The fact that the full extent of the function of the pineal gland has not yet been elucidated, has stimulated melatonin research worldwide. This review introduces melatonin's mechanism of action, direct and indirect antioxidant actions as well as the antioxidant properties of its metabolites, 6-hydroxymelatonin (6-OHM) and N-acetyl-N-formyl-5-methoxykynurenamine (AFMK). At present the mechanism of action is proposed to be receptor-, protein- and nonprotein-mediated. From its popular role in the treatment of jetlag, melatonin is now implicated in the reduction of oxidative stess, both as a free radical scavenger and antioxidant. Melatonin's direct scavenging action in respect of the following will be discussed: superoxide anions, hydrogen peroxide, hydroxyl radicals, singlet oxygen, peroxy radicals and nitric oxide/peroxy nitrite anions. In addition melatonin also possesses indirect antioxidant activity and the role of its metabolites, AFMK and 6-OHM will be presented. It is these free radical scavenging and antioxidant properties of melatonin that has shifted the focus from that of merely strengthening circadian rhythms to that of neuroprotectant: a new place in therapy.
Abbreviation: 6-OHM, 6-hydroxymelatonin; AFMK, N-acetyl-N-formyl-5-methoxykynurenamine; GPx, Glutathione peroxidase; GRd, Glutathione reductase; SOD, Superoxide dismutase; NOS, Nitic oxide synthase; CaCaM, Ca2+-calmodulin; NO·, Nitric oxide; iNOS, inducible Nitric oxide synthetase; ·OH, Hydroxyl radical; O2−•, Superoxide anions; H2O2, Hydrogen peroxide; CAT, Catalase; THA, Terephthalic acid; DHBA, Dihydroxybenzoic acid; 1O2, Singlet oxygen; LOO·, Peroxyl radicals; ONOO-, Nitric oxide/peroxynitrite anions; G6PD, Glucose-6-phosphate dehydrogenase; GSH, Reduced glutathione; AD, Alzheimers disease; PD, Parkinsons disease