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This study evaluated the effects of topically applied hydrogels (HG) containing nanoencapsulated indol-3-carbinol (I3C) and its free form in a rat model of skin wounds. Formulations were topically applied twice a day for five days to the wounds. On days 1, 3, and 6, the wound area was measured to verify the % of regression. On the sixth day, the animals were euthanized for the analysis of the inflammatory and oxidative profile in wounds. The nanocapsules (NC) exhibited physicochemical characteristics compatible with this kind of suspension. After five hours of exposure to ultraviolet C, more than 78% of I3C content in the suspensions was still observed. The NC-I3C did not modify the physicochemical characteristics of HG when compared to the HG base. In the in vivo study, an increase in the size of the wound was observed on the 3rd experimental day, which was lower in the treated groups (mainly in HG-NC-I3C) compared to the control. On the 6th day, HG-I3C, HG-NC-B, and HG-NC-I3C showed lower regression of the wound compared to the control. Additionally, HG-NC-I3C exhibited an anti-inflammatory effect (as observed by decreased levels of interleukin-1B and myeloperoxidase), reduced oxidative damage (by decreased reactive species, lipid peroxidation, and protein carbonylation levels), and increased antioxidant defense (by improved catalase activity and vitamin C levels) compared to the control. The current study showed more satisfactory results in the HG-NC-I3C group than in the free form of I3C in decreasing acute inflammation and oxidative damage in wounds.

Dexamethasone is a synthetic glucocorticoid that has been associated with oxidative stress in central and peripheral tissues. p -Chloro-diphenyl diselenide (( p -ClPhSe) 2 ) is an antioxidant organoselenium compound. The present study evaluated whether nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap-1) signaling contributes to the ( p -ClPhSe) 2 antioxidant effects in the kidney of mice exposed to dexamethasone. Adult Swiss mice received dexamethasone (intraperitoneal) at a dose of 2 mg/kg or its vehicle for 21 days. After that, mice were treated with ( p -ClPhSe) 2 (intragastric) (1, 5, or 10 mg/kg) for 7 days. Samples of kidneys were collected for biochemical assays. ( p -ClPhSe) 2 at a dose of 1 mg/kg reversed the renal reactive oxygen species (ROS) and carbonyl protein (CP) levels increased by dexamethasone. ( p -ClPhSe) 2 at doses of 5 and 10 mg/kg was effective against the increase of thiobarbituric acid reactive substances, ROS, and CP, as well as the decrease of δ-aminolevulinic acid dehydratase activity and nonprotein sulfhydryl levels induced by dexamethasone. At 5 mg/kg, ( p -ClPhSe) 2 reduced the renal levels of 4-OH-2-HNE and heme oxygenase (HO-1), as well as modulated the Nrf2/Keap-1 signaling in mice exposed to dexamethasone. The present findings revealed that ( p -ClPhSe) 2 antioxidant effects were associated with the modulation of Nrf2/Keap-1 signaling pathway in the kidney of mice exposed to dexamethasone.

Sports-related concussions are particularly common during adolescence, and there is insufficient knowledge about how recurrent concussions in this phase of life alter the metabolism of essential structures for memory in adulthood. In this sense, our experimental data revealed that seven recurrent concussions (RC) in 35-day-old rats decreased short-term and long-term memory in the object recognition test (ORT) 30 days after injury. The RC protocol did not alter motor and anxious behavior and the immunoreactivity of brain-derived neurotrophic factor (BDNF) in the cerebral cortex. Recurrent concussions induced the inflammatory/oxidative stress characterized here by increased glial fibrillary acidic protein (GFAP), interleukin 1β (IL 1β), 4-hydroxynonenal (4 HNE), protein carbonyl immunoreactivity, and 2',7'-dichlorofluorescein diacetate oxidation (DCFH) levels and lower total antioxidant capacity (TAC). Inhibited Na + ,K + -ATPase activity (specifically isoform α 2/3 ) followed by K m (Michaelis-Menten constant) for increased ATP levels and decreased immunodetection of alpha subunit of this enzyme, suggesting that cognitive impairment after RC is caused by the inability of surviving neurons to maintain ionic gradients in selected targets to inflammatory/oxidative damage, such as Na,K-ATPase activity., (Copyright © 2021. Published by Elsevier Inc.)

