Antioxidant function of melatonin is well established. However, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK), a melatonin metabolite is a sparingly investigated biogenic amine, especially in relation to its in vivo antioxidant function. We have evaluated the oxidative damage to biomolecules (DNA, protein and lipid) induced by X-irradiation in C57BL mice and the prophylactic action of AFMK. The extent of DNA damage was analyzed by single-cell gel electrophoresis in cerebral cortex and serum 8-hydroxydeoxyguanosine (8-OHdG) levels by enzyme-linked immunosorbent assay. Oxidative modification of protein and lipid was measured in the terms of carbonyl content and 4-HAE + MDA (4-hydroxyalkenal + malondialdehyde) status of brain cortex. Radiation exposure dramatically augmented the level of 8-OHdG in serum as well as DNA migration in the comet tail. AFMK pretreatment significantly inhibited DNA damage. In addition, radiation-induced augmentation of protein carbonyl content and HAE + MDA was ameliorated by AFMK pretreatment. Whole-body exposure of mice to X-irradiation also reduced the level of brain sulfhydryl contents (protein-bound sulfhydryl, total sulfhydryl, and nonprotein sulfhydryl) which were significantly protected by AFMK. Radiation-induced decline in the total antioxidant capacity of plasma was significantly reversed in AFMK pretreated mice. Moreover, AFMK showed a very high level of in vitro hydroxyl radical scavenging potential which was measured by an electron spin resonance (ESR) study of the 2-hydroxy-5,5-dimethyl-1-pyrrolineN-oxide (DMPO-OH) adduct. IC(50) values resulting from ESR analysis was 338.08 nm. The present study indicate that AFMK is a potent antioxidant in both in vivo and in vitro systems.
Evaluation of potential health effects from high energy charged particle radiation exposure during long duration space travel is important for the future of manned missions. Cognitive health of an organism is considered to be maintained by the capacity of hippocampal precursors to proliferate and differentiate. Environmental stressors including irradiation have been shown to inhibit neurogenesis and are associated with the onset of cognitive impairments. The present study reports on the protective effects of N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK), a melatonin metabolite, against high energy charged particle radiation-induced oxidative damage to the brain. We observed that radiation exposure (2.0 Gy of 500 MeV/nucleon (56)Fe beams, a ground-based model of space radiation) impaired the spatial memory of mice at later intervals without affecting the motor activities. AFMK pretreatment significantly ameliorated these neurobehavioral ailments. Radiation-induced changes in the population of immature and proliferating neurons in the dentate gyrus were localized using anti-doublecortin (Dcx) and anti-Ki-67 expression. AFMK pretreatment significantly inhibited the loss of Dcx and Ki-67 positive cells. Moreover, AFMK pretreatment ameliorated the radiation-induced augmentation of protein carbonyls and 4-hydroxyalkenal + malondialdehyde (MDA + HAE) in the brain and maintained the total antioxidant capacity of plasma and nonprotein sulfhydryl contents in brain.
The present study investigated the prophylactic influence of melatonin against cyclophosphamide-induced oxidative stress in mouse tissues. Lipid peroxidation, reduced glutathione (GSH), glutathione disulphide (GSSG), glutathione peroxidase (GSH-Px) and serum phosphatase levels were analyzed in brain, spleen liver, lungs, kidney and testes. Fifteen days oral administration with melatonin (0.1 mg/kg bw per day) before treatment checked the augmentation of the level of lipid peroxidation, blood GSSG and acid phosphatase caused by an acute treatment with a radiomimetic drug, cyclophosphamide (75 mg/kg bw). Cyclophosphamide-induced depletion in the level of GSH, GSH-Px and alkaline phosphatase was made up statistically significant by chronic melatonin administration given orally. The results indicate the antioxidative properties of melatonin resulting into its prophylactic property against the cyclophosphamide-induced biochemical alterations. The finding support the idea that melatonin is a potent free-radical scavenger and antioxidant.
Radiation is an important therapeutic tool in the treatment of cancer. The tremendous development in radiotherapeutic techniques and dosimetry has made it possible to augment the patient survival. Therefore, attention has focused on long-range treatment side effects especially in relation to the neurocognitive changes. As cognitive health of an organism is considered to be maintained by the capacity of hippocampal neurogenesis, this study designed to evaluate the delayed effect of cranial irradiation on hippocampal neurogenesis, possible implication of oxidative stress and prophylactic action of melatonin in mice. One month after cranial irradiation (6 Gy, X-ray), changes in the population of immature and proliferating neurons in dentate gyrus were localized through the expression of the microtubule binding protein doublecortin (Dcx) and proliferation marker Ki-67. We found a substantial reduction in the Dcx and Ki-67 positive cells after irradiation. Melatonin pretreatment significantly ameliorated the radiation-induced decline in the Dcx and Ki-67 positive cells. In addition, profound increase in the 4-hydroxynonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine positive cells were reported in subventricular zone, granular cell layer and hilus after day 30 postirradiation. Immunoreactivity of these oxidative stress markers were significantly inhibited by melatonin pretreatment. To confirm the magnitude of free-radical scavenging potential of melatonin, we measured the in-vitro OH radical scavenging power of melatonin by electron spin resonance. Interestingly, the melatonin was capable of scavenging the OH radicals at very low concentration (IC(50) = 214.46 nm). The findings indicate the possible benefit of melatonin treatment to combat the delayed side effects of cranial radiotherapy.
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