Anti-Inflammatory Comparison of Melatonin and Its Bromobenzoylamide Derivatives in Lipopolysaccharide (LPS)-Induced RAW 264.7 Cells and Croton Oil-Induced Mice Ear Edema.

Pimpichaya Sangchart,Pramote Mahakunakorn,Ploenthip Puthongking,Teerasak Damrongrungruang,Aroonsri Priprem,Panyada Panyatip

doi:10.3390/molecules26144285

Pimpichaya Sangchart, Pramote Mahakunakorn + Show 4 more

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https://doi.org/10.3390/molecules26144285

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Abstract

The pineal gland is a neuroendocrine organ that plays an important role in anti-inflammation through the hormone melatonin. The anti-inflammatory effects of melatonin and its derivatives have been reported in both in vitro and in vivo models. Our previous study reported the potent antioxidant and neuroprotective activities of bromobenzoylamide substituted melatonin. In silico analysis successfully predicted that melatonin bromobenzoylamid derivatives were protected from metabolism by CYP2A1, which is a key enzyme of the melatonin metabolism process. Therefore, the anti-inflammatory activities of melatonin and its bromobenzoylamide derivatives BBM and EBM were investigated in LPS-induced RAW 264.7 macrophages and croton oil-induced ear edema in mice. The experiments showed that BBM and EBM significantly reduced production of the inflammatory mediators interleukin-6 (IL-6), prostaglandin E2 (PGE2), and nitric oxide (NO) in a dose-dependent manner, but only slightly affected TNF-α in LPS-induced RAW 264.7 macrophages. This suggests that modifying melatonin at either the N1-position or the N-acetyl side chain affected production of NO, PGE2 and IL-6 in in vitro model. In the croton oil-induced mouse ear edema model, BBM, significantly decreased ear edema thickness at 2–4 h. It leads to conclude that bromobenzoylamide derivatives of melatonin may be one of the potential candidates for a new type of anti-inflammatory agent.

Highlights

Inflammation is a defense mechanism against pathogens
Macrophages play an important role in the inflammatory response to pathogens by releasing pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, cyclooxygenase (COX)-2, and nitric oxide (NO) [1]
Overproduction of these mediators and non-resolution of inflammation leads to the pathophysiology of many chronic inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), chronic obstructive pulmonary disease (COPD), Crohn’s disease, ulcerative colitis and some neurodegenerative diseases [2]

Summary

Introduction

Inflammation is a defense mechanism against pathogens. It is a complex process involving multiple cell types and mediators. Macrophages play an important role in the inflammatory response to pathogens by releasing pro-inflammatory mediators, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, cyclooxygenase (COX)-2, and nitric oxide (NO) [1]. N1-acetyl-5-methoxykynuramine (AMK), have antioxidant and anti-inflammatory ules 2021, 26, x FOR PEER REVIEW activities They are highly efficient NO scavengers [3,4,5,6], and melatonin has been shown to reduce the production of pro-inflammatory cytokines such as interferon gamma (IF-γ), TNFα, IL-1β, and IL-6, inhibit NO production, and suppress inducible nitric oxide synthase (iNOS) and COX-2 gene expression [4,7,8]. It is well known that inflammation processes are related to in free radicals such as reactive oxygen species (ROS) [6]

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