José S.S. Neto

Antioxidant effect of a novel class of telluroacetilene compounds: studies in vitro and in vivo.

AIMS The effect of telluroacetylenes a-d on pharmacological assays was investigated in vitro. A second objective of this study was to investigate the antioxidant action of compound b against the oxidative damage induced by sodium nitroprusside (SNP) in mouse brain. MAIN METHODS In in vitro experiments, lipid peroxidation (LP) and protein carbonyl (PC) levels and delta-aminolevulinate dehydratase (delta-ALA-D) activity were carried out in rat brain homogenate. The thiol peroxidase-like activity and DPPH radical scavenging of telluroacetylenes a-d were investigated. In in vivo experiments, mice received SNP (0.335 micromol per site) intra cerebroventricular (i.c.v.) thirty minutes after oral administration of telluroacetylene b (10 mg/kg). After 1 h, animals were euthanized. The levels of LP and delta-ALA-D, catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST) activities were carried out in mouse brain homogenate. KEY FINDINGS Telluroacetylenes a-d, at low muM range, reduced LP and PC levels in rat brain homogenate. Telluroacetylenes a-d showed effect of scavenging DPPH radicals. delta-ALA-D activity was inhibited by telloruacetylenes a-d, at high muM range, in rat brain homogenate. Brains of mice treated with SNP showed an increase in LP and the reduction in delta-ALA-D, GR and GST activities. Telluroacetylene b protected against the oxidative stress caused by SNP in brain of rats. SIGNIFICANCE The results support an antioxidant effect of telluroacetylenes a-d in vitro. Telluroacetylene b protected against oxidative damage caused by SNP in mouse brain, suggesting an antioxidant effect of this compound.

2-Phenylethynyl-butyltellurium enhances learning and memory impaired by scopolamine in mice.

Taking into account the memory-enhancing properties of 2-phenylethynyl-butyltellurium (PEBT) and the constant search for drugs that improve cognitive performance, the present study was designed to investigate the effect of PEBT on cognitive impairment induced by scopolamine in mice. PEBT (10 mg/kg, gavage) was administered to mice 1 h before the probe trial in the Morris water maze task. Memory impairment was induced by scopolamine (1 mg/kg, intraperitoneally) 30 min before the probe trial. PEBT significantly ameliorated the scopolamine-induced impairment of long-term memory, as indicated by a decrease in escape latency and an increase in the number of crossings of the platform location when compared with the amnesic mice. To evaluate the effect of PEBT on different phases of memory (acquisition, consolidation, and retrieval) impaired by scopolamine, the step-down inhibitory avoidance task was used. Scopolamine was administered 30 min before training (acquisition), test (retrieval), or immediately after training (consolidation). PEBT, administered 30 min before scopolamine, increased step-down latency in memory-impaired mice, improving the consolidation and retrieval stages, but not acquisition. No significant alterations in locomotor or exploratory behaviors were found in animals treated with PEBT and/or scopolamine. PEBT improved memory deficits during consolidation and retrieval induced by scopolamine.

Diphenyl diselenide elicits antidepressant-like activity in rats exposed to monosodium glutamate: A contribution of serotonin uptake and Na(+), K(+)-ATPase activity.

Depression is a disorder with symptoms manifested at the psychological, behavioral and physiological levels. Monosodium glutamate (MSG) is the most widely used additive in the food industry; however, some adverse effects induced by this additive have been demonstrated in experimental animals and humans, including functional and behavioral alterations. The aim of this study was to investigate the possible antidepressant-like effect of diphenyl diselenide (PhSe)2, an organoselenium compound with pharmacological properties already documented, in the depressive-like behavior induced by MSG in rats. Male and female newborn Wistar rats were divided in control and MSG groups, which received, respectively, a daily subcutaneous injection of saline (0.9%) or MSG (4g/kg/day) from the 1st to 5th postnatal day. At 60th day of life, animals received (PhSe)2 (10mg/kg, intragastrically) 25min before spontaneous locomotor and forced swimming tests (FST). The cerebral cortices of rats were removed to determine [(3)H] serotonin (5-HT) uptake and Na(+), K(+)-ATPase activity. A single administration of (PhSe)2 was effective against locomotor hyperactivity caused by MSG in rats. (PhSe)2 treatment protected against the increase in the immobility time and a decrease in the latency for the first episode of immobility in the FST induced by MSG. Furthermore, (PhSe)2 reduced the [(3)H] 5-HT uptake and restored Na(+), K(+)-ATPase activity altered by MSG. In the present study a single administration of (PhSe)2 elicited an antidepressant-like effect and decrease the synaptosomal [(3)H] 5-HT uptake and an increase in the Na(+), K(+)-ATPase activity in MSG-treated rats.

2-Phenylethynyl-butyltellurium attenuates amyloid-β peptide(25-35)-induced learning and memory impairments in mice.

