Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and n1-acetyl-5-methoxykynuramine (AMK), in macrophages

被引:254
作者
Mayo, JC [1 ]
Sainz, RM
Tan, DX
Hardeland, R
Leon, J
Rodriguez, C
Reiter, RJ
机构
[1] Univ Oviedo, Dept Morfol & Biol Celular, Asturias, Spain
[2] Univ Oviedo, IUOPA, Oviedo, Spain
[3] Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78284 USA
[4] Univ Gottingen, Inst Zool & Anthropol, D-3400 Gottingen, Germany
关键词
melatonin; AFMK; AMK; COX-2; INOS; raw; 264.7; macrophage; Lps;
D O I
10.1016/j.jneuroim.2005.05.002
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Inflammation is a complex phenomenon involving multiple cellular and molecular interactions which must be tightly regulated. Cyclooxygenase-2 (COX) is the key enzyme that catalyzes the two sequential steps in the biosynthesis of PGs from arachidonic acid. The inducible isoform of COX, namely COX-2, plays a critical role in the inflammatory response and its over-expression has been associated with several pathologies including neurodegenerative diseases and cancer. Melatonin is the main product of the pineal gland with well documented antioxidant and immuno-modulatory effects. Since the action of the indole on COX-2 has not been previously described, the goal of the present report was to test the effect of melatonin on the activities of COX-2 and inducible nitric oxide synthase (NOS), using lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as a model. Melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), prevented COX-2 activation induced by LPS, without affecting COX-1 protein levels. The structurally reviewed compound 6-methoxy-melatonin only partially prevented the increase in COX-2 protein levels induced by the toxin. Likewise melatonin prevented NOS activation and reduced the concentration of products from both enzymes, PGE(2) and nitric oxide. Another energenous antioxidant like N-acetyl-cysteine (NAC) did not reduced COX-2 significantly. The current finding corroborates a role of melatonin as an anti-inflammatory agent and, for the first time, COX-2 and NOS as molecular targets for either melatonin or its metabolites AFM - and AMK. These anti-inflammatory actions seem not to be exclusively mediated by the free radical scavenging properties of melatonin. As a consequence, the present work suggests these substances as a new class of potential anti-inflammatory agents without the classical side effects due to COX-1 inhibition. (C) 2005 Elsevier B.V. All rights reserved.
引用
收藏
页码:139 / 149
页数:11
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