Introduction of high-fat and very-high-fat diets associated with fructose drink in critical development periods causes cardiovascular damage in rats at the beginning of adult life.

OBJECTIVES: Exposure to an obesogenic environment at critical stages of human development may lead to cardiovascular damage during early adulthood, such as left ventricular hypertrophy (LVH). The objective of this study is to investigate whether the consumption of diets with different levels of fat associated with fructose drink, introduced to newly weaned rats, leads to cardiovascular damage. METHODS: Male Wistar rats (age 21 d) were divided into the following groups: Control (C group) fed an American Institute of Nutrition 93G diet (16.3 % kcal of lipid); high-fat diet (HF group: 45% kcal of lipids), and very-high-fat diet (VHF group: 60% kcal of lipids). The HF and VHF groups also received a fructose solution (10%) for hydration. RESULTS: After 70 d, the animals in the HF and VHF groups presented with cardiovascular damage as a comorbidity of obesity, with increased creatine kinase-MB levels, high heart and left ventricle (LV) mass, and an increase in the LV:tibia ratio. The positive correlation was observed between serum leptin levels and LV mass. In addition, the signal transducer and activator of transcription 3 content in LV was lower. CONCLUSIONS: The administration of diets with different fat and carbohydrate contents associated with fructose drinks introduced to newly weaned rats leads to LVH during early adulthood. The data suggest that the change in leptin-signal transducer and activator of transcription 3 pathway signaling in the groups is related to the occurrence of LVH.

Acute supplementation of growing rats with Brazil nut flour increases hepatic lipid content but prevents oxidative damage in the liver.

Brazil nuts (BN) (Bertholletia excels, Bonpl.), are of great importance because of their nutritional properties and economic value. They can be consumed in natura or as flour (BNF). In this study, we evaluated the effects of BNF and BN intakes (Both 5% and 15%) on metabolic parameters of rats for 15 days. Serum Selenium (Se) levels were higher in BN-15% and BNF-15% groups. Lipid content was reduced in retroperitoneal and epididymal adipose tissues in all groups and in the BN-5% group in the liver. However, liver lipids increased in the BNF-15% group. The levels of carbonylated proteins and lipid peroxidation in the liver were not altered. The data reveal that the increase in hepatic lipids in the BNF-15% group probably occurred due to the high concentration of free fatty acids present in the flour. The Se bioavailability in the diet contributed to the preservation of the liver function in rats. PRACTICAL IMPLICATIONS: The consumption of BN is common in the population. However, changes in eating habits have led to a more frequent consumption of vegetable derivatives, such as drinks and oils. The cake residue generated after processing is still considered of high nutritional value, since it is a source of protein and minerals such as Se. Because of its low cost, the use of pie at the industrial level is becoming increasingly more interesting for the development of new products, and the Brazil nut flour (BNF) is considered a good option. Our study showed that just like BN, BNF can be a source of selenium for the body, although changes in lipid metabolism and physiological parameters can be observed depending on the amount used. We believe that the results of this investigation can be used to guide the development of new technologies and products containing BN.

The antioxidant system in the soleus muscle of growing rats is stimulated by the administration of a low-protein/high-carbohydrate diet.

The aim of this study was to evaluate the generation of reactive oxygen species (ROS) by xanthine oxidase (XO), the enzymatic antioxidant system and oxidative damage in soleus and extensor digitorum longus (EDL) muscles of growing rats fed a low-protein, high-carbohydrate (LPHC; 6% protein, 74% carbohydrate) diet for 15 days. The LPHC diet increased the total antioxidant capacity by 45% and the activities of glutathione peroxidase (GPx), glutathione reductase and catalase in the soleus muscles. There was an increase in the carbonylated proteins with no increase thiobarbituric acid reactive substances (TBARS), although the XO activity had increased 20%. In EDL muscles, the LPHC diet increased XO activity by 66% and the TBARS levels by 80%, and only GPx had its activity increased. These results suggest that the enzymatic antioxidant system of the soleus muscle has a better response to the increase of ROS production stimulated by LPHC diet.