Our previous study demonstrated that 2‐phenylethynyl‐butyltellurium (PEBT), an organotellurium compound, enhances memory in mice. In this study, the effects of PEBT on cognitive impairment induced by Aβ25–35 were assessed by Morris water maze and step‐down inhibitory avoidance tasks. Mice received a single intracerebroventricular injection of Aβ25–35 (3 nmol/3 μl/per site) and a daily oral administration of PEBT (1 mg/kg, for 10 days). PEBT significantly improved Aβ‐induced learning deficits on the training session in the Morris water maze. At the probe trial session, PEBT significantly decreased the escape latency and increased the number of crossings in the platform local compared with the Aβ‐treated group. PEBT significantly improved Aβ‐induced memory impairment in the step‐down inhibitory avoidance task. General locomotor activity was similar in all groups. This study showed that PEBT ameliorated the impairments of spatial and nonspatial long‐term memory evaluated on Morris water maze and step‐down inhibitory avoidance tasks, respectively. The results suggest that PEBT could be considered a candidate for the prevention of memory deficits such as those observed in Alzheimers disease.

2-Phenylethynyl-butyltellurium improves memory in mice

The present study was conducted to evaluate the effect of 2-phenylethynyl-butyltellurium (PEBT), an organotellurium compound, at doses of 5 and 10 mg/kg on memory, employing the step-down inhibitory avoidance task in mice. Moreover, the involvement of glutamate uptake and release in cerebral cortex and hippocampus of mice was investigated. A single oral administration (p.o.) of PEBT at the dose of 10 mg/kg 1h before training (acquisition), immediately after training (consolidation) or 1 h before the test session (retrieval) of the step-down inhibitory avoidance task increased the step-through latency time in comparison to the control mice. In the open-field test, no significant differences in the number of crossings and rearings were observed among groups. The [(3)H]glutamate uptake by cerebral cortex and hippocampal slices of mice was significantly inhibited after 1h of treatment with PEBT. After 24h of PEBT exposure, only the hippocampal [(3)H]glutamate uptake was inhibited. The [(3)H]glutamate release by cerebral cortex and hippocampal synaptosomes of mice was not altered. These results suggest that PEBT improved memory stages (acquisition, consolidation and retrieval) in the step-down inhibitory avoidance task in mice. The improvement of memory by PEBT seems most likely to be mediated through an interaction with the amino acid transporters of the glutamatergic system.

Cognitive effects of diphenyl diselenide and estradiol treatments in ovariectomized mice.

This study investigated the effects of co-administration of diphenyl diselenide [(PhSe)(2)] and 17β-estradiol (E(2)) on spatial reference, recognition, and working memories in ovariectomized (OVX) female mice. Sixty-day-old female adult Swiss mice were submitted to ovariectomy. From the 30th until 32nd day after ovariectomy, different doses of (PhSe)(2) (0.5-10mg/kg p.o.) were administrated to OVX mice 30min before each training of Morris Water Maze (MWM) test in order to find the highest subeffective dose for this drug. After that, OVX mice were divided into four groups: Oil, (PhSe)(2), E(2), and (PhSe)(2)+E(2). (PhSe)(2) (0.5mg/kg) and E(2) (0.1mg/kg) were administered to OVX mice from 30th to 32nd day after surgery, 30min before the training phases of behavioral tests (Open Field, MWM, Object Recognition, and T-maze). Our results demonstrated that 0.5mg/kg (PhSe)(2) plus 0.1mg/kg E(2) combined treatment improved spatial memory in the MWM test. By contrast, this same co-administration therapy was not effective in ameliorating neither delayed spontaneous alternation in the T-maze test nor object recognition memory deficits in OVX mice, although the dose of 0.5mg/kg (PhSe)(2) enhanced per se the object recognition memory in OVX mice. In conclusion, the current behavioral data suggest that a combination of (PhSe)(2) plus E(2) treatment seems to be a promising alternative to treat the cognitive decline related to menopause. Further studies should be conducted in order to determine an effective dose for (PhSe)(2) plus E(2) therapy on Object Recognition and T-maze tests.

Evidence for the contribution of multiple mechanisms in the feeding pattern of rats exposed to p-chloro-diphenyl diselenide-supplemented diets

