César Augusto Brüning

Antidepressant-like effect of m-trifluoromethyl-diphenyl diselenide in the mouse forced swimming test involves opioid and serotonergic systems.

Serotonergic and opioid systems have been implicated in major depression and in the action mechanism of antidepressants. The organoselenium compound m-trifluoromethyl-diphenyl diselenide (m-CF(3)-PhSe)(2) shows antioxidant and anxiolytic activities and is a selective inhibitor of monoamine oxidase A activity. The present study was designed to investigate the antidepressant-like effect of (m-CF(3)-PhSe)(2) in female mice, employing the forced swimming test. The involvement of the serotonergic and opioid systems in the antidepressant-like effect of (m-CF(3)-PhSe)(2) was appraised. (m-CF(3)-PhSe)(2) at doses of 50 and 100mg/kg (p.o.) exhibited antidepressant-like action in the forced swimming test. The effect of (m-CF(3)-PhSe)(2) (50mg/kg p.o.) was prevented by pretreatment of mice with WAY100635 (0.1mg/kg, s.c. a selective 5-HT(1A) receptor antagonist), ritanserin (4 mg/kg, i.p., a non-selective 5HT(2A/2C) receptor antagonist), ondansetron (1mg/kg, i.p., a selective 5-HT(3) receptor antagonist) and naloxone (1mg/kg, i.p., a non-selective antagonist of opioid receptors). These results suggest that (m-CF(3)-PhSe)(2) produced an antidepressant-like effect in the mouse forced swimming test and this effect seems most likely to be mediated through an interaction with serotonergic and opioid systems.

Diphenyl diselenide improves scopolamine-induced memory impairment in mice.

This study was conducted to evaluate the effects of exposure to diphenyl diselenide (PhSe)2 on cognitive impairment induced by scopolamine, a muscarinic antagonist, using the Y-maze and Morris water maze tests in mice. One hour before the tests, mice were treated with (PhSe)2 (50 mg/kg, oral) and 30 min later memory impairment was induced by administration of scopolamine (1 mg/kg, intraperitoneal). (PhSe)2 (50 mg/kg, oral) significantly improved scopolamine-induced memory impairment in the Y-maze test. At the probe trial session in Morris water maze, (PhSe)2 (50 mg/kg, oral) significantly decreased the escape latency, increased the number of crossings in the platform local, and increased the time spent in the platform quadrant when compared with the scopolamine-treated group. General locomotor activity was similar in all groups. This study showed that (PhSe)2 ameliorated the impairments of spatial long-term memory and short-term memory, showed by the performance of mice in the Morris water maze and Y-maze tasks, respectively. These results suggest that (PhSe)2 may be useful for the treatment of cognitive impairment that may hold significant therapeutic value in alleviating certain memory deficits observed in Alzheimers disease.

Diphenyl diselenide ameliorates behavioral and oxidative parameters in an animal model of mania induced by ouabain.

Bipolar disorder (BD) is a common and severe mood disorder associated with higher rates of suicide and disability. Ouabain, a Na(+)/K(+)-ATPase inhibitor, induces behavioral changes in rats and has been used as a model of mania. The aim of this study was to investigate if diphenyl diselenide [(PhSe)(2)], an organoselenium compound with pharmacological properties, is effective against ouabain-induced hyperactivity and alterations in cerebral oxidative status of rats. Male Wistar rats were treated with a single dose of (PhSe)(2) (50 mg/kg, p.o.) 30 min before i.c.v. injection of ouabain (5 μl, 10(-5) M) or with the mood stabilizer, lithium chloride (LiCl) (45 mg/kg, p.o.), twice a day, for 7 days before the administration of ouabain. Open-field locomotion was quantified after ouabain administration. Thiobarbituric acid reactive substances (TBARS), oxidatively modified proteins, tyrosine nitration, ascorbic acid and non-protein thiols (NPSH) levels and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activities were determined in the whole brain. Ouabain increased locomotor activity in the open-field test and pretreatment with (PhSe)(2) or LiCl blocked this effect. In addition, ouabain increased lipid peroxidation and oxidatively modified proteins, demonstrated by a significant increase in TBARS levels and carbonyl content, which were attenuated by pretreatment with (PhSe)(2) or LiCl. The activities of SOD and CAT were increased by ouabain. LiCl was effective on preventing the increases of both enzyme activities, but (PhSe)(2) attenuated the ouabain effect in SOD activity. GPx and GR activities, ascorbic acid, NPSH and tyrosine nitration levels were not altered in all experimental groups. Similarly to LiCl, (PhSe)(2) produced an antimanic-like action, since it was effective against the locomotor hyperactivity elicited by ouabain. The results also indicated that (PhSe)(2) was effective against oxidative stress caused by ouabain in rats.

