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Journal Article 2002; 23(Suppl 1): 3-8 PubMed PMID: 12019343 Citation  Keywords:  Animals, Antioxidants:pharmacology, Free Radical Scavengers:pharmacology, Free Radicals:adverse effects, Humans, Melatonin:pharmacology,.   

: Endogenously produced metabolites of ground state oxygen are highly reactive and destructive to intracellular and extracellular molecules. The resulting damage, referred to as oxidative stress, leads to molecular and cellular dysfunction. The destruction of essential macromolecules by oxygen-based reactants is the basis of some diseases and is believed to be involved in the processes of aging. Free radical scavengers and antioxidants neutralize and/or metabolically remove reactive species from cells before they carry out their destructive activities. Melatonin is a highly ubiquitous direct free radical scavenger and indirect antioxidant. This brief report summarizes the interactions of melatonin with reactive species and identifies the resulting products. The paper also defines the melatonin antioxidant cascade wherein not only melatonin but at least one of the products, i.e., N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, formed as a result of melatonin scavenging hydrogen peroxide is also a potent scavenger. The review summarizes the data which shows that melatonin is not only a pharmacologically useful free radical scavenger but that it functions in this capacity at physiological concentrations as well. Finally, this report identifies high oxidative stress situations in humans where melatonin has proven effective in reducing the severity of the disease state. In the last decade there have been hundreds of publications documenting melatonin's protective actions against a vast array of conditions, e.g., ischemia/reperfusion injury, toxin exposure, lipopolysaccharide exposure, etc., where free radical damage is a component of the condition....

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Journal Article 2002; 23(2): 115-118 PubMed PMID: 12011796 Citation  Keywords:  Adnexal Diseases:complications, Animals, Antioxidants:pharmacology, Female, Guinea Pigs, Lung:chemistry, Malondialdehyde:analysis, Melatonin:pharmacology, Ovariectomy, Pulmonary Edema:drug therapy, Reperfusion Injury:complications, Torsion Abnormality,.   

OBJECTIVES: Pulmonary edema has been shown to occur following ischemia-reperfusion injury in a variety of organs and effects of several pharmacological agents on ischemia-reperfusion-induced damage has been investigated previously. However, there are only a few studies in the literature about pulmonary injury following adnexial ischemia-reperfusion. In this study we aimed at investigating pulmonary changes following adnexial ischemia-reperfusion and the effects of melatonin on noncardiogenic pulmonary edema secondary to adnexial ischemia-reperfusion.

METHODS: A total of 32 Dunkin-Harley guinea pigs were randomly divided into four groups. In group I, oopherectomy was performed following adnexial torsion of three hours (ischemia). Adnexial torsion of three hours followed by a 3 hours detorsion period (reperfusion) and then oopherectomy was performed in remaining three groups. No therapy was given in group one and two while isotonic saline and melatonin was applied intraperitoneally in groups three and four, respectively. Serum malondialdehyde (MDA) levels of operated ovaries and lungs and polimorphonuclear leucocyte infiltration of lungs were determined.

RESULTS: MDA levels in serum, ovary and lungs were higher in detorsion groups (groups II, III) than torsion group (group I) (p<0.01). Melatonin administration significantly decreased the polimorphonuclear leukocytes infiltration of lung parenchime and MDA levels in serum, ovaries and lungs (groups II and IV; groups III and IV; p<0.01, p<0.01). MDA levels and lung tissue PNL infiltration levels of melatonin administered detorsioned group was similar to those levels of only salphingo-oopherectomy performed group (Group I and IV, p>0.05).

CONCLUSION: Pathophysiology of ischemia-reperfusion must be considered in the cases of adnexial torsion where detorsion is thought. As an antioxidant, melatonin administration might be helpful in decreasing post-operative morbidity by decreasing reperfusion injury of lungs....

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Journal Article 2001; 22(6): 441-447 PubMed PMID: 11781542 Citation  Keywords:  Age Factors, Animals, Antioxidants:pharmacology, Female, Gene Expression Regulation, Neoplastic:drug effects, Mammary Neoplasms, Experimental:drug therapy, Melatonin:pharmacology, Mice, Mice, Transgenic, Photoperiod, RNA, Messenger:analysis, Receptor, Erb.   