Preliminary findings suggest that food intake reduction induced by p-chloro-diphenyl diselenide [(p-ClPhSe)2] in rats is mediated by a satiating action; however, additional experiments are necessary to clarify its actions. The purpose of this study was to investigate the effects of diets supplemented with (p-ClPhSe)2 on feeding behavior of rats as well as the (p-ClPhSe)2 effectiveness in producing aversive reactions or specific flavor. The results demonstrated that behavioral satiety sequence (BSS) was preserved in animals exposed to (p-ClPhSe)2-supplemented diets (0.01 and 0.1%) and associated with a shift of the onset of resting to the left indicating a satiating action at the first contact. In addition, the frequency, the mean duration and the mean size of meals were decreased in rats exposed to a 0.1% (p-ClPhSe)2 diet. Alternatively, a second contact with a 0.01% (p-ClPhSe)2 diet caused disruption of BSS and pronounced changes in the meal pattern, suggesting that it produces aversiveness. In fact, rats developed a significant taste aversion to the saccharin solution after receiving the administration of (p-ClPhSe)2 (1 and 10mg/kg; i.p.). Lastly, a diet containing 0.1% of (p-ClPhSe)2 seems to alter the palatability of food given that rats had a preference for the control diet. The findings of the present study suggest that (p-ClPhSe)2 reduced the food intake of rats by inducing a satiating action at the first contact, but it also produced aversive reactions when rats were re-exposed to it. A specific flavor seems also to contribute to (p-ClPhSe)2 suppressant effects on feeding.

Involvement of the serotonergic system in the anxiolytic-like effect of 2-phenylethynyl butyltellurium in mice

Anxiety is a serious disorder with symptoms manifested at the psychological, behavioral, and physiological levels, accompanied by alterations in the serotonergic system and monoaminergic signaling. In this study, the anxiolytic-like effect of 2-phenylethynyl butyltellurium (PEBT), in three well-consolidated anxiety mouse models (light-dark test, novelty suppressed-feeding, elevated plus-maze), was investigated. The involvement of the serotonergic system, synaptosomal [(3)H] serotonin (5-HT) uptake and monoamine oxidase (MAO A and B) activities on cerebral cortices of mice, was examined. Mice received PEBT (1mg/kg, by intragastric route, i.g.) or canola oil (10 ml/kg, i.g.) 30 min before behavioral tests. The results showed that PEBT was effective in increasing the time spent by mice in the illuminated side on the light-dark box and in the open arms on the elevated plus-maze. PEBT decreased the latency to begin eating on the novelty suppressed-feeding test, indicating an anxiolytic-like effect of PEBT. Furthermore, PEBT reduced [(3)H] 5-HT uptake and selectively inhibited MAO-A activity in cerebral cortex, suggesting the involvement of the serotonergic system in the mechanism of action of this tellurium compound.

Phenylethynyl-Butyltellurium Inhibits the Sulfhydryl Enzyme Na + , K + -ATPase: An Effect Dependent on the Tellurium Atom

Organotellurium compounds are known for their toxicological effects. These effects may be associated with the chemical structure of these compounds and the oxidation state of the tellurium atom. In this context, 2-phenylethynyl-butyltellurium (PEBT) inhibits the activity of the sulfhydryl enzyme, δ-aminolevulinate dehydratase. The present study investigated on the importance of the tellurium atom in the PEBT ability to oxidize mono- and dithiols of low molecular weight and sulfhydryl enzymes in vitro. PEBT, at high micromolar concentrations, oxidized dithiothreitol (DTT) and inhibited cerebral Na+, K+-ATPase activity, but did not alter the lactate dehydrogenase activity. The inhibition of cerebral Na+, K+-ATPase activity was completely restored by DTT. By contrast, 2-phenylethynyl-butyl, a molecule without the tellurium atom, neither oxidized DTT nor altered the Na+, K+-ATPase activity. In conclusion, the tellurium atom of PEBT is crucial for the catalytic oxidation of sulfhydryl groups from thiols of low molecular weight and from Na+, K+-ATPase.

(p-ClPhSe)2 stabilizes metabolic function in a rat model of neuroendocrine obesity induced by monosodium glutamate

Obesity is a chronic and complex medical condition characterized by excessive fat accumulation and its complications include metabolic syndrome, diabetes and chronic inflammation. The aim of this study was to expand the knowledge about p-chloro-diphenyl diselenide (p-ClPhSe)2 effects on enzymes and proteins involved in the metabolism of lipids and carbohydrates in a model of neuroendocrine obesity induced by MSG. Male Wistar rats were treated during the first ten postnatal days with MSG (4 g/kg, s.c.) and received (p-ClPhSe)2 (10 mg/kg, i.g.) from 90th to 97th postnatal day. The hypothalamic function, insulin resistance and other biochemical parameters were determined in the rat blood, liver and skeletal muscle. The MSG administration induced hypothalamic neurotoxicity accompanied by metabolic disorders, including obesity, a transient insulin resistance, and metabolic alterations, demonstrated in the blood, liver and skeletal muscle, and lipotoxicity, characterized in the liver and skeletal muscle. The metabolic disorders in the liver and skeletal muscle were accompanied by the decrease in AMPK phosphorylation and activation of Akt. (p-ClPhSe)2 restored most of metabolic parameters altered by MSG administration in rats. The hypothalamic neurotoxicity induced by MSG was accompanied by metabolic disorders in rats, which were regulated by (p-ClPhSe)2.