One of the major causes of early pregnancy loss is heat stress. In ruminants, interferon tau (IFNT) is the embryo signal to the mother. Once the interferon signaling pathway is activated, it drives gene expression for interferon-stimulated genes (ISGs) and alters neutrophils responses. The aim of the present study was to evaluate interferon (IFN) pathway, ISGs and gene expression in polymorphonuclear leukocytes (PMN) and oxidative stress in dairy cows under heat stress. Pregnant cows had their estrous cycle synchronized and randomly assigned to a comfort or heat stress group. Blood samples were collected at artificial insemination (AI) and on Days 10, 14 and 18 following AI. Pregnant cows were pregnancy checked by ultrasound on Day 30 and confirmed on Day 60 post-AI. Results are presented as mean ± SEM. The corpus luteum (CL) diameter was not different between groups of pregnant cows; concentration of progesterone of pregnant cows on Day 18 following AI was greater in comfort group compared to heat stressed group. Comfort pregnant cows had higher expression of all analyzed genes from interferon pathway, except for IFNAR1, on both Days 14 and 18. Conversely, heat stressed cows did not show altered expression of IFNT pathway genes and ISGs between Days 10, 14, and 18 after AI. The oxidative stress, determined as malondialdehyde (MDA) levels, was greater in heat stress group on Days 10, 14 and 18, independent of pregnancy status. Heat stress negatively influences expression of ISGs, IFN pathway gene expression in neutrophils, and oxidative stress. Our data suggest that lower conception rates in cows under heat stress are multifactorial, with the association of interferon pathway activation and the unbalanced oxidative stress being main contributing factors., Competing Interests: The authors have declared that no competing interests exist.

Streptozotocin (STZ) is a substance used experimentally to induce a diabetes model, a metabolic disease associated with oxidative tissue damage. This study evaluated if 4-4'-dichloro-diphenyl diselenide ( p -ClPhSe) 2 modulates oxidative stress in peripheral tissues of diabetic mice. Male Swiss mice received a single STZ injection (i.p.) at a dose of 200 mg/kg or its vehicle and were treated with ( p -ClPhSe) 2 (7 days, 5 mg/kg) or metformin (200 mg/kg, twice per day). After, the mice were euthanized to collect liver, kidney, and skeletal muscle samples. In the liver, ( p -ClPhSe) 2 reduced thiobarbituric acid reactive substances (TBARS) and protein carbonyl levels and normalized the superoxide dismutase activity in STZ-treated mice. In the kidney, ( p -ClPhSe) 2 reversed the increase in the reactive species levels but not the catalase (CAT) activity reduction in STZ-treated mice. There was no evidence of oxidative damage in the skeletal muscle of STZ-treated mice, but an increase in the CAT activity and a reduction in non-protein thiol levels were found. ( p -ClPhSe) 2 did not reverse a decrease in hepatic and renal δ-aminolevulinic acid dehydratase activity in STZ-treated mice. The results show that the liver and kidney of STZ-treated mice were more susceptible to oxidative stress. This study reveals that ( p -ClPhSe) 2 modulated oxidative stress, which differently affected peripheral tissues of diabetic mice.

Studies reveal that oxidative stress is associated with adverse effects of long-term morphine treatment. The m -trifluoromethyl-diphenyl diselenide (CF3) is a multi-target organoselenium compound that has antioxidant properties in different experimental models. This study aimed to investigate the CF3 effects against redox imbalance in peripheral and central tissues of mice, after single or multiple morphine doses. Swiss male mice received a single dose of morphine (5 mg/kg, s.c.) and CF3 (10 mg/kg, i.g.), or morphine was repeatedly injected (5 mg/kg, s.c.) and CF3 (10 mg/kg, i.g.) administered twice daily for 7 days. Oxidative stress was determined in the hippocampus, liver, and kidney. CF3 reversed the increase in reactive species caused by single and multiple morphine doses in the peripheral tissues. CF3 increased hepatic non-protein thiol levels and the superoxide dismutase (SOD) activity decreased by a single morphine dose. CF3 reversed the reduction in SOD activity in the kidney of mice repeatedly exposed to morphine. The study demonstrates that peripheral tissues were more susceptible than the hippocampus to oxidative stress induced by morphine in mice. The results show that CF3 modulated parameters of oxidative stress modified by single and multiple morphine administrations in peripheral and central tissues of mice.