OBJECTIVES AND DESIGN: The effect and the mechanism of light regimen and melatonin on the development of mammary tumors in HER2/neu transgenic mice were investigated. Female HER-2/neu mice starting from the age of 2 months were kept under standard light/dark regimen (LD) or constant light illumination (LL) and a part of each group was given melatonin (20 mg/l) during the night time.

RESULTS: The exposure to LL failed to change the incidence of spontaneous mammary adenocarcinoma development, the size of mammary tumors, as well as the incidence and size of lung metastases. However, the number of tumors per mouse was significantly increased in the LL group as compared to the LD group. The number of mice bearing 4 and more tumors was higher in the LL group than in the LD group, whereas the number of mice bearing 1 to 3 tumors was lower in the LL group in comparison with the LD group. Melatonin decreased the incidence and size of mammary adenocarcinomas, and the incidence of lung metastases in the LD group but not in the LL group. The mean number of tumors per mouse was not changed by melatonin treatment in both light regimens. The number of mice bearing 4 and more tumors was reduced by melatonin more significantly in the LL group than in LD group. Melatonin treatment resulted in a 2.5-fold reduction in the expression of HER-2/neu mRNA in mammary tumors from HER-2 /neu transgenic mice.

CONCLUSION: The data demonstrate the influence of the LD light regiment and melatonin treatment in the development of spontaneous mammary tumors in HER-2/neu mice suggesting a melatonin-dependent modulation of HER-2/neu gene expression in mammary adenocarcinoma....

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Journal Article 2001; 22(6): 432-434 PubMed PMID: 11781540 Citation  Keywords:  Animals, Antioxidants:pharmacology, Carcinoma, Ehrlich Tumor:drug therapy, Cattle, Cell Extracts:pharmacology, Male, Melatonin:pharmacology, Mice, Mice, Inbred AKR, Neoplasm Transplantation, Pineal Gland:physiology, Survival Rate,.   

UNLABELLED: OBJECTIVES Pineal gland may have a role in organism's protection against cancer. Melatonin as well as still unidentified low-weight molecular pineal substance(s) have been reported to have growth inhibitory effect on different tumor cells. We tested the influence of melatonin and of a bovine pineal extract on the survival rate of AKR mice inoculated with Ehrlich ascites. The tumor is known to have an accelerated development after pinealectomy.

MATERIAL AND METHODS: Male AKR mice, kept under a 14/10 hours - Light /Dark cycle, were inoculated intraperitoneally (i.p.) with 1.5x 10(6) Ehrlich ascites cells. On day three after inoculation the animals were divided in three groups (n=10). Each animal received i.p. daily (20.00H), until their death, 250 microl of solution containing melatonin (250 microg), pineal extract (equivalent of 1 bovine pineal gland) or saline.

RESULTS: The average survival rate of the animals treated with melatonin was shorter (14.8+/-2.23 days) compared to control animals (21.9+/-2.21 days)(p=0.01). The animals treated with the pineal extract had a longer survival rate (22.6 +/- 1.8 days) but not statistically significant. The pineal extract was not available for testing at higher doses.

CONCLUSION: In our model, melatonin had a deleterious effect on the survival rate raising the question whether it is correct to assume that the hormone shows lack of adverse reactions....

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Journal Article 2001; 22(6): 417-426 PubMed PMID: 11781538 Citation  Keywords:  Aflatoxin B1:toxicity, Animals, Antioxidants:pharmacology, Apoptosis:drug effects, Caspase 3, Caspases:metabolism, Glutathione:metabolism, Glutathione Peroxidase:metabolism, Glutathione Reductase:metabolism, Glutathione Transferase:metabolism, Lipid Perox.   

OBJECTIVES: A study of liver apoptosis after aflatoxin B1 (AFB1) administration and the effect of melatonin (MEL) was investigated in male rats.

