Identification of \u03b2-carboline and canthinone alkaloids as anti-inflammatory agents but with different inhibitory profile on the expression of iNOS and COX-2 in lipopolysaccharide-activated RAW 264.7 macrophages

Pan Liu,Qiuli Chao,Kazuo Koike,Feng Zhao,Keiichi Matsuzaki,Ruiling Luan,Yanan Liu,Guiyan Huang,Huaying Fan,Linyu Li,Mengdi Wang,Wei Li,Danna Li,Daquan Chen,Liying Wang,Huixiang Li

doi:10.1007/s11418-018-1251-5

Abstract

A compound library, which consists of 75 natural β-carboline-type or canthinone-type alkaloids from Simaroubaceae plants and their chemical synthetic analogues, was screened for the anti-inflammatory activity by inhibition of the overproduction of inflammatory mediator nitric oxide (NO) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophage cells. Six compounds, namely, benzalharman (23), kumujian (27), 1-ethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (37), 1-acetophenone-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (42), cathin-6-one (46), and 9-methoxy-cathin-6-one (57), exhibited significant inhibitory activity on the overproduction of NO with good dose dependency. Further investigation demonstrated that all of the six compounds down-regulated the high expression of inducible nitric oxide synthase (iNOS) protein. Among them, two canthinone-type alkaloids (46 and 57) potently down-regulated cyclooxygenase-2 (COX-2) protein expression in a dose-dependent manner and also inhibited the overproduction of inflammatory mediator prostaglandin E2 (PGE2). However, the β-carboline-type alkaloids (23, 27, 37, and 42) exhibited no obvious inhibition on the overproduction of PGE2 and the expression of COX-2 protein. The results suggested that β-carboline-type alkaloids and canthinone-type alkaloids may exert an anti-inflammatory effect through different mechanism.

Highlights

Nitric oxide (NO) is a biological messenger molecule and neurotransmitter, which is synthesized by NO synthase (NOS) in multiple cells
Many studies have reported that the high expression of inducible nitric oxide synthase (iNOS) and COX-2 promotes the overproduction of NO and PGE2 in activated macrophages, respectively
The results indicated the potential of a number of β-carbolinetype alkaloids and canthinone-type alkaloids in the compound library as anti-inflammatory agents

Summary

Introduction

Nitric oxide (NO) is a biological messenger molecule and neurotransmitter, which is synthesized by NO synthase (NOS) in multiple cells. Three types of NOS, namely neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), produce NO through the catalytic reaction of l-arginine and dioxygen. COX-2, the key enzyme in the process of P GE2 synthesis, is highly expressed during the process of inflammatory reaction induced by LPS [4]. Many studies have reported that the high expression of iNOS and COX-2 promotes the overproduction of NO and PGE2 in activated macrophages, respectively. Excessive production of such inflammatory mediators and high expression of inflammatory proteins can result in chronic inflammatory diseases [5,6,7]. Chronic inflammation has been linked with various diseases, such as systemic lupus erythematosus, rheumatoid arthritis, hepatitis, cancer, and so on [8,9,10,11]

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Results

Conclusion