Energy-dense foods and ethanol consumption are associated with mood disorders. m-Trifluoromethyl-diphenyl diselenide [(m-CF 3 -PhSe) 2 ] has been a prominent pharmacological target due to its antidepressant-like effects. This study investigated if the modulation of opioid and glucocorticoid receptors and its well-known antioxidant property contribute to the (m-CF 3 -PhSe) 2 antidepressant-like effect in young mice subjected to an energy-dense diet and ethanol intake. Swiss male mice [postnatal day (PND) 25] were exposed to an energy-dense diet (containing 20% fat and 20% carbohydrate) or standard chow until the PND 67. Mice received ethanol (2 g/kg) or water administration (3 times a week, intragastrically [i.g.]) from PND 45 to PND 60. After that, mice received (m-CF 3 -PhSe) 2 (5 mg/kg/day; i.g) or vegetal oil administration from PND 60 to 66. Mice performed the behavioral tests to evaluate the depressive-like phenotype. The results showed that individually neither an energy-dense diet nor ethanol group induced a depressive-like phenotype, but the association of both induced this phenotype in young mice. Oxidative stress was characterized by the increase of malondialdehyde, the decrease in the superoxide dismutase activity, and non-protein sulfhydryl levels in the cerebral cortex of depressive-like mice. Depressive-like mice showed an increase in the protein levels of opioid receptors and depletion in those of glucocorticoid. (m-CF 3 -PhSe) 2 abolished depressive-like phenotype and oxidative stress as well as modulated the levels of glucocorticoid and opioid receptors. In conclusion, the modulation of opioid and glucocorticoid receptors and the antioxidant property contributed to the (m-CF 3 -PhSe) 2 antidepressant-like effect in young mice exposed to an energy-dense diet and ethanol intake.

Interferon tau (IFNT) is the cytokine responsible for the maternal recognition of pregnancy in ruminants and plays a role modulating embryo-maternal communication in the oviduct inducing a local response from immune cells. We aimed to investigate IFNT production, reactive oxygen species, and oxidative stress under the influence of heat stress (HS) during different stages of bovine in vitro embryo production. HS was established when the temperature was gradually raised from 38.5°C to 40.5°C in laboratory incubator, sustained for 6 hr, and decreased back to 38.5°C. To address the HS effects on IFNT production, reactive oxygen species, and oxidative stress, ovaries from a slaughterhouse were used according to treatments: control group (38.5°C); oocytes matured under HS; oocytes fertilized under HS; zygotes cultured in the first day under HS; and cells submitted to HS at oocyte maturation, fertilization, and the first day of zygote culture. The HS negatively affected cleavage and blastocyst rates, in all HS groups. On Day 7, all HS-treated embryos showed decrease IFNT gene and protein expressions, whereas reactive oxygen species were increased in comparison to the control. In conclusion, the compromised early embryo development due to higher temperatures during in vitro oocyte maturation, fertilization, and/or zygote stage have diminished IFNT expression and increased reactive oxygen species in bovine., (© 2020 Wiley Periodicals LLC.)

