Lidun Chen

Melatonin stimulates brain glutathione peroxidase activity

Exogenously administered melatonin causes a 2-fold rise in glutathione peroxidase activity within 30 min in the brain of the rat. Furthermore, brain glutathione peroxidase activity is higher at night than during the day and is correlated with high night-time tissue melatonin levels. Glutathione peroxidase is thought to be the principal enzyme eliminating peroxides in the brain. This antioxidative enzyme reduces the formation of hydroxyl radicals formed via iron-catalyzed Fenton-type reactions from hydrogen peroxide by reducing this oxidant to water. Since the hydroxyl radical is the most noxious oxygen radical known, induction of brain glutathione peroxidase might be an important mechanism by which melatonin exerts its potent neuroprotective effects.

Melatonin, hydroxyl radical‐mediated oxidative damage, and aging: A hypothesis

Abstract: Melatonin is a very potent and efficient endogenous radical scavenger. The pineal indolamine reacts with the highly toxic hydroxyl radical and provides on‐site protection against oxidative damage to biomolecules within every cellular compartment. Melatonin acts as a primary non‐enzymatic antioxidative defense against the devastating actions of the extremely reactive hydroxyl radical. Melatonin and structurally related tryptophan metabolites are evolutionary conservative molecules principally involved in the prevention of oxidative stress in organisms as different as algae and rats. The rate of aging and the time of onset of age‐related diseases in rodents can be retarded by the administration of melatonin or treatments that preserve the endogenous rhythm of melatonin formation. The release of excitatory amino acids such as glutamate enhances endogenous hydroxyl radical formation. The activation of central excitatory amino acid receptors suppress melatonin synthesis and is therefore accompanied by a reduced detoxification rate of hydroxyl radicals. Aged animals and humans are melatonin‐deficient and more sensitive to oxidative stress. Experiments investigating the effects of endogenous excitatory amino acid antagonists and stimulants of melatonin biosynthesis such as magnesium may finally lead to novel therapeutic approaches for the prevention of degeneration and dysdifferentiation associated with diseases related to premature aging.

Melatonin reduces both basal and bacterial lipopolysaccharide-induced lipid peroxidation in vitro

The protective effect of melatonin against lipopolysaccharide (LPS)-induced oxidative damage was examined in vitro. Lung, liver, and brain malonaldehyde (MDA) plus 4-hydroxyalkenals (4-HDA) concentrations were measured as indices of induced membrane peroxidative damage. Homogenates of brain, lung, and liver were incubated with LPS at concentrations of either 1, 10, 50, 200, or 400 micrograms/ml for 1 h and, in another study, LPS at a concentration of 400 micrograms/ml for either 0, 15, 30, or 60 min. Melatonin at increasing concentrations from 0.01-3 mM either alone or together with LPS (400 micrograms/ml) was used. Liver, brain, and lung MDA + 4-HDA levels increased after LPS at concentrations of 10, 50, 200 or 400 micrograms/ml; this effect was concentration-dependent. The highest levels of lipid peroxidation products were observed after tissues were incubated with an LPS concentration of 400 micrograms/ml for 60 min; in liver and lung this effect was totally suppressed by melatonin and partially suppressed in brain in a concentration-dependent manner. In addition, melatonin alone was effective in brain at concentrations of 0.1 to 3 mM, in lung at 2 to 3 mM, and in liver at 0.1 to 3 mM; in all cases, the inhibitory effects of melatonin on lipid peroxidation were always directly correlated with the concentration of melatonin in the medium. The results show that the direct effect of LPS on the lipid peroxidation following endotoxin exposure is markedly reduced by melatonin.

Paraquat toxicity and oxidative damage: Reduction by Melatonin

The ability of melatonin to protect against paraquat-induced oxidative damage in rat lung, liver, and serum was examined. Changes in the levels of malondialdehyde (MDA) plus 4-hydroxyalkenals (4-HDA) and reduced and oxidized glutathione concentrations were measured. Paraquat (50 mg/kg) was injected i.p. into either Sprague-Dawley or Wistar rats with or without the co-administration of 5 mg/kg melatonin. Paraquat alone increased MDA + 4-HDA levels in serum and lungs of both rat strains, with these increases being abolished by melatonin co-treatment. Paraquat also decreased reduced glutathione levels and increased oxidized glutathione concentrations in lung and liver; these changes were negated by melatonin. The effect of melatonin on paraquat-induced mortality was also studied. Paraquat at a dose of 79 mg/kg was lethal for 50% of animals within 24 hr; when administered together with melatonin, the LD50 for paraquat increased to 251 mg/kg.

Elevation of cyclic GMP levels in the rat pineal gland induced by nitric oxide.

Guerrero JM, Reiter RJ, Poeggeler B, Chen L‐D, Tan D‐X. Elevation of cyclic GMP levels in the rat pineal gland induced by nitric oxide. J Pineal Res. 1994:16:210–214.

Mg2+‐dependent and Ca2+, Mg2+‐dependent ATPase activities in the Harderian gland of rodents: Age and sex influences

Three experiments employing male and female Syrian hamsters (aged 1, 2, and 8–10 months), male Sprague‐Dawley rats (aged 1, 2, and 10 months) and male C57Bl mice (aged 2, 7, 13, and 29 months) examined the effects of age and sex on Mg2+‐dependent and Ca2+, Mg2+‐dependent ATPase activity in the Harderian gland. Significant differences due to age and sex were observed in the hamsters and rats but not with age in mice. Generally, male hamsters had significantly higher Mg2+‐dependent and Ca2+, Mg2+‐dependent (exception at one timepoint) ATPase activity than did females. Age‐matched male and female rats had similar values of Mg2+‐dependent ATPase activity, but males had significantly higher Ca2+, Mg2+‐dependent ATPase activity than females at 2 months of age.