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

Parkinson's 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 Parkinson's disease induced by 6-hydroxydopamine (6-OHDA) in rats. For this, male Wistar rats received 20µg/3µl 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 (1mg/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 Parkinson's disease in rats, demonstrating a potential neurorestorative role. Additionally, the BDNF/TrkB signaling recovery can be involved in its neurorestorative effect.

The hypolipidemic action of a diet supplemented with p,p'-methoxyl-diphenyl diselenide is not directly related to its antioxidant property.

The present study investigated whether a p,p'-methoxyl-diphenyl diselenide (MeOPhSe)2-supplemented diet causes toxicity in rats. A second aim of this study was to determine whether a 10 ppm (MeOPhSe)2-supplemented diet has hypolipidemic effect on Triton WR-1339-induced hyperlipidemia in rats. To rule out the antioxidant property of (MeOPhSe)2 in its hypolipidemic action, parameters of oxidative stress were carried out. Wistar rats were fed with 3, 10, or 30 ppm of (MeOPhSe)2-supplemented diet for 30 days. None of (MeOPhSe)2-supplemented diets caused alteration in general parameters of toxicity and lipid profile of rats. The hypolipidemic effect of 10 ppm of (MeOPhSe)2-supplemented diet on rats treated with Triton WR-1339 (400 mg/kg, intraperitoneal) was investigated. The (MeOPhSe)2-supplemented diet partially protected against the levels of total cholesterol (TC) and non-HDL-C and reduced the atherogenic index (AI) increased by Triton WR-1339 in rats. A positive correlation between TC and triglyceride levels (r = 0.679) and non-HDL-C levels (r = 0.929) and AI (r = 0.889) was demonstrated. Triton WR-1339 altered parameters of oxidative stress in livers of rats but (MeOPhSe)2-supplemented diet did not protect against these alterations. The results demonstrated that the hypolipidemic action of (MeOPhSe)2-supplemented diet is not directly related to its antioxidant property and devoid of systemic toxicity in rats at the parameters analyzed.

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.

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.

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.

Depression-related behavior and mechanical allodynia are blocked by 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene in a mouse model of neuropathic pain induced by partial sciatic nerve ligation.

Clinically, it is suggested that chronic pain might induce mood disorders like depression and anxiety. Based on this antidepressant drugs have emerged as a new therapy for pain. In this study, the effect of acute and subchronic treatments with 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene (F-DPS) on behavioral changes induced by partial sciatic nerve ligation (PSNL) was evaluated. At the 4th week after surgery, PSNL caused a significant depression-like behavior in mice evaluated in the forced swimming test (FST) and the tail suspension test (TST), which was accompanied by increased pain sensitivity. The anxiety-like behavior assessed in the light-dark test (LDT) was not modified by PSNL. Acute treatment with F-DPS, at a dose of 1 mg/kg, intragastrically (i.g.) administered 30 min before the FST, produced a significant anti-immobility effect in PSNL mice. The antidepressant drug paroxetine showed acute antidepressant-like action at a dose 10 times higher than F-DPS. Subchronic treatment with F-DPS (0.1 mg/kg, i.g.) reversed depression-like behavior of sciatic nerve-ligated mice in the TST and FST and produced a significant anxiolytic-like action in both sham-operated and PSNL animals. Although the acute F-DPS treatment did not produce anti-allodynic effect, F-DPS subchronic treatment significantly reduced pain sensitivity in PSNL mice. These findings demonstrated that F-DPS blocked behavioral changes induced by neuropathic pain, suggesting that it might be attractive in the pharmacological approach of pain-emotion diseases.

An organoselenium compound improves behavioral, endocrinal and neurochemical changes induced by corticosterone in mice.

