Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages.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 pineal gland (pĭn`eəl), small organ (about the size of a pea) situated in the brain. Long considered vestigial in humans, the structure, which is also called the pineal body or the epiphysis, is present in most vertebrates. with well documented antioxidant and immuno-modulatory effects. Since the action of the indole indole /in·dole/ (in´dol) a compound obtained from coal tar and indigo and produced by decomposition of tryptophan in the intestine, where it contributes to the peculiar odor of feces. It is excreted in the urine in the form of indican. 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 The nitric oxide synthase (NOS; EC 1.14.13.39) is an enzyme in the body that contributes to transmission from one neuron to another, to the immune system and to dilating blood vessels. (iNOS), using lipopolysaccharide lipopolysaccharide /lipo·poly·sac·cha·ride/ (-pol?e-sak´ah-rid) 1. a molecule in which lipids and polysaccharides are linked. 2. (LPS LPS - Sets with restricted universal quantifiers. ["Logic Programming with Sets", G. Kuper, J Computer Sys Sci 41:44-64 (1990)]. )-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 related compound 6-methoxy-melatonin only partially prevented the increase in COX-2 protein levels induced by the toxin. Likewise melatonin prevented iNOS activation and reduced the concentration of products from both enzymes, PGE(2) and nitric oxide. Another endogenous antioxidant like Nacetyl- cysteine cysteine (sĭs`tēn), organic compound, one of the 20 amino acids commonly found in animal proteins. Only the l-stereoisomer participates in the biosynthesis of mammalian protein. (NAC See network access control. ) did not reduced COX-2 significantly. The current finding corroborates a role of melatonin as an antiinflammatory agent and, for the first time, COX-2 and iNOS as molecular targets for either melatonin or its metabolites AFMK 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. J Neuroimmunol. 2005 Aug;165(1-2):139-49 |
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