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.

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.

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 ß 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.

Diphenyl ditelluride induces anxiogenic-like behavior in rats by reducing glutamate uptake.

Anxiety-related disorders are a common public health issue. Several lines of evidence suggest that altered glutamatergic neurotransmission underlies anxiety. The present study evaluated the effect of diphenyl ditelluride [(PhTe)2] exposure on the behavioral performance of rats and examined whether the behavioral effects could be attributed to changes in the modulation of glutamatergic function. Rats were exposed to (PhTe)2 (subcutaneously) during 8 weeks-final dose one third LD50 (124 µg/kg). The testing schedule included elevated plus-maze, open-field, T-maze, rotorod, and Morris water maze tests. Synaptosomal basal [(3)H] glutamate release and uptake were also evaluated. The time spent in the open arm and the ratio of time spent in the open arm/total were decreased in the (PhTe)2 group. Furthermore, the [(3)H] glutamate uptake was decreased in this experimental group. The results suggest that exposure to (PhTe)2 did not change motor abilities whereas it may result in anxiogenic-like behavior, induced by changes in the glutamatergic system at the pre-synaptic level.

Acute exposure to diphenyl ditelluride causes oxidative damage in rat lungs.

The present study evaluated the effect of acute exposure to diphenyl ditelluride [(PhTe)(2)] on oxidative status in lungs of rats. Rats were exposed to a single subcutaneous application of (PhTe)(2) at the doses of 0.3, 0.6, 0.9 µmol/kg or vehicle. After 72 h of exposure to (PhTe)(2), biochemical parameters of oxidative stress were carried out in lungs of rats. The lungs of rats exposed to (PhTe)(2) showed an increase in the levels of lipid peroxidation, reactive species and non-protein thiol. Alterations in superoxide dismutase activity were observed at all tested doses. (PhTe)(2) caused an increase in catalase activity and a reduction in ascorbic acid levels at the dose of 0.9 µmol/kg. The oxidative damage was more pronounced in animals treated with the highest dose of (PhTe)(2). Thus, this study demonstrated that acute exposure to (PhTe)(2) induced oxidative damage and an adaptive response of antioxidants in pulmonary tissue of rats.

Diphenyl diselenide and diphenyl ditelluride: neurotoxic effect in brain of young rats, in vitro.

This study examined whether maturity of rat brain may be relevant for the sensitivity to diphenyl diselenide (PhSe)(2) and diphenyl ditelluride (PhTe)(2) on [(3)H]glutamate uptake and release, in vitro. Brain synaptosomes were isolated from young (14- and 30-day-old) and adult rats and incubated at different concentrations of (PhSe)(2) or (PhTe)(2). The results demonstrated that the highest concentration (100 microM) of (PhSe)(2) and (PhTe)(2) inhibited the [(3)H]glutamate uptake by synaptosomes of brain at all ages. In the adult brain, (PhSe)(2) did not inhibit the [(3)H]glutamate uptake at the lowest concentration (10 microM). The highest concentration of (PhTe)(2) inhibited the [(3)H]glutamate uptake more in the 14-day-old than in the 30-day-old rats or adult rats. In the 30-day-old animals, the highest concentration of (PhSe)(2), and the lowest concentration of (PhTe)(2), increased the basal [(3)H]glutamate release. At the highest concentration, (PhTe)(2) increased the basal and K(+)-stimulated glutamate release on all ages evaluated. The results suggest that (PhSe)(2) and (PhTe)(2) caused alterations on the homeostasis of the glutamatergic system at the pre-synaptic level. These alterations were age-, concentration-, and compound-dependent. The maturity of rat brain is relevant for the glutamatergic system sensitivity to (PhSe)(2) and (PhTe)(2) .

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, delta-aminolevulinate dehydratase (delta-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 delta-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 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.

Exposure to diphenyl ditelluride, via maternal milk, causes oxidative stress in cerebral cortex, hippocampus and striatum of young rats.

The present study evaluated the effect of diphenyl ditelluride [(PhTe)(2)] exposure to mothers on the cerebral oxidative status of their offspring. The dams received (PhTe)(2) or canola oil via subcutaneous injection once daily during the first 14 days of lactational period. At post natal day 28, biochemical parameters of oxidative stress were evaluated in cerebral structures-cortex, hippocampus and striatum-of young rats. Exposure to (PhTe)(2) increased lipid peroxidation levels and inhibited delta-ALA-D, catalase and SOD activities in hippocampus and striatum of young rats. (PhTe)(2) induced changes in the levels of non-enzymatic antioxidant defenses in cortex and striatum of young rats. The exposure to (PhTe)(2), via maternal milk, caused oxidative stress in cerebral structures of young rats. Thus, the possible role of disrupted prooxidant/antioxidant balance in (PhTe)(2) toxicity was demonstrated. These results highlighted a possible molecular mechanism involved in toxicity caused by (PhTe)(2).