Intracerebroventricular streptozotocin injection (icv STZ) is a well established sporadic Alzheimer's disease (AD) model in rodents. AD is characterized by neuronal degeneration accompanied by central oxidative stress. Studies also indicate peripheral oxidative damage in AD, but if the icv STZ model of sporadic AD mimics this feature is an open question. This study aimed to investigate if icv STZ administration induces peripheral oxidative stress and the antioxidant action of Ebselen, compared to the reference drug (donepezil), in this sporadic AD model. Male adult Swiss mice received icv STZ (days 1 and 3). Mice received Ebselen (10 mg/kg, i.p) or Donepezil (5 mg/kg, i.p) for 14 days. Mice were killed and the kidney and liver were excised to determine parameters of oxidative stress and toxicity markers. The mice icv STZ-injected showed peripheral oxidative stress. Ebselen reversed renal lipid peroxidation in the icv STZ administered mice by modulating NPSH levels, SOD and CAT activities, whereas Donepezil, modulated only NPSH levels. Ebselen and Donepezil counteracted hepatic lipid peroxidation in STZ-injected mice by modulating NPSH levels and CAT activity. The δ-ALA-D activity was inhibited in the kidney, but not in the liver, whereas the icv STZ-injected mice had an increase in the GST activity in both tissues. Ebselen reversed the increase in the hepatic GST activity of the STZ-injected mice. Donepezil increased renal GST activity in the control mice. In conclusion, this study demonstrates that the icv STZ administration induced peripheral oxidative stress. Ebselen, similar to Donepezil, was effective against peripheral oxidative stress in a mouse model of sporadic AD.

Rationale and Objectives: Stress-induced alterations in oxidative and inflammatory parameters have been implicated in the pathophysiology of mood disorders. Based on the antioxidant and anti-inflammatory properties of the selenium-containing compound 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI), we assessed its ability to reverse depression-like behavioral alterations, neuroinflammation, and oxidative imbalance induced by acute restraint stress., Methods: Mice submitted to restraint for 240 min received CMI (1 or 10 mg/kg, orally) 10 min after the end of the stress induction. Behavioral and biochemical tests were carried out after further 30 min., Results: Restraint-induced depression-like behavior in the tail suspension test (TST), splash test, and new object exploration test was reversed by CMI. None of the treatments evoked locomotor alteration. In addition, CMI abrogated restraint-induced increases in plasma levels of corticosterone and in markers of oxidative stress and impaired superoxide dismutase and catalase activity in the prefrontal cortex (PFC) and hippocampus (HC). CMI also blocked stress-induced downregulation of mRNA levels of glucocorticoid receptor and brain-derived neurotrophic factor and upregulation of nuclear factor kappa B, inducible nitric oxide synthase, tumor necrosis alpha, indoelamine-2,3-dioxygenase, and glycogen synthase kinase 3 beta in PFC and HC., Conclusions: These preclinical results indicate that administration of selenium-containing compounds might help to treat depression associated with inflammation and oxidative stress. Graphical abstract ᅟ.

The current study evaluated whether fructose supplementation affects oxidative stress and metabolic parameters in the liver and gastrocnemius muscle of rats subjected to swimming exercise. Male adult Wistar rats received a fructose solution (10%) or water during 1 h before exercise and during the rest interval by the intragastric route. The swimming protocol consisted of 6 days: each day, rats underwent 3 sessions of 17 min each, with a load of 5% of body mass, and rest intervals of 3 min. Fructose supplementation changed metabolic and oxidative parameters in the liver and gastrocnemius muscle of sedentary rats. Swimming exercise counteracted the increase of triglyceride levels in plasma and liver induced by fructose supplementation. It also reduced thiobarbituric acid reactive species levels in the liver, and catalase and superoxide dismutase activities in the gastrocnemius muscle of supplemented rats. However, fructose supplementation worsened metabolic (hepatic triglyceride levels) and oxidative parameters (thiobarbituric acid reactive species levels) in the liver and gastrocnemius of exercised rats. This study demonstrates that oxidative stress and metabolic parameters were differently affected by fructose supplementation when rats were kept sedentary or underwent swimming exercise. The present results indicate the need of a new insight of the role of fructose supplementation during physical exercise.

