Eluza Curte Stangherlin

Protective role of aryl and alkyl diselenides on lipid peroxidation

The concept that selenium-containing molecules may be better nucleophiles (and therefore antioxidants) than classical antioxidants has led to the design of synthetic organoselenium compounds. In the present study we appraised the antioxidant potential, thiol peroxidase activity, and rate of dithiotreitol and reduced glutathione oxidation of simple organodiselenide compounds in rats and mice. The present results demonstrate that alkyl and aryl diselenides are antioxidant compounds. We verified that the substitution on the aromatic moiety of diphenyl diselenide or the replacement of on aryl group by an alkyl substitute on diselenides changes their antioxidant and thiol peroxidase-like properties. The diaryl diselenides (PhSe)(2) and (p-ClPhSe)(2) presented higher thiol peroxidase activity and demonstrated better antioxidant potential than the other diselenides tested. In fact, the results revealed that alkyl diselenides, at low concentrations, were prooxidants and that aryl diselenides did not present this effect. Alkyl diselenides [(C(2)H(5)Se)(2) and (C(3)H(7)Se)(2)] demonstrated a higher potential for -SH group oxidation than aryl diselenides. In addition, this study demonstrated that diselenide protection against lipid peroxidation was different in mice and rats. The compounds tested acted more as antioxidants in the brains of mice than in the brains of rats.

Antioxidant effect of diphenyl diselenide on oxidative damage induced by smoke in rats: involvement of glutathione.

In the present study, the involvement of glutathione system in the restorative effect of diphenyl diselenide (PhSe)(2) on damage induced by cigarette smoke was investigated. Rat pups were progressively exposed to four, five, and six cigarettes for exposure periods of 15 min during their first, second, and third weeks of life. Thiobarbituric acid reactive species (TBARS) levels, components of the enzymatic antioxidant defenses (superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) activities), and non-enzymatic antioxidant defenses (vitamin C and non-protein thiol (NPSH) levels) were examined in lungs of pups. The results demonstrated an increase in lipid peroxidation and the alteration in non-enzymatic and enzymatic antioxidant defenses induced by cigarette smoke exposure in lung of pups. Administration of (PhSe)(2) (0.5mg/kg) restored TBARS levels and antioxidant defenses in lungs of rat pups exposed to cigarette smoke. (PhSe)(2) treatment increased NPSH levels and GST activity per se in lungs of rat pups. Together these results indicate that (PhSe)(2) restored oxidative damage induced by cigarette smoke exposure in lungs of rat pups. The glutathione system is involved in antioxidant effect of this compound.

Sub-chronical exposure to diphenyl diselenide enhances acquisition and retention of spatial memory in rats

The present study was conducted to evaluate the effects of exposure to diphenyl diselenide [(PhSe)2] on cognitive performance and glutamatergic parameters in normal Wistar rats. Animals were subcutaneously exposed to (PhSe)2 acutely (G1) and sub-chronically for 4 weeks (G20) at the dose of 5.0 mg/kg or 8 weeks (G40) at the dose of 2.5 mg/kg and evaluated for behavioral and neurochemical analyses. In the water-maze, a significant increase in the number of crossing in the platform local was observed in the probe trial for both groups exposed to (PhSe)2 (G20 and G40). In the T-maze, the latency to reach the extremity of the arm in the trial 2 was lower in both groups exposed to (PhSe)2 (G20 or G40) when compared to the respective control groups. In the open-field test, no significant differences in the number of crossing and rearing were observed among groups. Furthermore, the basal [3H]glutamate release by synaptosomes from whole brain of rats was significantly decreased in the G40 when compared to the control group. These findings suggest that sub-chronic exposure to (PhSe)2 improved the performance of Wistar rats in the water-maze, a test that evaluates cognitive functions.

Diphenyl ditelluride impairs short-term memory and alters neurochemical parameters in young rats

The aim of this study was to investigate if maternal exposure to 0.03 mg/kg of diphenyl ditelluride (PhTe)2 during the first 14 days of lactational period in Wistar rats alters recognition memory and neurochemical parameters in young rats. Object recognition memory task, evaluation of synaptosomal [3H]glutamate uptake and release as well as cerebral Na+/K+ATPase activity were evaluated in 4 week-old rats. There were no significant specific overt signs of maternal intoxication. The body weight gain of rats was similar among groups. (PhTe)2-exposed group showed a significantly lower time exploring the novel object when compared to the performance of the control group in short-term memory (STM) test. In addition, (PhTe)2 significantly inhibited synaptosomal [3H]glutamate uptake and cerebral Na+/K+ATPase activity in animals. The synaptosomal [3H]glutamate release was similar between (PhTe)2 and control groups. In conclusion, the present study establishes that young rats presented cognitive impairment after exposure to (PhTe)2 via maternal milk, demonstrated by the performance of animals in object recognition memory task. The possible mechanism involved in (PhTe)2 action in memory of recognition might involve inhibition of cerebral Na+/K+ATPase activity and synaptosomal [3H]glutamate uptake.

The antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in the mouse forced swimming test is mediated by serotonergic and dopaminergic systems.

