Melatonin is essentially a non-toxic endogenous compound synthesized mainly by the pineal gland in human brain. It co-regulates several vital physiological processes in mammals and reportedly has anti-aging and life-prolonging effects. Of particular interest is the demonstration that melatonin has the ability to scavenge free radicals. Both in vitro and in vivo investigations revealed that melatonin scavenges hydroxyl and peroxyl radicals, and peroxynitrite anion, and to act as an antioxidant. On a molar basis, the oxygen radical scavenging capacity of melatonin was found to be twice as high as vitamin C and vitamin E. Melatonin is also reported to activate several cellular enzymatic antioxidant defense mechanisms. In mammalian tissues, both endogenously produced and exogenously administered melatonin is reported to be more highly concentrated in the nucleus than in the cytosol. Thus, melatonin may be present in highest concentrations in the portions of the cell that contains the most sensitive target molecule (nuclear and mitochondrial DNA) for the action of ionizing radiation.
The radioprotective ability of melatonin was examined in several investigations. In in-vitro studies, human peripheral blood lymphocytes which were pre-treated with melatonin exhibited significantly reduced extent (60-70%) of in vitro gamma radiation-induced genetic damage, determined from the incidence of chromosomal aberrations and micronuclei, as compared with irradiated cells which were not pre-treated with melatonin (Vijayalaxmi et al. 1995a,b; 1996a). In an in vivo study, it has been demonstrated that the lymphocytes in the blood samples (from human volunteers) collected at 1 and 2 hours after a single oral dose of 300 mg of melatonin and exposed in vitro to 1.5 Gy gamma radiation exhibited a significant decrease in the extent of primary DNA damage in the form of single strand breaks (20-30%), and in the incidence of chromosomal aberrations and micronuclei (60-70%), as compared with similarly irradiated lymphocytes from the blood sample collected before melatonin ingestion (Vijayalaxmi et al., 1996b, 1998a). From these data, it is hypothesized that the (i) melatonin in the nucleus bestow a direct protection in reducing the primary DNA damage by scavenging the radiation-induced free radicals, and (ii) melatonin may be acting at the cell membrane and in the cytosol by generating "signals" that trigger the activation of one or more of the existing DNA repair enzymes, and/or activation of a set of gene(s) that lead to de novo protein synthesis associated with the repair of damaged DNA. The newly synthesized and/or activated DNA repair enzymes provide the cells with additional repair of damaged DNA, thereby reducing the incidence of chromosomal aberrations and micronuclei determined after 48 and 72 hours, respectively (Vijayalaxmi et al., 1998b). Whole-body irradiation studies have also demonstrated that pre-treatment of mice with melatonin significantly increased their survival from lethal effects of acute LD50/30 dose of gamma radiation (Vijayalaxmi et al., 1999a), and significantly reduced the extent of ionizing radiation-induced genetic damage in their peripheral blood and bone marrow cells (Vijayalaxmi et al. 1999b). These data will be presented in detail.
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