Contrasting Findings on Melatonin Concerning Inflammation and Glucose Tolerance - Consequences to the Development of Melatonergic Drugs
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2017, Vol 1, Issue 1
Abstract
The pleiotropy of melatonin is a reason for using this hormone or synthetic melatonergic agonists for testing their suitability in various diseases and disorders. However, it is important to remain aware that many preclinical findings cannot be translated to humans, because of the different relationship between melatonin and sleep or activity in diurnally compared to nocturnally active mammals. Other uncertainties concern the dual role of melatonin as an either anti- or proinflammatory agent, depending on conditions. A particular problem has emerged by findings on prodiabetic actions of melatonin in humans, which strongly contrast with antidiabetic results obtained in rats. As these undesired actions are gradually receptor subtype-dependent, it may be worthwhile to test in the future agonists that are more strongly subtype-selective. Melatonin is a highly pleiotropic regulator that exerts effects in the majority of mammalian cells. In the pineal gland, it is mainly synthesized at night, released to the circulation and, via the pineal recess, into the third ventricle of the brain. It transmits the information ‘darkness’ to peripheral organs and to brain areas as well. This association with darkness already implies a profound difference between nocturnally active rodents and day active species such as the human. In rats and mice, high melatonin is related to enhanced alertness, locomotor activity and food intake, whereas the opposite is the case in humans, in whom melatonin acts as a sleep-promoting compound. The correlation with darkness is, except for the retina, either absent or less expressed in melatonin synthesized in extrapineal sites. Concerning immunological actions of melatonin, the gastrointestinal tract (GIT) and leukocyte subtypes are of particular interest, because they synthesize melatonin and express melatonin receptors [1]. Notably, the amounts present in the GIT are about 400 – 500 times higher than in the pineal gland and in the circulation. Functions of extrapineal melatonin have been poorly considered in the context of drug development. The short half life of melatonin in the circulation (20 - 30, maximally 45 min) has prompted investigators to develop synthetic melatonergic agonists with longer persistence in the blood [2-6]. Additionally, the various synthetic agonists differ with regard to receptor affinity and receptor subtype specificity. However, most clinical studies on these compounds have focused on applications in sleep promotion [2-4,7] and, partially, treatment of depression [8,9].
Authors and Affiliations
Rüdiger Hardeland
Keywords
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- EP ID EP566566
- DOI 10.26717/BJSTR.2017.01.000103
- Views 276
- Downloads 0
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