The role of melatonin on intracellular oxidative stress: Interaction with Fe-overload

Abstract

Melatonin (MLT) is a ubiquitous compound present in bacteria andeukaryotes, which in vertebrates, is released at night from the pinealgland to induce sleep. There are also extrapineal MLT sources, since it issynthesized in most tissues and organs, such as the retina, immune cells,intestine, and bone marrow. Unlike that of pineal origin, this extrapinealMLT does not get into the bloodstream, it is not under the chronobioticeffect, and shows local antioxidant/anti-inflammatory protection abilitiesfor the tissue or organ that synthesizes it. MLT has been also related withbinding proteins, receptor distribution, and secondary effects bymetabolites. Actions via hormonal subsystems, growth factors andneurotransmission lead to further secondary effects. In the present report,we review the studies on the potential effect of MLT against Fe-overloadinducedtoxicity through its chelating effect on Fe and improvement ofantioxidant status. Up to now, signaling by MLT in the context ofantioxidant protection has been mainly related to the induction ofprotective enzymes and to the suppression of others involved in radicalgeneration, to protect cells from O2 and N2 radical molecules. MLT alsoinfluences both antioxidant enzyme activity and cellular mRNA levels forthese enzymes. Fe-overload induces severe damage to several vital organssuch as the liver, heart and bone, and thus contributes to the dysfunctionof these organs, leading to functional impairment and reduced lifeexpectancy. Moreover, it can affect the balance between pro-oxidants andantioxidants, leading to the decrease in total antioxidant capacity. MLTeffects are uncommonly widespread in several organs since its actions aremediated via membrane receptors, nuclear receptors/binding sites andreceptor-independent mechanisms, i.e., the direct scavenging of freeradicals. Up to now, it is not clear whether the protective actions of MLTare due to MLT per se, to its metabolites, to its ability to stimulateantioxidant enzymes, or due to its action of inhibiting pro-oxidativeenzymes. Taken together, this review briefly summarizes the actions ofMLT in a broad range of effects with a significant regulatory influenceover many of the protection processes against Fe-overload effects.