500 mg/60 kg bw of 3-CH 2 Cl (rat dosage converted to human) to LPS-induced rats, we observed a significant reduction of both TNF-α (5.70+/-1.04 × 10 3 pg/mL, p=<0.001) and IL-1β (2.32+/-0.28 × 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-CH 2 Cl 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-CH 2 Cl was found to be stable until 3 years at 25°C with a relative humidity of 75 ± 5%.
Conclusion: 3-CH 2 Cl 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-CH 2 Cl 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.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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