Role of Melatonin in Aluminum-Related Neurodegenerative Disorders: a Review.

Aluminum (Al), a potentially neurotoxic element, provokes various adverse effects on human health such as dialysis dementia, osteomalacia, and microcytic anemia. It has been also associated with serious neurodegenerative diseases such as Alzheimer's disease (AD), amyotrophic lateral sclerosis, and Parkinsonism dementia of Guam. The "aluminum hypothesis" of AD assumes that the metal complexes can potentiate the rate of aggregation of amyloid-ß (Aß), enhancing the toxicity of this peptide, and being able of contributing to the pathogenesis of AD. It has been supported by a number of analytical, epidemiological, and neurotoxicological studies. On the other hand, melatonin (Mel) is a potent direct free radical scavenger and indirect antioxidant, which acts increasing the activity of important related antioxidant enzymes, and preventing oxidative stress and cell death of neurons exposed to Aß-induced neurotoxicity. Therefore, Mel might be useful in the treatment of AD by reducing the Aß generation and by inhibiting mitochondrial cell death pathways. The present review on the role of Mel in Al-related neurodegenerative disorders concludes that the protective effects of this hormone, together with its low toxicity, support the administration of Mel as a potential supplement in the treatment of neurological disorders, in which oxidative stress is involved.

Role of deferoxamine on enzymatic stress markers in an animal model of Alzheimer's disease after chronic aluminum exposure.

The effect of the chelator deferoxamine (DFO) on the activity of enzymatic stress markers was assessed in amyloid beta peptide (AßPP) transgenic mice, an animal model of Alzheimer's disease, after oral aluminum (Al) exposure for 6 months. AßPP transgenic (Tg2576) and C57BL6/SJL wild-type mice of 5 months of age were fed a diet supplemented with Al lactate (1 mg of Al/g food). Four groups of Tg2576 and wild-type animals were used: control, Al only, DFO only, and Al plus DFO. Mice in the DFO-treated groups received also subcutaneous injections of 0.20 mmol/kg/d of this chelating agent twice a week until the end of the study at 11 months of age. The hippocampus, cerebellum, and cortex were removed and processed to examine a number of oxidative stress markers. Furthermore, the expression of Cu-Zn superoxide dismutase, glutathione reductase, and catalase was evaluated by quantitative reverse transcriptase polymerase chain reaction analysis. Aluminum levels in the hippocampus of Tg2576 mice were higher than those found in cerebellum and cortex, while the main oxidative effects were evidenced in the presence of DFO only. Oral Al exposure of AßPP transgenic mice would have some potential to promote pro-oxidant events, while DFO administration would not help in preventing these deleterious effects.

Oxidative stress status and RNA expression in hippocampus of an animal model of Alzheimer's disease after chronic exposure to aluminum.

It is well established that aluminum (Al) is a neurotoxic agent that induces the production of free radicals in brain. Accumulation of free radicals may cause degenerative events of aging such as Alzheimer's disease. On the other hand, melatonin (Mel) is a known antioxidant, which can directly act as free radical scavenger, or indirectly by inducing the expression of some genes linked to the antioxidant defense. In this study, AbetaPP female transgenic (Tg2576) (Tg) and wild-type mice (5 months of age) were fed with Al lactate supplemented in the diet (1 mg Al/g diet). Simultaneously, animals received oral Mel (10 mg/kg) dissolved in tap water until the end of the study at 11 months of age. Four treatment groups were included for both Tg and wild-type mice: control, Al only, Mel only, and Al+Mel. At the end of the period of treatment, hippocampus was removed and processed to examine the following oxidative stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), and thiobarbituric acid reactive substances (TBARS). Moreover, the gene expression of Cu-ZnSOD, GR, and CAT was evaluated by real-time RT-PCR. Aluminum concentration in hippocampus was also determined. The biochemical changes observed in this tissue suggest that Al acts as a pro-oxidant agent. Melatonin exerts an antioxidant action by increasing the mRNA levels of the antioxidant enzymes SOD, CAT, and GR evaluated in presence of Al and Mel, with independence of the animal model.

Protective role of melatonin on oxidative stress status and RNA expression in cerebral cortex and cerebellum of AbetaPP transgenic mice after chronic exposure to aluminum.

