Mercedes Gómez

Toxicology of vanadium compounds in diabetic rats: The action of chelating agents on vanadium accumulation

The possible use of vanadium compounds in the treatment of diabetic patients is now being evaluated. However, previously to establish the optimal maximum dose for diabetes therapy, it should be taken into account that vanadium is a highly toxic element to man and animals. The toxic effects of vanadium are here reviewed. The tissue vanadium accumulation, which would mean an additional risk of toxicity following prolonged vanadium administration is also discussed. Recently, it has been shown that coadministration of vanadate and TIRON, an effective chelator in the treatment of vanadium intoxication, reduced the tissue accumulation of this element, decreasing the possibility of toxic side effects derived from chronic vanadium administration without diminishing the hypoglycemic effect of vanadium. However, previously to assess the effectiveness of this treatment in diabetic patients, a critical reevaluation of the antidiabetic action of vanadium and its potential toxicity is clearly needed.

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

Abstract:  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.

Oral vanadium administration to streptozotocin-diabetic rats has marked negative side-effects which are independent of the form of vanadium used.

In the present investigation, the effects of oral administration of sodium metavanadate, sodium orthovanadate and vanadyl sulphate to alleviate some signs of diabetes in streptozotocin-treated rats have been evaluated. Streptozotocin-induced diabetic rats drank aqueous solutions (NaCl, 80 mM) containing sodium metavanadate (0.15 mg/ml), sodium orthovanadate (0.23 mg/ml), or vanadyl sulphate pentahydrate (0.31 mg/ml) for 28 days. The vanadium-treated animals were compared to controls, either diabetic or nondiabetic, receiving drinking water containing NaCl (80 mM) only. Daily food and fluid intake were significantly decreased in the vanadium-treated animals relative to diabetic controls. Also, vanadium treatment reduced the level of hyperglycemia in diabetic rats, with sodium metavanadate being the most effective of the vanadium compounds tested. However, daily vanadium intake was significantly lower in the animals receiving sodium metavanadate. Signs of toxicity were observed in all vanadium-treated animals as evidenced by some deaths, decreased weight gain, and increased serum concentrations of urea and creatinine. Moreover, vanadium was detected in all tissues analyzed. Although some signs of diabetes were improved by vanadium treatment, because of the severe toxic side effects noted in all of the vanadium-treated animals, it seems evident that oral vanadium administration is not a suitable therapy of diabetes mellitus in streptozotocin-diabetic rats.

Aluminum-induced pro-oxidant effects in rats: protective role of exogenous melatonin

Abstract: In recent years, it has been suggested that oxidative stress is a feature of Alzheimers disease in which aluminum (Al) could exacerbate oxidative events. The goal of the present study was to assess in rats the pro‐oxidant effects induced by Al exposure, as well as the protective role of exogenous melatonin. Two groups of male rats were intraperitoneally injected with Al only or melatonin only, at doses of 5 and 10 mg/kg/day, respectively for 8 wk. During this period, a third group of animals received Al (5 mg/kg/day) and melatonin (10 mg/kg/day). At the end of the treatment period, rats were anesthesized and arterial blood was obtained. Thereafter, animals were killed and liver and brain (cortex, hippocampus and cerebellum) were removed. These tissues were processed to examine 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. Samples of these tissues were also used to determine Al, Fe, Mn, Cu and Zn concentrations. The results show that Al exposure promotes oxidative stress in different neural areas, including those in which Al concentrations were not significantly increased. The biochemical changes observed in neural tissues show that Al acts as pro‐oxidant, while melatonin exerts an antioxidant action in Al‐treated animals. The protective effects of melatonin against cellular damage caused by Al‐induced oxidative stress, together with its low toxicity, make melatonin worthy of investigation as a potential supplement to be included in the treatment of neurological disorders in which the oxidative effects must be minimized.