RATIONALE: 3-(4-Fluorophenylselenyl)-2,5-diphenylselenophene (F-DPS) is a promising organoselenium compound that shows antidepressant-like properties related to interaction with the serotonergic system. OBJECTIVES: In this study, a mouse model of anxiety/depressant-like behavior induced by long-term corticosterone treatment was used to evaluate behavioral, endocrinal, and neurochemical changes in mice and their possible modulation of F-DPS treatment. METHODS: Swiss mice were subjected to 4 weeks of corticosterone administration (20 µg/ml in drinking water) and a new therapeutic approach with F-DPS (0.1 mg/kg/day, intragastric route, during 1 week) was employed to modulate changes induced by corticosterone exposure. RESULTS: Treatment with corticosterone caused a significant depressant-like behavior in the forced swimming test and tail suspension test, which was accompanied by anxiety-like condition in the light-dark test and novelty suppressed-feeding; similarly to the classical antidepressant drug paroxetine, F-DPS treatment was effective in reversing these behavioral changes. Further, F-DPS normalized serum levels of corticosterone and adrenocorticotropic hormone, which were increased after corticosterone exposure. Corticosterone also significantly inhibited glutamate uptake in the prefrontal cortex of mice, whereas glutamate release was not modified. Besides normalizing glutamate uptake in the corticosterone-exposed mice, F-DPS promoted an inhibition of 5-HT uptake in the prefrontal cortex and hippocampus. In addition, hippocampal monoamine oxidase-A activity was also inhibited by F-DPS treatment. CONCLUSIONS: These findings suggest a modulation of both serotonergic and glutamatergic systems by F-DPS after a long-term corticosterone exposure in mice, which may be involved in the antidepressant- and anxiolytic-like actions of this organoselenium compound.

Diphenyl diselenide reduces mechanical and thermal nociceptive behavioral responses after unilateral intrastriatal administration of 6-hydroxydopamine in rats.

Parkinson's disease (PD) patients, in addition to motor dysfunction, also present alterations in pain sensation. The present study characterized the antinociceptive effects of diphenyl diselenide ((PhSe)2) in a model of nociception induced by unilateral, intrastriatal 6-hydroxydopamine (6-OHDA) injection in rats. Male adult Wistar rats received 20 µg/3 µl of 6-OHDA (in saline solution containing 0.02 % of ascorbic acid) or 3 µl of vehicle into the right striatum (1.0 mm anterior, 3.0 mm lateral, and 5.0 mm ventral-with respect to the bregma). Thirty days after injection, rats received (PhSe)2 intragastrically at a dose of 10 mg/kg 1 h before behavioral tests (von Frey hairs, hot plate, tail immersion, formalin, and open field). Our results demonstrated that 6-OHDA injection to rats augmented the response frequency of von Frey hairs (VHF) stimulation, besides reducing the thermal withdrawal latency in the hot plate test. Importantly, the (PhSe)2 treatment decreased the mechanical allodynia measured by the response frequency of VHF stimulation and diminished the thermal nociception in the hot plate test in 6-OHDA-injected rats. In conclusion, these results revealed that a single oral administration of (PhSe)2 1 h prior to the accomplishment of the behavioral tests was effective to attenuate the increased mechanical and thermal nociception caused by a single intrastriatal 6-OHDA injection to rats. Furthermore, other clarifying studies are warranted to improve the evidence bases for future clinical use of (PhSe)2 as a new alternative therapy for the treatment of painful symptoms associated to PD.

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.

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.

m-Trifluoromethyl diphenyl diselenide attenuates glutaric acid-induced seizures and oxidative stress in rat pups: involvement of the γ-aminobutyric acidergic system.

Glutaric acidemia type I (GA-I) is an inherited metabolic disease characterized by accumulation of glutaric acid (GA) and seizures. The intrastriatal GA administration in rats has been used as an animal model to mimic seizures presented by glutaric acidemic patients. m-Trifluoromethyl diphenyl diselenide, (m-CF(3) -C(6) H(4) Se)(2) , is an organoselenium compound that protects against seizures induced by pentylenetetrazole in mice. Thus, the aim of this study was to investigate whether (m-CF(3) -C(6) H(4) Se)(2) is effective against GA-induced seizures and oxidative stress in rat pups 21 days of age. Our findings demonstrate that (m-CF(3) -C(6) H(4) Se)(2) preadministration (50 mg/kg; p.o.) protected against the reduction in latency and the increased duration of GA (1.3 µmol/right striatum)-induced seizures in rat pups. In addition, (m-CF(3) -C(6) H(4) Se)(2) protected against the increase in reactive species generation and the reduction in antioxidant defenses glutathione peroxidase and glutathione S-transferase activities induced by GA. By contrast, no change in glutathione reductase or catalase activities was found. In addition, (m-CF(3) -C(6) H(4) Se)(2) was effective in protecting against inhibition of Na(+) ,K(+) -ATPase activity caused by GA in striatum of rat pups. This study showed for the first time that GA administration caused an increase in [(3) H]GABA uptake from striatum slices of rat pups and that (m-CF(3) -C(6) H(4) Se)(2) preadministration protected against this increase. A positive correlation between duration of seizures and [(3) H]GABA uptake levels was demonstrated. The results indicate that (m-CF(3) -C(6) H(4) Se)(2) protected against GA-induced seizures. Moreover, these findings suggest that the protection against oxidative stress, the inhibition of Na(+) ,K(+) -ATPase activity, and the increase in [(3) H]GABA uptake are possible mechanisms for the potential anticonvulsant action of (m-CF(3) -C(6) H(4) Se)(2).