Involvement of the serotonergic system in the anxiolytic-like effect caused by m-trifluoromethyl-diphenyl diselenide in mice

The organoselenium compound diphenyl diselenide (PhSe)(2) has shown interesting antioxidant and neuroprotective activities. On the other hand, this compound has also presented some toxic effects. m-Trifluoromethyl-diphenyl diselenide (m-CF(3)-C(6)H(4)Se)(2), a structural analog of (PhSe)(2), has proven to be antipsychotic and antioxidant in mice. The present study was designed to investigate the anxiolytic-like effect of (m-CF(3)-C(6)H(4)Se)(2) in female mice, employing light/dark box and elevated plus-maze (EPM) tests. The involvement of 5-hydroxytryptamine (5-HT) receptors and monoamine oxidase (MAO) activity in the anxiolytic-like effect was also evaluated. (m-CF(3)-C(6)H(4)Se)(2) (0.1, 10 and 100 mg/kg, p.o.) did not affect locomotor activity as evaluated in the open-field test (OFT). (m-CF(3)-C(6)H(4)Se)(2) at the dose of 100 mg/kg produced an anxiolytic-like action, both in light-dark box and the EPM tests. To evaluate the role of 5-HT receptors in the anxiolytic-like effect of (m-CF(3)-C(6)H(4)Se)(2), a selective 5-HT(1A) receptor antagonist, WAY100635 (0.1 mg/kg, s.c.), a non-selective 5-HT(2A/2C) receptor antagonist, ritanserin (2 mg/kg, i.p.) and a selective 5-HT(3) receptor antagonist, ondansetron (0.1 mg/kg, i.p.) were used. All the antagonists used were able to abolish the anxiolytic-like effect of (m-CF(3)-C(6)H(4)Se)(2). (m-CF(3)-C(6)H(4)Se)(2), at the dose of 100 mg/kg, inhibited the MAO-A activity in mice brain. Taken together these data demonstrated that the anxiolytic-like effect caused by (m-CF(3)-C(6)H(4)Se)(2) seems to be mediated by the involvement of the serotonergic system.

m-Trifluoromethyl-diphenyl diselenide, a multi-target selenium compound, prevented mechanical allodynia and depressive-like behavior in a mouse comorbid pain and depression model.

Chronic pain and depression are two complex states that often coexist in the clinical setting and traditional antidepressants and analgesics have shown limited clinical efficacy. There is an intricate communication between the immune system and the central nervous system and inflammation has been considered a common mediator of pain-depression comorbidity. This study evaluated the effect of m-trifluoromethyl diphenyl diselenide [(m-CF3-PhSe)2], an organoselenium compound that has been reported to have both antinociceptive and antidepressant-like actions, in the comorbidity of chronic pain and depression induced by partial sciatic nerve ligation (PSNL) in an inflammatory approach. Mice were submitted to PSNL during 4weeks and treated with (m-CF3-PhSe)2 acutely (0.1-10mg/kg, i.g.) or subchronically (0.1mg/kg, i.g., once a day during the 3rd and 4th weeks). Both treatments prevented PSNL-increased pain sensitivity and depressive-like behavior observed in Von-Frey hair (VFH) and forced swimming (FST) tests, respectively. These effects could be mainly associated with an anti-inflammatory action of (m-CF3-PhSe)2 which reduced the levels of pro-inflammatory cytokines, NF-κB and COX-2, and p38 MAPK activation that were increased by PSNL. (m-CF3-PhSe)2 also increased the BDNF levels and reduced glutamate release and 5-HT uptake altered by PSNL. Although acute and subchronic treatments with (m-CF3-PhSe)2 prevented these alterations induced by PSNL, the best results were found when (m-CF3-PhSe)2 was subchronically administered to mice. Considering the potential common mechanisms involved in the comorbidity of inflammation-induced depression and chronic pain, the results found in this study indicate that (m-CF3-PhSe)2 could become an interesting molecule to treat long-lasting pathological pain associated with depression.

