Bibiana Mozzaquatro Gai

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.

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.

Sporadic dementia of Alzheimer's type induced by streptozotocin promotes anxiogenic behavior in mice

Alzheimer disease, a form of dementia in which loss of memory is the first and the most characteristic symptom, is frequently accompanied by affective symptoms. Intracerebroventricular (i.c.v.) injection of streptozotocin (STZ) to rodents has been reported as an appropriate model for sporadic dementia of Alzheimers type (SDAT), characterized by a progressive impairment of memory. However, very little or nothing is known about non-cognitive behavioral effects (e.g. anxiety-like behavior) in the STZ model. In this context, the hypothesis to be tested in this study is if i.c.v. injection of STZ (0.1mg/site, 4 μl) induces anxiety-like behavior in mice. The findings of the present study indicate that i.c.v. injection of STZ in mice resulted in an anxiogenic behavior. Mice spent less time and decreased the number of entries in the open arms in the elevated plus-maze task. The latency to the first entry in the dark side in the light-dark box task was reduced by STZ. No difference was found in anxiety-like behavior between early and late time (i.e., at 7 and 21 days after infusion, respectively). These results indicate that i.c.v. STZ injection caused an anxiogenic behavior in mice.

The antidepressant-like action of a simple selenium-containing molecule, methyl phenyl selenide, in mice.

Selenium-containing molecules show promising pharmacological properties. The antidepressant-like action of CH(3)SePh in the mouse forced swimming test (FST) and the tail suspension test (TST), models predictive of depressant activity, were investigated in this study. Moreover, the involvement of dopaminergic system in the antidepressant-like action of CH(3)SePh was studied. The behavioral results showed that CH(3)SePh significantly reduced the immobility time in the FST (25 and 50 mg/kg, intragastrically; i.g.) and the TST (50 mg/kg, i.g.), without accompanying changes in ambulation when assessed in the open-field test (OFT). The anti-immobility effect of CH(3)SePh (50 mg/kg, intragastrically; i.g.) in the FST was prevented by pretreatment of mice with haloperidol (0.2 mg/kg, i.p., a dopamine D(2) receptor antagonist), SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D(2) and D(3) antagonist). These results suggest that CH(3)SePh produced an antidepressant-like action in the mouse FST and TST. The antidepressant-like action of CH(3)SePh, a simple selenium-containing molecule, seems most likely to be mediated through an interaction with the dopaminergic system.

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.

Involvement of BDNF/TrkB signaling in the effect of diphenyl diselenide on motor function in a Parkinson's disease rat model.

ABSTRACT Parkinsons disease is a progressive neurodegenerative disorder characterized by degeneration of nigrostriatal dopaminergic neurons. Diphenyl diselenide [(PhSe)2] is a compound with pharmacological proprieties, such as antidepressant and neuroprotective. Therefore, this study investigated whether (PhSe)2 reverses motor impairment and neurochemical alterations in a model of Parkinsons disease induced by 6‐hydroxydopamine (6‐OHDA) in rats. For this, male Wistar rats received 20 &mgr;g/3 &mgr;l of 6‐OHDA or vehicle into the right striatum. Three weeks later, animals were subjected to rotational behavioral test induced by D‐amphetamine and randomly divided into four groups: Sham; (PhSe)2; 6‐OHDA and 6‐OHDA+(PhSe)2. The rats received (PhSe)2 (1 mg/kg/day; i.g.) or vehicle (canola oil) during 30 days. After treatment, behavioral tests were performed in order to evaluate the motor function and the ipsilateral striatal tissue was collected for immunoblotting assay. (PhSe)2 treatment restored the normal motor behavior of 6‐OHDA‐infused rats in the cylinder, stepping and bridge tests, but not in the rotarod test. The 6‐OHDA infusion and/or (PhSe)2 treatment did not alter the muscle strength and spontaneous locomotion in the forelimb support and open‐field tests, respectively. Additionally, striatal brain‐derived neurotrophic factor (BDNF), proBDNF and tyrosine hydroxylase (TH) levels of 6‐OHDA‐lesioned rats were decreased, while the tropomyosin‐related kinase B (TrkB) levels were increased. (PhSe)2 treatment restored striatal proBDNF, TrkB and TH levels. Thus, (PhSe)2 treatment reversed some motor impairment and TH levels in a 6‐OHDA model of Parkinsons disease in rats, demonstrating a potential neurorestorative role. Additionally, the BDNF/TrkB signaling recovery can be involved in its neurorestorative effect.