Involvement of GABAergic and glutamatergic systems in the anticonvulsant activity of 3-alkynyl selenophene in 21 day-old rats.

In this study, we investigated the role of GABAergic and glutamatergic systems in the anticonvulsant action of 3-alkynyl selenophene (3-ASP) in a pilocarpine (PC) model of seizures. To this purpose, 21 day-old rats were administered with an anticonvulsant dose of 3-ASP (50 mg/kg, per oral, p.o.), and [(3)H]γ-aminobutyric acid (GABA) and [(3)H]glutamate uptakes were carried out in slices of cerebral cortex and hippocampus. [(3)H]GABA uptake was decreased in cerebral cortex (64%) and hippocampus (58%) slices of 21 day-old rats treated with 3-ASP. In contrast, no alteration was observed in [(3)H]glutamate uptake in cerebral cortex and hippocampus slices of 21 day-old rats that received 3-ASP. Considering the drugs that increase synaptic GABA levels, by inhibiting its uptake or catabolism, are effective anticonvulsants, we further investigated the possible interaction between sub-effective doses of 3-ASP and GABA uptake or GABA transaminase (GABA-T) inhibitors in PC-induced seizures in 21 day-old rats. For this end, sub-effective doses of 3-ASP (10 mg/kg, p.o.) and DL-2,4-diamino-n-butyric acid hydrochloride (DABA, an inhibitor of GABA uptake--2 mg/kg, intraperitoneally; i.p.) or aminooxyacetic acid hemihydrochloride (AOAA; a GABA-T inhibitor--10 mg/kg, i.p.) were co-administrated to 21 day-old rats before PC (400 mg/kg; i.p.) treatment, and the appearance of seizures was recorded. Results demonstrated that treatment with AOAA and 3-ASP or DABA and 3-ASP significantly abolished the number of convulsing animals induced by PC. The present study indicates that 3-ASP reduced [(3)H]GABA uptake, suggesting that its anticonvulsant action is related to an increase in inhibitory tonus.

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.

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 Alzheimer's 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.

Neuroprotector effect of p,p'-methoxyl-diphenyl diselenide in a model of sporadic dementia of Alzheimer's type in mice: contribution of antioxidant mechanism.

The present study investigated whether the antioxidant activity of p,p'-methoxyl-diphenyl diselenide [(MeOPhSe)(2)] is involved in its protective effect against cognitive impairment induced by streptozotocin (STZ) in a model of sporadic dementia of Alzheimer's type (SDAT). Swiss mice were treated with STZ or vehicle [2 µl of 2·5 mg ml(-1) solution; intracerebroventricularly (i.c.v.)] twice, 48 h apart. (MeOPhSe)(2) (25 mg kg(-1)) or vehicle was orally administered 30 min prior to each STZ treatment. Neuroprotector effect of (MeOPhSe)(2) on the behavioral performance of mice on spatial recognition memory consolidation was investigated in the Y-maze test. After that, mouse brains were removed for measuring antioxidant parameters. (MeOPhSe)(2) protected against the impairment in learning and memory caused by i.c.v. administration of STZ in mice. (MeOPhSe)(2) protected against the increase in reactive species and the reduction of glutathione levels, as well as, the increase in superoxide dismutase and glutathione S-transferase activities caused by STZ in whole brain. These results suggest that antioxidant property is involved, at least in part, in the neuroprotective effect of (MeOPhSe)(2) on SDAT induced by STZ in mice.

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.