Melatonin as an antioxidant: physiology versus pharmacology

Despite more than 1000 scientific publications (more than 50% of which were performed in vivo) documenting that melatonin reduces free radical damage, in the last decade there are small number of reports that claim that melatonin is not an antioxidant because it must be given in what is referred to as pharmacological doses to abate the molecular destruction associated with toxic reactants. A recent paper from Wurtman [1] argued this point. Making this statement indicates that the author either is unfamiliar with or ignored the published literature. In fact, even under extremely intensive oxidative stress conditions, surgical removal of the pineal gland, which reduces physiological circulating melatonin levels and renders animals somewhat melatonin deficient, exaggerates the degree of free radicalmediated molecular destruction and tissue loss. Furthermore, there is also evidence that endogenous concentrations of melatonin limit the amount of molecular destruction that occurs [2, 3]. Thus, even physiological levels of melatonin normally combat some free radical damage [4–6]. So the statement that physiological levels of melatonin are inconsequential in resisting oxidative damage may be erroneous. Wurtman [1] goes on to claim that for exogenously administered melatonin to have antioxidative actions, it must be given in doses that increase blood concentrations up to 100,000-fold above physiological levels. While the amounts of melatonin often given unquestionably cause much higher than physiological levels in blood, these values may not be as exaggerated relative to melatonin levels in some bodily fluids or within cells [7]. By claiming the doses used cause such high levels, the author implies that melatonin concentrations throughout the body are in equilibrium and equivalent to those in blood. Maximal blood concentrations are normally in the low nanomolar range. In some bodily fluids, e.g. bile [8] and cerebrospinal fluid (CSF) [9], measured melatonin concentrations are orders of magnitude greater than in the circulation; this may also be true for some other bodily fluids. Furthermore, melatonin concentrations within cells (especially those that produce melatonin for their own use, e.g. gut, retina, skin, some bone marrow cells, etc.), are also very likely significantly greater than in blood. Until melatonin concentrations are, in fact, known for all bodily fluids and subcellular organelles [7], the statement that melatonin doses >0.3 mg cause pharmacological elevations in humans may be wrong when referring these levels to those in the CSF and bile (and subcellular organelles). Admittedly, the amounts of melatonin given do normally cause melatonin levels to exceed physiological concentrations in blood; however, for other fluids, cells and subcellular organelles this statement may be invalid. Finally, the expectation that physiological concentrations of melatonin (or any antioxidant) could overcome the massive free radical destruction that occurs under severe oxidative stress conditions, e.g. during ischaemia/reperfusion injury, is naı̈ve. The reason that so much molecular damage and cellular death occurs under these extreme conditions is that all physiological antioxidants combined, i.e. b-carotene, vitamin E, vitamin C, melatonin, glutathione, uric acid, antioxidative enzymes, etc. are incapable of resisting the tissue destruction that accompanies these damaging episodes. Thus, any antioxidant used to effectively reduce free radical damage under such severe conditions must be administered in pharmacological doses. Wurtman [1] also states that melatonin’s efficacy as an antioxidant has not been satisfactorily compared with vitamin C or E in terms of their relative antioxidative capacities. Melatonin has been compared in a number of reports to the classic vitamin antioxidants, and in virtually all these studies it was either equivalently effective and, in many reports, more effective in subduing free radical-based molecular damage [10–12]. Considering the low toxicity of melatonin and the fact that it has been effectively used to reduce free radical damage and prevent death in human newborns with high free radical-related conditions [13, 14], should make it of extreme clinical interest. Many conditions under which massive free radical damage is conspicuous are of short duration, e.g. stroke, heart attack, septic shock, etc. so the interval of melatonin administration would also be of short duration and the presumptive long-term effects, if there are any, of its use would not be a consideration. In summary, melatonin has antioxidant capability at both physiological and pharmacological levels and it should not be overlooked as a protective agent against free radical damage. As a matter of semantics, an author may dispute the specific term antioxidant when applied to melatonin, but cannot deny its ability to reduce free radical damage. Total length limitations of this article prevented the authors from citing all of the germane literature; further published reports can be found by doing the appropriate searches.