The aim of the present study was to investigate the role of monoaminergic system in the antidepressant-like action of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a derivative of isoquinoline class, in Swiss mice. The antidepressant-like effect of FDPI was characterized in the modified forced swimming test (FST) and the possible mechanism of action was investigated by using serotonergic, dopaminergic and noradrenergic antagonists. Monoamine oxidase (MAO) activity and [(3)H]serotonin (5-HT) uptake were determined in prefrontal cortices of mice. The results showed that FDPI (1, 10 and 20mg/kg, i.g.) reduced the immobility time and increased the swimming time but did not alter climbing time in the modified FST. These effects were similar to those of paroxetine (8mg/kg, i.p.), a positive control. Pretreatments with p-chlorophenylalanine (100mg/kg, i.p., an inhibitor of 5-HT synthesis), WAY100635 (0.1mg/kg, s.c., 5-HT1A antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), haloperidol (0.2mg/kg, i.p., a non-selective D2 receptor antagonist) and SCH23390 (0.05mg/kg, s.c., a D1 receptor antagonist) were effective to block the antidepressant-like effect of FDPI at a dose of 1mg/kg in the FST. Ritanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), sulpiride (50mg/kg, i.p., a D2 and D3 receptor antagonist), prazosin (1mg/kg, i.p., an α1 receptor antagonist), yohimbine (1mg/kg, i.p., an α2 receptor antagonist) and propranolol (2mg/kg, i.p., a β receptor antagonist) did not modify the effect of FDPI in the FST. FDPI did not change synaptosomal [(3)H]5-HT uptake. At doses of 10 and 20mg/kg FDPI inhibited MAO-A and MAO-B activities. These results suggest that antidepressant-like effect of FDPI is mediated mostly by serotonergic and dopaminergic systems.

Exposure of mothers to diphenyl ditelluride during the suckling period changes behavioral tendencies in their offspring

The long-lasting possible influence of maternal exposure to 0.03 mg/kg of diphenyl ditelluride during the first 14 days of lactational period on later offspring behavior was examined in Wistar rats. Open-field locomotor activity, spontaneous alternation in the T-maze, behavior in the elevated plus-maze, motor coordination in the coat-hanger and rotorod tasks were evaluated in 30 day old pups. There were no significant specific overt signs of maternal intoxication. There were a small (less than 5%) but significant transitory differences in the body weight gain of pups between exposed and control groups, which were apparent from day 30 of suckling. Locomotor activity in the open-field task was similar between telluride and control groups. In the coat-hanger test, the latency before falling for the tellurium group was higher than that of the control group. However, the behavior of both groups was similar in the rotorod test and spontaneous alternation in the T-maze. Tellurium-treated pups presented a higher number of entries and spent more time in the open arms of the elevated plus-maze than control pups. The behavioral alterations observed here after tellurium exposure can be cautiously interpreted as an indication of behavioral disinhibition. In conclusion, this study demonstrated that dam exposure to diphenyl ditelluride can cause subtle behavioral changes in the offspring, which can be related to neurotoxic effects of diphenyl ditelluride.

Passive smoke exposure induces oxidative damage in brains of rat pups: Protective role of diphenyl diselenide

The protective effect of diphenyl diselenide, (PhSe)2, on oxidative stress induced by cigarette smoke exposure in brains of rat pups was evaluated. Animals were exposed to passive cigarette smoke (15 min/day) in two different experimental protocols: P1 (1, 2, and 3 cigarettes) and P2 (4, 5, and 6 cigarettes) for 3 weeks. Before each period of smoke exposure, animals received an oral administration of (PhSe)2 (0.5 mg/kg). A number of toxicological parameters in the brain were examined, such as lipid peroxidation, δ-aminolevulinate dehydratase (δ-ALA-D) activity, and components of enzymatic (superoxide dismutase and catalase activities) and non-enzymatic antioxidant defenses (ascorbic acid and non-protein thiol levels). In P1, smoke exposure induced an inhibition of catalase activity and an increase of ascorbic acid levels. (PhSe)2 treatment was able to protect catalase activity but not ascorbic acid levels. In P2, an augmentation of lipid peroxidation, a reduction of enzymatic and non-enzymatic antioxidant status, and an inhibition of δ-ALA-D activity caused by smoke exposure were found. (PhSe)2 protected the brains of rat pups against oxidative damage induced by smoke exposure. The results are consistent with the antioxidant effect of (PhSe)2 demonstrated by the reduction of oxidative changes caused by smoke exposure in the brains of pups.