METHODS: Five groups of 15 rats each were used: controls, MEL Soln-treated rats (MEL dose,5 mg/Kg body wt), AFB1-treated rats (50 microg/Kg body wt), MEL Soln+AFB1-treated rats, and MEL micro-capsules (MEL-MC)+ AFB1-treated rats. After 8 weeks of treatment, biochemical measurements in liver homogenates and histopathological examination of liver sections of different groups using light and transmission electron microscope were done. The caspase-3 enzyme activity, apoptotic marker, was determined in liver tissues. Because hepatic antioxidants represent the major defence against toxic liver injury, and they act as anti-apoptosis. So, the levels of glutathione (GSH) and zinc (Zn) and the enzyme activities of glutathione reductase (GR), glutathione peroxidase (GSPx) and glutathione-S-transferase (GST) were determined. In addition, the levels of malondialdehyde (MDA), a lipid peroxidation product, and nitric oxide (NO) levels were measured.

RESULTS: The levels of caspase-3 activities in AFB1 group were significantly higher than control group. The apoptosis was associated with degenerative and necrotic changes in the hepatocytes. Concomitantly, the levels of MDA and NO in liver tissues were significantly increased while the levels of GSH, Zn and enzyme activities of GSPx and GR in liver tissues were significantly decreased in AFB1 group compared to their levels in controls. Caspase-3 activity was positively correlated with MDA while negatively correlated with GSH, GSPx and GR in rat livers treated with AFB1. The apoptotic rate was significantly reduced when MEL co-administrated with AFB1. In rats which received MEL with AFB1, the levels of MDA and NO in liver tissues were significantly reduced while GSH and Zn levels and GSPx, GR and GST activities were significantly increased compared to AFB1 group. When MEL-MC co-administrated with AFB1 appeared more effective in reduction of apoptotic rate as detected by decline of caspase-3 activities (inhibition 66.82%) and confirmed by histopathology.

CONCLUSION: AFB1 can lead to direct or indirect caspase-3 activation and consequently to apoptosis in rat liver. MEL treatment of rats could enhance hepatic antioxidant/detoxification system which consequently reduce the apoptotic rate and the necrobiotic changes in the liver. MEL-MC exhibited an efficient protective effect against AFB1. Thus, clinical application of MEL as therapy should be considered in cases of aflatoxicosis....

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Journal Article 2001; 22(1): 9-18 PubMed PMID: 11335874 Citation  Keywords:  Adult, Aged, Aged, 80 and over, Aging:drug effects, Animals, Antioxidants:metabolism, Catalase:drug effects, Drosophila melanogaster, Free Radicals:metabolism, Humans, Lipid Peroxidation:drug effects, Melatonin:metabolism, Middle Aged, Oxidation-Reduction.   

OBJECTIVES: The review on our own data on the effect of the pineal peptide preparation Epithalamin on free radical processes in rodents and humans is presented in this paper.

RESULTS: The activity of Cu, Zn-superoxide dismutase (SOD) was found decreased in the brain of aged rats (30 months old) by 46.8% as compared to young animals. Concentration of Schiff's bases in the brain also went down with age (by 13.6%), while the level of dien conjugates (DC) and protein peroxidation (PPO) remained unchanged. General antioxidation activity (AOA) in the brain also remained stable with age. The liver of aged rats showed significant increase of Schiff's bases (by 27.1%) and PPO products (by 109.2%) and considerable decrease of SOD activity. The level of DC and general AOA in the liver remained unchanged with age. Considerable elevation of protein and lipid peroxidation products contents was registered in the blood serum of aged rats. At the same time, general AOA and SOD activity remarkably decreased. The results obtained evidence from both significant age-related alterations in the activity of free radical processes in animal organism and organic peculiarities of their dynamics. Application of peptide drug epithalamin suppressed significantly the intensity of peroxide chemoluminescence in the blood serum (2.8-fold) and lipid peroxide oxidation (LPO) expressed in the considerably decreased DC contents (4,1-fold). The contents of Schiff's bases showed only a tendency towards decrease (by 14.4%, p > 0.05) and PPO level remained unchanged. Epithalamin administration was followed by considerable (by 36.6%, p < 0.01) increase of general AOA and increased SOD activity (by 19.7%) in males. Epithalamin decreased significantly the contents of conjugated hydroperoxides and ketodienes in tissues of D.melanogaster females, increased catalase activity in drosophila males and females, and increased SOD activity in males of D.melanogaster by 41%. Humans reveal significant age-related decrease of antioxidation defence indices.

CONCLUSION: Epithalamin administration to patients with age-related pathology eliminates imbalance in prooxidation and antioxidation systems....

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