Aluminum (Al) has been associated with pro-oxidant effects, as well as with various serious neurodegenerative diseases such as Alzheimer's disease (AD). On the other hand, melatonin (Mel) is a known antioxidant, which can directly act as free radical scavenger, or indirectly by inducing the expression of some genes linked to the antioxidant defense. In this study, 5-month-old AssPP female transgenic (Tg2576) (Tg) and wild-type mice were fed with Al lactate supplemented in the diet (1 mg Al/g diet). Concurrently, animals received oral Mel (10 mg/kg) until the end of the study at 11 months of age. Four treatment groups were included for both Tg and wild-type mice: control, Al only, Mel only, and Al + Mel. At the end of the treatment period, cortex and cerebellum were removed and processed to examine the following oxidative stress markers: reduced glutathione, oxidized glutathione, cytosolic Cu-Zn superoxide dismutase (SOD1), glutathione reductase (GR), glutathione peroxidase, catalase (CAT), and thiobarbituric acid reactive substances. Moreover, the gene expression of SOD1, GR, and CAT was evaluated by real-time RT-PCR. The biochemical changes observed in cortex and cerebellum suggest that Al acted as a pro-oxidant agent. Melatonin exerted an antioxidant action by increasing the mRNA levels of the enzymes SOD1, CAT, and GR evaluated in presence of Al and Mel, independently on the animal model.

Aluminum exposure through the diet: metal levels in AbetaPP transgenic mice, a model for Alzheimer's disease.

Aluminum (Al), iron (Fe), copper (Cu), and zinc (Zn) cause have been implicated in the etiology of certain neurodegenerative disorders. Moreover, these elements cause the conformational changes of Alzheimer's amyloid beta protein. In this study, we determined the concentrations of Al, Cu, Zn, Fe, and Mn in various tissues of Tg 2576 (AbetaPP transgenic) Al-treated mice. Female Tg 2576 mice and wild-type littermates were exposed through the diet to 1mg Al/g for 6 months. At 11 months of age, metal concentrations were measured in various tissues. In brain, Al levels were higher in hippocampus than in cortex and cerebellum. In hippocampus, Cu concentrations decreased in non-treated Tg 2576 mice, while Zn levels were higher in Al-treated mice. Copper, Zn, Mn and Fe concentrations in liver, kidney and bone were not affected by Al exposure. The current results show that Al exposure of Tg 2576 and wild-type mice did not produce important metal changes related with the genotype, responding similarly both groups of animals. As Tg 2576 mice have been considered as a potential model for Alzheimer's disease (AD), the present results would not support the hypothetical role of Al in the etiology of AD.

Melatonin reduces oxidative stress and increases gene expression in the cerebral cortex and cerebellum of aluminum-exposed rats.

The pro-oxidant activity of aluminum (Al), the protective role of exogenous melatonin, as well as the mRNA levels of some antioxidant enzymes, were determined in cortex and cerebellum of rats following exposure to Al and/or melatonin. Two groups of male rats received intraperitoneal injections of Al lactate or melatonin at doses of 7 mg Al/kg/day and 10 mg/kg/day, respectively, for 11 wk. A third group of animals received concurrently Al lactate (7 mg Al/kg/day) plus melatonin (10 mg/kg/day) during the same period. A fourth group of rats was used as control. At the end of the treatment, the cerebral cortex and cerebellum were removed and processed to examine the following oxidative stress markers: glutathione transferase (GST), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase, glutathione peroxidase (GPx), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as protein content. Moreover, gene expression of Cu-ZnSOD, MnSOD, GPx and CAT was evaluated by real-time RT-PCR. On the other hand, Al, Fe, Mn, Cu and Zn concentrations were determined in cortex and cerebellum of rats. Oxidative stress was promoted in both neural regions following Al administration, resulting from the pro-oxidant activity related with an increase in tissue Al concentrations. In contrast, melatonin exerted an antioxidant action which was related with an increase in the mRNA levels of the antioxidant enzymes evaluated. The results of the present investigation emphasize the potential use of melatonin as a supplement in the therapy of neurological disorders in which oxidative stress is involved.

Pro-oxidant activity of aluminum in the rat hippocampus: gene expression of antioxidant enzymes after melatonin administration.

Aluminum (Al)-induced pro-oxidant activity and the protective role of exogenous melatonin, as well as the mRNA levels of some antioxidant enzymes, were determined in the hippocampi of rats following administration of Al and/or melatonin. Two groups of male rats were intraperitoneally injected with Al (as Al lactate) or melatonin only, at doses of 7 and 10 mg/kg/day, respectively, for 11 weeks. During this period, a third group of animals received Al (7 mg/kg/day) plus melatonin (10 mg/kg/day). At the end of the treatment, hippocampus was removed and processed to examine the following oxidative stress markers: glutathione transferase (GST), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as protein content. Gene expression of Cu-ZnSOD, MnSOD, GPx, and CAT was evaluated by real-time RT-PCR. On the other hand, Al, Fe, Mn, Cu, and Zn concentrations in hippocampus were also determined. The results show that Al exposure promotes oxidative stress in the rat hippocampus, with an increase in Al concentrations. The biochemical changes observed in this tissue indicate that Al acts as pro-oxidant agent, while melatonin exerts antioxidant action by increasing the mRNA levels of the antioxidant enzymes evaluated. The protective effects of melatonin, together with its low toxicity and its capacity to increase mRNA levels of antioxidant enzymes, suggest that this hormone might be administered as a potential supplement in the treatment of neurological disorders in which oxidative stress is involved.