Melatonin was originally described as a hormone biosynthesized from L-tryptophan within the pineal gland in the brain; it was found to regulate sleep patterns. Since its discovery, this remarkable molecule has been found to be a potent antioxidant, protecting mitochondria from oxidative stress [reviewed by Leon J, Acuna-Castroviejo D, Sainz RM, Mayo JC, Tan DX, Reiter RJ. Melatonin and mitochondrial function. Life Sci. 2004 Jul 2;75(7):765-90.] It may also act directly on the electron transport chain, increasing ATP synthesis while preventing the oxidative damage associated with such an increase. [Acuna-Castroviejo D, Escames G, Leon J, Carazo A, Khaldy H. Mitochondrial regulation by melatonin and its metabolites. Adv Exp Med Biol. 2003;527:549-57.] These authors also found that melatonin restored levels of the important antioxidant glutathione.
Melatonin is a remarkably mobile molecule and is able to pass into any tissue, cell or cell compartment with ease. [reviewed by Hardeland R, Pandi-Perumal SR. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutr Metab (Lond). 2005 Sep 10;2(1):22.] These authors observe that, unusually for a hormone, melatonin is a normal dietary constituent, and is found in yeasts and plants; walnuts are a particularly rich source. Dietary melatonin can markedly influence blood-levels. [Reiter RJ, Manchester LC, Tan DX.Melatonin in walnuts: Influence on levels of melatonin and total antioxidant capacity of blood. Nutrition. 2005 Sep;21(9):920-4.] The fact that melatonin is found in the diet removes some of the hesitation which one may have in using it for supplementation.
Melatonin protects against endotoxin-induced lipid peroxidation. [Sewerynek E, Melchiorri D, Chen L, Reiter RJ. Melatonin reduces both basal and bacterial lipopolysaccharide-induced lipid peroxidation in vitro. Free Radic Biol Med. 1995 Dec;19(6):903-9.] This is very important in the CNS, where key lipids are relatively unprotected by other antioxidants.
Reiter and colleagues, in a comprehensive review, observe: 'Melatonin reduces oxidative stress by several means. Thus, the indole [melatonin] is an effective scavenger of both the highly toxic hydroxyl radical, produced by the 3 electron reduction of oxygen, and the peroxyl radical, which is generated during the oxidation of unsaturated lipids and which is sufficiently toxic to propagate lipid peroxidation. Additionally, melatonin may stimulate some important antioxidative enzymes, i.e., superoxide dismutase, glutathione peroxidase and glutathione reductase. In in vivo tests, melatonin in pharmacological doses has been found effective in reducing macromolecular damage that is a consequence of a variety of toxic agents, xenobiotics and experimental paradigms which induce free radical generation. In these studies, melatonin was found to significantly inhibit oxidative damage that is a consequence of paraquat toxicity, potassium cyanide administration, lipopolysaccharide treatment, kainic acid injection, carcinogen administration, carbon tetrachloride poisoning, etc., as well as reducing the oxidation of macromolecules that occurs during strenuous exercise or ischemia-reperfusion. In experimental models which are used to study neurodegenerative changes associated with Alzheimer's and Parkinson disease, melatonin was found to be effective in reducing neuronal damage. Its lack of toxicity and the ease with which melatonin crosses morphophysiological barriers and enters subcellular compartments are essential features of this antioxidant.' [Reiter RJ, Carneiro RC, Oh CS. Melatonin in relation to cellular antioxidative defense mechanisms. Horm Metab Res. 1997 Aug;29(8):363-72.]
Melatonin was found to inhibit the production of endotoxin-induced Tumour Necrosis Factor [Sacco S et al., Mechanism of the inhibitory effect of melatonin on tumor necrosis factor production in vivo and in vitro. Eur J Pharmacol. 1998 Feb 19;343(2-3):249-55.] and in an animal model was found to exert immunoregulatory effects via T-helper 2 (Th2) cell products. Th2 products may modulate the secretion and/or action of inflammatory cytokines, which play an important role in the development of septic shock associated with endotoxemia. [Maestroni GJ. Melatonin as a therapeutic agent in experimental endotoxic shock. J Pineal Res. 1996 Mar;20(2):84-9.]
Post-mortem studies showed diminished levels of melatonin in the ventricular CSF of those who had died with Alzheimer's disease compared with age-matched controls. The same authors found that CSF levels of melatonin in the elderly were much lower than in younger persons. However, melatonin levels were uniformly low in those who had died with presenile and senile dementia. [Liu RY, Zhou JN, van Heerikhuize J, Hofman MA, Swaab DF. Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype. J Clin Endocrinol Metab. 1999 Jan;84(1):323-7.] Melatonin depletion was found to be an early event in the development of Alzheimer's disease. [Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF. Early neuropathological Alzheimer's changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res. 2003 Sep;35(2):125-30.] A loss of the diurnal rhythm of melatonin levels may precede clinical signs of the disease. [Wu YH, Feenstra MG, Zhou JN, Liu RY, Torano JS, Van Kan HJ, Fischer DF, Ravid R, Swaab DF. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab. 2003 Dec;88(12): 5898-906.]
Sleep disorders are common in MS, with a flattening of the normal circadian sleeping/waking rhythm, leading to wakefulness at night and a tendency to somnolence during the day. [Fleming WE, Pollak CP. Sleep disorders in multiple sclerosis. Semin Neurol. 2005 Mar;25(1):64-8. Review.] One cause of this may be decreased nocturnal biosynthesis of melatonin. [Wu YH et al., Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab. 2003 Dec;88(12):5898-906.] Decreased melatonin biosynthesis is associated with pineal calcification. [Kunz D et al., A new concept for melatonin deficit: on pineal calcification and melatonin excretion. Neuropsychopharmacology. 1999 Dec;21(6):765-72.] Pineal calcification is common in MS. [Sandyk R, Awerbuch GI. The pineal gland in multiple sclerosis. Int J Neurosci. 1991 Nov;61(1-2):61-7.] Indeed, nocturnal melatonin levels were found to be lower than daytime levels in 11 of 25 patients with MS. [Sandyk R, Awerbuch GI. Nocturnal plasma melatonin and alpha-melanocyte stimulating hormone levels during exacerbation of multiple sclerosis. Int J Neurosci. 1992 Nov-Dec;67(1-4):173-86. Review] Melatonin is a major antioxidant in the brain, and chronic depletion would be expected to allow widespread oxidative damage in the CNS. [Reiter RJ et al., Reactive oxygen intermediates, molecular damage, and aging. Relation to melatonin. Ann N Y Acad Sci. 1998 Nov 20;854:410-24. Review.]
Melatonin would thus seem a valuable supplement in disease forms characterized by oxidative stress.
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