Depressive-like behavior induced by tumor necrosis factor-α is attenuated by m-trifluoromethyl-diphenyl diselenide in mice

A growing body of evidence associates activation of immune system with depressive symptoms. Accordingly, pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), have been shown to play a pivotal role in the pathophysiology of depression. The aim of this study was to evaluate the effectiveness of acute and subchronic treatments with (m-CF3-PhSe)2 to prevent the depressive-like behavior induced by intracerebroventricular injection of TNF-α in mice. TNF-α induced depressive-like behavior in the forced swimming test (FST) and tail suspension test (TST) (0.1 and 0.001 ƒg/5 μL/site, respectively) without changing locomotor activity, performed in the locomotor activity monitor (LAM). Acute (0.01-50 mg/kg; intragastric (i.g.); 30 min) and subchronic (0.01 and 0.1 mg/kg; i.g.; 14 days) treatments with (m-CF3-PhSe)2 at low doses were effective against the effect of TNF-α in the FST and TST. Nuclear factor-κB (NF-κB) and p38 mitogen-activated protein kinase (p38 MAPK), important proteins in TNF-activated signaling, were determined in the prefrontal cortex and hippocampus of mouse. TNF-α (0.1 ƒg/5 μL/site) increased NF-κB levels and p38 MAPK activation in both brain areas and acute (10 mg/kg; i.g.) and subchronic (0.01 mg/kg; i.g.) treatments with (m-CF3-PhSe)2 were effective in attenuating this increase. Although more studies are necessary to indicate this compound as a therapeutic alternative to depression, the antidepressant-like and anti-inflammatory effects of (m-CF3-PhSe)2 demonstrated herein may support it as an interesting molecule in the search for new drugs to treat depressive disorders that have been largely linked to immune process and inflammation.

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.

Evidence for the involvement of μ-opioid and δ-opioid receptors in the antinociceptive effect caused by oral administration of m-trifluoromethyl-diphenyl diselenide in mice.

Pain is one of the most prevalent conditions, which limits productivity and diminishes quality of life. This study examined the antinociceptive effects of m-trifluoromethyl-diphenyl diselenide [(m-CF3–C6H4Se)2] on behavioral models of pain in mice. The involvement of opioid receptors in (m-CF3–C6H4Se)2-induced antinociception was evaluated in the tail-immersion test. (m-CF3–C6H4Se)2 exhibited significant inhibition of nociception induced by capsaicin (1.6 μg/paw, intraplantarly) (10–100 mg/kg, orally), and acetic acid (1.6%, 10 ml/kg, intraperitoneally) (1–100 mg/kg, orally), and in tail-immersion (50–100 mg/kg) and hot-plate (10–100 mg/kg) tests. The antinociception caused by (m-CF3–C6H4Se)2 in the tail-immersion test was significantly attenuated by naloxone (a nonselective opioid antagonist, 1 mg/kg, subcutaneously), naloxonazine (a selective μ-opioid receptor antagonist, 35 mg/kg, subcutaneously), or naltrindole (a selective δ-opioid receptor antagonist, 5 mg/kg, intraperitoneally). In contrast, (m-CF3–C6H4Se)2-induced antinociception was not affected by treatment with nor-binaltorphimine (a selective κ-opioid receptor antagonist, 10 mg/kg, subcutaneously) or naloxone methiodide (a peripherally restricted opioid antagonist, 1 mg/kg, subcutaneously). These results indicate that (m-CF3–C6H4Se)2-elicited antinociception in different models of pain through mechanisms that seem to involve an interaction with the central opioid system, more specifically μ-opioid and δ-opioid receptors.