Trypanosoma evansi infection impairs memory, increases anxiety behaviour and alters neurochemical parameters in rats.

The aim of this study was to investigate neurochemical and enzymatic changes in rats infected with Trypanosoma evansi, and their interference in the cognitive parameters. Behavioural assessment (assessment of cognitive performance), evaluation of cerebral L-[3H]glutamate uptake, acetylcholinesterase (AChE) activity and Ca+2 and Na+, K+-ATPase activity were evaluated at 5 and 30 days post infection (dpi). This study demonstrates a cognitive impairment in rats infected with T. evansi. At 5 dpi memory deficit was demonstrated by an inhibitory avoidance test. With the chronicity of the disease (30 dpi) animals showed anxiety symptoms. It is possible the inhibition of cerebral Na+, K+-ATPase activity, AChE and synaptosomal glutamate uptake are involved in cognitive impairment in infected rats by T. evansi. The understanding of cerebral host–parasite relationship may shed some light on the cryptic symptoms of animals and possibly human infection where patients often present with other central nervous system (CNS) disorders.

Hyperthermic seizures enhance responsiveness to pentylenetetrazole and induce cognitive dysfunction: Protective effect of 3-alkynyl selenophene

AIMS In this study we investigated the effect of pre-treatment with 3-alkynyl selenophene (3-ASP) against the increase in responsiveness to pentylenetetrazole [PTZ seizure threshold] and cognitive dysfunction induced by experimental febrile seizures (FS). The effects of 3-ASP were compared to those of diazepam (DZP). MAIN METHODS Young rats, at postnatal day 21, developed seizures after exposure to a stream of heated air to approximately 41°C. A non-spatial long-term memory and PTZ seizure threshold were determined 30 days after FS. The behavioural seizures were stereotyped followed by facial automatisms, often followed by body flexion. Young rats were pre-treated with 3-ASP (50 and 100mg/kg; per oral route), DZP (1 and 5mg/kg; intraperitoneally) or vehicle. KEY FINDINGS 3-ASP and DZP pre-treatments were not effective in protecting against seizures induced by FS. 3-ASP pre-treatment protected against the increase in responsiveness to PTZ and cognitive dysfunction induced by FS. DZP pre-treatment was effective in protecting against the increase in responsiveness to PTZ, but not, against the impaired memory induced by FS. SIGNIFICANCE 3-ASP pre-treatment protected against impairment of memory performance in the step-down passive avoidance task and the increase in the susceptibility to seizures caused by FS early in life of rats.

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.

ERK1/2 phosphorylation is involved in the antidepressant-like action of 2,5-diphenyl-3-(4-fluorophenylseleno)-selenophene in mice

We investigated the antidepressant-like action of 5 compounds belonging to the selenophene class. The involvement of ERK and CREB activation in this action was also demonstrated. In the experiment 1, time-course and dose-response effect of H-DPS, CH3-DPS, Cl-DPS, F-DPS and CF3-DPS were accompanied in the mouse forced swimming test (FST). Firstly, animals received compounds at a dose of 50mg/kg, by intragastric (i.g.) route, at different times (15-240 min) before test. Results showed that the peak of maximum anti-despair behavior induced by Cl-DPS, F-DPS and CF3-DPS was at 30 min; maximum effect of H-DPS and CH3-DPS was found at 60 min, which was maintained until 120 min. Regarding dose-response effect, all compounds reduced immobility time and increased latency for the first episode of immobility at a dose of 50mg/kg. In addition, F-DPS also showed antidepressant-like action at a dose of 25mg/kg, whilst H-DPS, CH3-DPS, Cl-DPS and CF3-DPS were not effective at lower doses. Thus, F-DPS was chosen for further investigation of its mechanism of action. Experiment 2 showed that treatment of animals with F-DPS (50 mg/kg, i.g.) significantly increased phosphorylated ERK1/2 levels in the prefrontal cortex and hippocampus; however, pCREB levels were not affected. Additionally, in the experiment 3 anti-immobility effect of F-DPS was completely blocked by pretreatment of animals with PD 98,059, an inhibitor of ERK phosphorylation, suggesting that ERK signalling activation is involved in its antidepressant-like action in mice. Together our data appoint F-DPS as a promising molecule for the development of a new antidepressant therapy.