Diphenyl diselenide ameliorates monosodium glutamate induced anxiety-like behavior in rats by modulating hippocampal BDNF-Akt pathway and uptake of GABA and serotonin neurotransmitters

UNLABELLED Monosodium glutamate (MSG), a flavor enhancer used in food, administered to neonatal rats causes neuronal lesions and leads to anxiety when adulthood. AIMS We investigated the anxiolytic-like effect of diphenyl diselenide (PhSe)2 and its mechanisms on anxiety induced by MSG. MAIN METHODS Neonatal male and female Wistar rats received a subcutaneous injection of saline (0.9%) or MSG (4 g/kg/day) from the 1st to 10th postnatal day. At 60 days of life, the rats received (PhSe)2 (1mg/kg/day) or vehicle by the intragastric route for 7 days. The spontaneous locomotor activity (LAM), elevated plus maze test (EPM) and contextual fear conditioning test (CFC) as well as neurochemical ([(3)H]GABA and [(3)H]5-HT uptake) and molecular analyses (Akt and p-Akt and BDNF levels) were carried out after treatment with (PhSe)2. KEY FINDINGS Neonatal exposure to MSG increased all anxiogenic parameters in LAM, EPM and CFC tests. MSG increased GABA and 5-HT uptake in hippocampus of rats, without changing uptake in cerebral cortex. The levels of BDNF and p-Akt were reduced in hippocampus of rats treated with MSG. The administration of (PhSe)2 to rats reversed all behavioral anxiogenic parameters altered by MSG. The increase in hippocampal GABA and 5-HT uptake induced by MSG was reversed by (PhSe)2. (PhSe)2 reversed the reduction in hippocampal BDNF and p-Akt levels induced by MSG. SIGNIFICANCE In conclusion, the anxiolytic-like action of (PhSe)2 in rats exposed to MSG during their neonatal period is related to its modulation of hippocampal GABA and 5-HT uptake as well as the BDNF-Akt pathway.

7-Fluoro-1,3-diphenylisoquinoline-1-amine abolishes depressive-like behavior and prefrontal cortical oxidative damage induced by acute restraint stress in mice

There is a complex relationship between stressful situations and the onset of depression. 7-Fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) has been reported to have an antidepressant-like effect in the forced swimming test (FST). The aim of this study was to investigate the antidepressant-like effect of FDPI administered to mice before or after the acute restraint stress (ARS). The mice were submitted to the ARS for 7 h. Two treatments with FDPI (10 mg/kg) were performed: in the first treatment, the mice received FDPI 30 min before ARS (pre-treatment) and in the second treatment mice received FDPI 10 min after the ARS (post-treatment). Thirty minutes after FDPI administration, the FST and locomotor activity were carried out. ARS induced depressive-like behavior in the FST. Both treatments with FDPI were effective against the increase in immobility time in the FST.Moreover, ARS increased lipid peroxidation and intracellular reactive oxygen species (ROS) levels as well as decreased catalase activity in prefrontal cortical samples of mice. Pre- and post-treatments with FDPI reduced lipid peroxidation and ROS, and post-treatment restored catalase activity. Superoxide dismutase was not altered by stress and/or FDPI. Monoamine oxidase (MAO) activities increased in the prefrontal-cortices of mice submitted to the ARS protocol and treatments with FDPI abolished this increase. Hepatic MAO activities were not altered in the livers of mice submitted to ARS and FDPI treatments. The serotonin uptake was increased in the prefrontal-cortices of mice submitted to the ARS protocol and both treatments with FDPI abolished this increase. The antidepressant-like effect of FDPI appears to involve the modulation of oxidative stress and the monoaminergic system, without inhibiting hepatic MAO activity.

Contribution of NMDA, GABAA and GABAB receptors and l-arginine-NO-cGMP, MEK1/2 and CaMK-II pathways in the antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine in mice.

It has been reported that the antidepressant-like effect of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI) may result from the modulation of brain monoaminergic systems. However, the mechanisms of FDPI action are not fully understood. The aim of this study was to investigate the contribution of N-methyl-d-aspartate (NMDA) and gamma-aminobutyric acid (GABA) systems as well as l-arginine-nitric oxide-(NO)-cyclic guanosine monophosphate-(cGMP), mitogen-activated protein/extracellular signal-regulated kinase (MEK1/2) and Ca(2+)/calmodulin-dependent protein kinase II (CaMK-II) signaling pathways in the antidepressant-like effect of FDPI in the mouse forced swimming test (FST). The levels of NO and uptake of [(3)H]glutamate and [(3)H]GABA were determined in prefrontal cortices of Swiss mice. Pretreatments with NMDA (0.1 pmol/site, i.c.v., a NMDA receptor agonist), bicuculline (1mg/kg, i.p., a GABAA receptor antagonist), phaclofen (2mg/kg, i.p., a GABAB receptor antagonist) and l-arginine (750mg/kg, i.p., a NO precursor), KN-62 (1μg/site, a CaMK-II inhibitor), U0126 (5μg/site, a MEK1/2 inhibitor) and PD09058 (5μg/site, a MEK1/2 inhibitor) blocked the antidepressant-like effect of FDPI, at a dose of 1mg/kg, in the FST. ODQ (30 pmol/site, i.c.v., a soluble guanylate cyclase (sGC) inhibitor) in combination with a sub-effective dose of FDPI (0.1mg/kg, i.g.) reduced the immobility time in the FST. The administration of FDPI (50mg/kg) to mice increased the glutamate uptake and reduced NO levels in the prefrontal cortex of mice. The results suggest a contribution of NMDA, GABAA and GABAB receptors and l-arginine-NO-cGMP pathway in the antidepressant-like action of FDPI in mice, and this effect is related to CaMK-II and MEK 1/2 activation.