A novel isoquinoline compound abolishes chronic unpredictable mild stress-induced depressive-like behavior in mice

Chronic unpredictable mild stress (CUMS) elicits aspects of cognitive and behavioral alterations that can be used to model comparable aspects of depression in humans. The aim of the present study was to investigate the antidepressant-like potential of 7-fluoro-1,3-diphenylisoquinoline-1-amine (FDPI), a novel isoquinoline compound, in CUMS, a model that meets face, construct and predictive criteria for validity. Swiss mice were subjected to different stress paradigms daily for a period of 35 days to induce the depressive-like behavior. The animals received concomitant FDPI (0.1 and 1mg/kg, intragastric) or paroxetine (8mg/kg, intraperitoneal) and CUMS. The behavioral tests (splash test, tail suspension test, modified forced swimming test and locomotor activity) were performed. The levels of cytokines, corticosterone and adrenocorticotropic (ACTH) hormones were determined in the mouse prefrontal cortex and serum. The synaptosomal [(3)H] serotonin (5-HT) uptake, nuclear factor (NF)-κB, tyrosine kinase receptor (TrkB) and pro-brain-derived neurotrophic factor (BDNF) levels were determined in the mouse prefrontal cortex. CUMS induced a depressive-like behavior in mice, which was demonstrated in the modified forced swimming, tail suspension and splash tests. FDPI at both doses prevented depressive-like behavior induced by CUMS, without altering the locomotor activity of mice. FDPI at the highest dose prevented the increase in the levels of NF-kB, pro-inflammatory cytokines, corticosterone and ACTH and modulated [(3)H]5-HT uptake and the proBDNF/TrkB signaling pathway altered by CUMS. The present findings demonstrated that FDPI elicited an antidepressant-like effect in a model of stress-induced depression.

Serotonergic systems are implicated in antinociceptive effect of m-trifluoromethyl diphenyl diselenide in the mouse glutamate test

The organoselenium compound m-trifluoromethyl diphenyl diselenide (m-CF3-PhSe)2 has antinociceptive actions in several animal models, which are mediated by interaction with endogenous opioid systems. It also shows antidepressant-like action mediated by both opioid and serotonergic systems. Considering that serotonin (5-HT) plays an important role in the descending control of pain, this study further investigated the role of serotonergic systems in the antinociceptive action of (m-CF3-PhSe)2 in the glutamate-induced licking behavior model in mice. (m-CF3-PhSe)2 (1-50 mg/kg, p.o.), morphine (2.5 mg/kg, s.c.) or paroxetine (5 mg/kg, i.p.) reduced glutamate-induced nociception. Selective 5-HT1A and 5-HT2A receptor antagonists, WAY100635 (0.7 mg/kg, i.p.) and ketanserin (0.3 mg/kg, i.p.), but not the selective 5-HT3 receptor antagonist, ondansetron (0.5 mg/kg, i.p.), prevented the antinociceptive effect of (m-CF3-PhSe)2 (10 mg/kg) in the glutamate test. In biochemical studies, (m-CF3-PhSe)2 (10 and 50 mg/kg) decreased [(3)H]5-HT uptake in crude synaptosomes of mouse brains and slightly inhibited in vitro [(3)H]5-HT binding. In kinetic studies, the selenium (Se) distribution was determined at different time points after the administration of (m-CF3-PhSe)2 (500 mg/kg, p.o.) to mice. After 30 min, a high amount of Se was found in liver and kidneys, followed by the lung, red blood cells, serum and brain. A significant amount of Se accumulated in fat over the course of 8h. Urine was an important route of Se excretion originating from (m-CF3-PhSe)2. Collectively, results of this study indicate an involvement of the serotonergic systems in the antinociceptive effect of (m-CF3-PhSe)2 and a wide distribution of Se derived from this compound.