IV.

ANTIOXIDANT ACTIONS (For background on free radicals and antioxidants, see THE FREE RADICAL THEORY OF AGING and General AntiOxidant Actions.) Melatonin is a very powerful anti-oxidant. Unlike Vitamin C or glutathione, which are only active in aqueous (watery) phase and Vitamin E, which is only active in lipid (oily) phase, melatonin is effective in both aqueous and lipid phases. Unlike Vitamin E and Vitamin C, which cannot readily cross the blood-brain barrier, melatonin easily crosses the blood-brain barrier [EXPERIMENTAL BIOLOGY AND MEDICINE; Reiter, RJ; 230:104-117 (2005)] Melatonin is twice as effective at protecting cell membranes from lipid peroxidation as Vitamin E [PHARMACOLOGY LETTERS; Pieri,C; 55(15):271276 (1994)]. Melatonin is five times more effective than glutathione for neutralizing hydroxyl radicals the free radicals normally responsible for more than half of all free radical damage in the body (causing lipid peroxidation, DNA damage and protein oxidation). Melatonin and adenosinemay be particularly important in protecting brain cells because glutathione concentrations are not very high in the brain. Melatonin in combination with deprenyl significantly counteracts hydroxyl radical production associated with dopamine autoxidation in the brain, and the combination effect is significantly greater than the effect of either agent alone [JOURNAL OF PINEAL RESEARCH; Khaldy,H; 29(2):100-107 (2000)]. In one study, melatonin was more than 60 times more effective than Vitamin C or water-soluble Vitamin E in protecting DNA from DNA damage [ENVIRONMENTAL HEALTH PERSPECTIVES; Qi, W; 108:399-402 (2000)]. Melatonin may bind to DNA, providing further protection beyond antioxidant activity. Melatonin concentrations are particularly high in mitochondria and the cell nucleus. DNA in mitochondria are particularly vulnerable to damage because mitochondria have fewer DNA-repair enzymes than nuclear DNA and because mitochondrial DNA lack the protective histone proteins which nuclear DNA have. By its ability to penetrate readily into mitochondria, by directly protecting mitochondrial DNA and by inducing antioxidant enzymes in mitochondria, melatonin may greatly protect mitochondria. Melatonin demonstrably protects mitochondrial DNA from the damaging effects of ethyl alcohol binges in brain, heart and skeletal muscle, as well as in the liver [JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS; Mansouri,A; 298(2):737-743 (2001)]. Twenty-five years after proposing the free-radical theory of aging, Denham Harman proposed a mitochondrial free-radical theory of aging based on the observation that mitochondria are the source of most cellular free radicals [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES

(USA); Harman,D; 78(11):7124-7128 (1981)]. Fruit flies given melatonin increased maximum lifespan by one-third and median lifespan by oneeighth [EXPERIMENTAL GERONTOLOGY; Bonilla,E; 37:629-638 (2002)]. Along with its antioxidant actions, melatonin directly facilitates mitochondrial electron transport chain enzymes in the production of ATP [THE INTERNATIONIAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY; Martin,M; 34(4):348-357 (2002)]. In addition to the hydroxyl & peroxyl radical, melatonin neutralizes superoxide, singlet oxygen, hydrogen peroxide and hypochlorous acid [ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 959:238-250 (2002)]. Melatonin inhibits peroxynitrite formation by inhibition of the enzyme nitric oxide synthetase in some brain tissues [LIFE SCIENCES; Leon, J.; 75:765-790 (2004)]. Melatonin increases gene expression and activity of the anti-oxidant enzymes glutathione peroxidase, superoxide dismutase and catalase [JOURNAL OF PINEAL RESEARCH; Rodriguez,C; 36(1):1-9 (2004)]. The effect of glutathione peroxidase induction is considerable a four-fold increase of the antioxidant enzyme in brain mitochondria and an eightfold increase in liver mitochondria with a 100 nanoMolar melatonin concentration [THE FASEB JOURNAL; Martin,M; 14(12):1677-1679 (2000)]. The chief metabolite of melatonin, 6-hydroxymelatonin (formed in the liver) has as much anti-oxidant activity as melatonin. In fact, the reaction products of melatonin with hydroxyl radical and hydrogen peroxide are themselves anti-oxidants [ACTA BIOCHEMICA POLONICA; Reiter,RJ; 54(1):1-9 (2007)]. Vitamin C can become a toxic pro-oxidant when exposed to free iron, and most anti-oxidants become weak free radicals after having neutralized a free radical. But melatonin's antioxidant action involves donation of two electrons, not one electron, thereby ensuring that melatonin does not become a free radical. (return to contents)