Developmental toxicity evaluation of oral aluminum in rats: Influence of citrate

To evaluate the influence of citrate on the potential developmental toxicity of high doses of aluminum (133 mg/kg/day), three groups of pregnant Sprague-Dawley rats were given by gavage aluminum hydroxide (384 mg/kg/day), aluminum citrate (1064 mg/kg/day), or aluminum hydroxide (384 mg/kg/day) concurrent with citric acid (62 mg/kg/day) on gestational days 6 through 15. Control animals received distilled water. At termination on gestation day 20, live fetuses were examined for external, visceral, and skeletal alterations. There were no significant differences between controls and Al-treated rats on pre- or postimplantation loss, number of live fetuses per litter, or sex ratio. Fetal body weight was significantly reduced in the group treated with Al(OH)3 and citric acid. Although no increases in the incidence of malformations were observed, the incidence of skeletal variations was significantly increased in the group given Al(OH)3 concurrent with citric acid. In summary, although the administration of citric acid did not modify the lack of embryotoxicity and teratogenicity of Al(OH)3 in rats, some signs of maternal toxicity and fetotoxicity could be observed in this group.

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 Alzheimers 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, AβPP 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.

The effect of age on aluminum retention in rats

The present study was designed to assess potential changes in aluminum (Al) retention during advanced age. Young (21 day old), adult (8 months), and old (16 months) rats were exposed to 0, 50, and 100 mg Al/kg/day administered as aluminum nitrate in drinking water for a period of 6.5 months. Urinary Al levels were measured after 3 and 6.5 months of Al exposure. Organ weights and tissue Al concentrations were examined at 6.5 months of Al administration. Differences in the tissue accumulation of Al with age included higher liver, kidneys, spleen, bone and testes levels in old rats than in tissues of both young or adult animals. In contrast, brain concentrations were higher in young rats. Urinary Al levels of young, adult or old Al-exposed rats showed different trends at 6.5 months of Al exposure: compared with young values adult values declined, while those of old rats tended to increase further. The current results show that tissue Al retention patterns may be significantly altered depending on the age at Al exposure. This finding may be of concern for future investigations on the potential role of Al in certain neurological disorders.

Aluminum exposure through the diet : Metal levels in AβPP 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 Alzheimers 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 Alzheimers disease (AD), the present results would not support the hypothetical role of Al in the etiology of AD.

Age-related effects of aluminum ingestion on brain aluminum accumulation and behavior in rats

Both aluminum and aging have been associated with neurobehavioral changes in mammals. This study assessed in young (21 day old), adult (8 months), and old rats (16 months) the effects of prolonged aluminum ingestion on open-field activity and passive-avoidance conditioning. Aluminum was administered in drinking water as aluminum nitrate at doses of 0, 50, and 100 mg Al/kg/day over a 6.5 month period. There were no aluminum effects on the horizontal and vertical activity in an open-field, or in passive-avoidance learning in any group. On the other hand, measurement of aluminum concentrations in a number of brain regions indicated that the olfactory bulb and the rhachidical bulb were the regions with the highest aluminum levels, while the cortex and the thalamus were the cerebral regions showing the lowest aluminum content. For most brain regions analyzed the highest aluminum concentrations were found in young rats, which would indicate that early stages of the life cycle must be considered for enhanced brain aluminum accumulation.

Citric, malic and succinic acids as possible alternatives to deferoxamine in aluminum toxicity

The effect of repeated intraperitoneal administration of deferoxamine, citric, malic and succinic acids on the distribution and excretion of aluminum was determined in male Swiss mice which had previously received aluminum nitrate intraperitoneally at a daily dose of 0.27 mmol/kg for five weeks. Chelating agents were administered for two weeks at doses approximately equal to one-fourth of their respective LD50. Treatment with DFOA, citric, malic or succinic acids significantly increased the fecal and urinary excretion of aluminum and reduced the concentration of aluminum found in various organs and tissues, with citric acid being the most effective. In sight of these results, citric, malic or succinic acids may be considered as alternatives to deferoxamine in aluminum toxicity. However, further investigations are required previous to the possible use of these compounds in human aluminum poisoning.