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.

Adult male rats sub-chronically exposed to diphenyl diselenide: Effects on their progeny.

The present study was conducted to evaluate the toxicity of diphenyl diselenide [(PhSe)2] exposure on the progeny of Wistar male rats. Male rats were exposed to (PhSe)2 subcutaneously for 4 weeks at the dose of 5.0 mg/kg and 8 weeks at the dose of 2.5 mg/kg, prior to mating with unexposed females. No lethality was noted in any group. At term of exposure period, 4-week exposed male rats presented significant decrease in the body weight. Sex organ weights were similar in (PhSe)2-exposed and control male groups. The number of implantation sites in females mated with males exposed to (PhSe)2 for 8 weeks was significantly higher than those of the respective control group. Male exposure to (PhSe)2, administered for 4 and 8 weeks, did not change fetal body weight. Gross examination of fetuses from 4- to 8-week exposed groups did not reveal the appearance of external anomalies. Examination of live fetuses for ossification centers did not show significantly difference between groups. No increase in the incidence of skeletal anomalies was observed in fetuses obtained from females impregnated with (PhSe)2-exposed males. The current study indicated that (PhSe)2 given sub-chronically (4 or 8 weeks) to male rats had no adverse effects on their progeny.

Sub-chronic exposure of adult male rats to diphenyl ditelluride did not affect the development of their progeny.

The present study was undertaken to evaluate the toxicity of diphenyl ditelluride [(PhTe)(2)] exposure on the progeny of Wistar male rats. Male rats were exposed to (PhTe)(2) subcutaneously for 4 weeks (wk) at the dose of 0.006 mg/kg and 8-wk at the dose of 0.003 mg/kg, prior to mating with unexposed females. The body and sex organ weights of male rats were not affected in both 4- and 8-wk (PhTe)(2)-exposed groups. The gravid uterus weight and the body weight gain (overall or corrected) during the pregnancy were not statistically different to those obtained from females mated with control males. The number of implantation sites, resorptions and live and dead fetuses were not affected by male exposure to (PhTe)(2). Fetal body weight and crown-rump length were not affected, as well. Examination of the fetuses from both exposed groups for external and skeletal changes did not reveal any male-mediated effect of (PhTe)(2). The current study indicated that (PhTe)(2) given sub-chronically (4- or 8-wk) to male rats had no adverse effects on their progeny.

Assessment of reproductive toxicity in male rats following acute and sub-chronic exposures to diphenyl diselenide and diphenyl ditelluride.

The present study was conducted to evaluate the toxicity of the exposure to diphenyl diselenide [(PhSe)2] and diphenyl ditelluride [(PhTe)2] on reproductive system in Wistar rats. Adult male rats were exposed intraperitonealy (acute) or subcutaneously (sub-chronic, during 4 or 8 weeks) to (PhSe)2 or (PhTe)2 prior to mating. A number of biochemical parameters in rat testes were examined, such as delta-aminolevulinate dehydratase (delta-ALA-D) activity, lipid peroxidation, glycogen content and components of the antioxidant defenses (superoxide dismutase (SOD) activity and ascorbic acid concentration). Furthermore, a possible effect on fertility and reproductive performance in male rats were studied. Sperm counts of caudal epididymis were also evaluated. No lethality was noted in any group. Reduction on body weight in rats which received (PhTe)2 was only evidenced in acute exposure, while (PhSe)2-exposed rats presented significant loss of body weight in acute and 4 week-exposure. Mating and fertility indexes were not affected after acute and sub-chronic exposure. Regarding other parameters studied, except for a decrease in testes glycogen content in acutely (PhSe)2-treated group, no alterations were found in treated groups. Sperm counts of rats treated acutely and sub-chronically were unaffected by drugs exposure. Histological evaluation revealed no modification on testicular tissue in rats exposed to (PhSe)2 and (PhTe)2. The results suggest the absence of the male reproductive toxicity induced by (PhSe)2 and (PhTe)2 administered intraperitonealy (acute) or subcutaneously (sub-chronical) to adult rats Wistar.