Previous findings showed that the nanoencapsulation of diphenyl diselenide [(PhSe) 2 ], an organoselenium compound, provided superior biological effects and lower toxicological potential than its free form in vitro. However, few studies reported the behavioral and biochemical effects of this nanocapsules formulation in vivo. Zebrafish (Danio rerio) has emerged as a useful animal model to determine the pharmacological and toxicological effects of nanoparticles. Here, we evaluated the behavioral and brain oxidative effects after zebrafish exposure to (PhSe) 2 -loaded nanocapsules. Formulations were prepared by interfacial deposition of preformed polymer method and later tested at concentrations ranging from 0.1 to 2.0 μM. Both locomotor and exploratory activities were assessed in the novel tank diving test. Moreover, brain oxidative status was determined by measuring thiobarbituric acid-reactive substance levels, glutathione peroxidase, glutathione redutase and glutathione S-transferase activities. (PhSe) 2 -loaded nanocapsules showed no alteration on travelled distance, immobility, and erratic swimming, suggesting the absence of behavioral impairments. Interestingly, the higher concentration tested had anxiolytic-like effects, since animals spent more time in the top area and showed a decreased thigmotaxis behavior. Biochemical analysis demonstrated that the concentrations used in this study did not affect oxidative stress-related parameters in brain samples, reinforcing the low toxicological potential of the formulation. In conclusion, the exposure to (PhSe) 2 -loaded nanocapsules caused no locomotor impairments as well as did not modify the oxidative status of zebrafish brain, indicating that this formulation is probably non-toxic and promising for future pharmacological studies., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Alzheimer 's disease (AD) is characterized by progressive cognitive decline including memory impairment, cortical dysfunction, and neuropsychiatric disturbances. The drug discovery to treat AD consists to develop compounds able to act in multiple molecular targets involved in the pathogenesis of the disease and the repositioning of old drugs for new application. This way, the intracerebroventricular (icv) injection of streptozotocin (STZ) has been used as a metabolic model of sporadic AD. The aim of the present study was to investigate whether ebselen (1-10 mg/kg), a multifunctional selenoorganic compound, ameliorates memory impairment, hippocampal oxidative stress, apoptosis and cell proliferation in a mouse model of sporadic AD induced by icv STZ (3 mg/kg, 1 μl/min). The administration of ebselen (10 mg/kg, i.p.) reversed memory impairment and hippocampal oxidative stress, by increasing the activities of antioxidant enzymes and the level of a non-enzymatic antioxidant defense, in Swiss mice administered with icv STZ. The anti-apoptotic property of ebselen was demonstrated by its effectiveness against the increase in the ratios of Bax/Bcl-2, cleaved PARP/PARP and the cleaved caspase-3 levels in the hippocampus of icv STZ mice. Although ebselen reversed memory impairment, it was ineffective against the reduction in the number of BrdU positive cells induced by icv STZ. In conclusion, the multifunctional selenoorganic compound ebselen was effective to reverse memory impairment, hippocampal oxidative stress and apoptosis in a mouse model of sporadic AD induced by icv STZ., (Copyright © 2018. Published by Elsevier Ltd.)

Monosodium glutamate (MSG), a food flavor enhancer used worldwide, has been studied because it may cause neurotoxicity, which is associated with oxidative stress. The aim of this study was to investigate whether spinal cord and brain regions are affected by oxidative stress and the temporal profile of nociceptive responses induced by MSG in newborn and adult rats. The newborn (post natal day, PND 1) Wistar rats received ten subcutaneous injections of MSG (4.0 g/kg) or saline solution. At PND 3, 11 or 90, the rats performed nociceptive tests and parameters of oxidative stress were evaluated in samples of spinal cord and brain regions. Adult rats (PND 90) were injected with MSG (4.0 g/kg, 10 injections) or saline solution, but MSG did not induce nociception or oxidative stress. The neonatal administration of MSG increased nociceptive behavior in the tail immersion, hot plate and formalin tests and decreased the SOD activity in spinal cord of PND 3 rats. In rats at PND 11 and 90, the neonatal administration of MSG increased mechanical allodynia and nociceptive behavior in the hot plate and formalin tests. The neonatal administration of MSG induced oxidative stress in the hippocampus of rats at PND 11 and in the cerebral cortex at PND 90. These findings demonstrate that nociception and oxidative stress was induced in rats dependent on the time of MSG administration, susceptibility of spinal cord and brain regions and the age of rats., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Bisphenol A (BPA) is a chemical toxicant that has deleterious effects on human. BPA causes oxidative stress in tissues, including the liver. Diphenyl diselenide (PhSe) 2 improves the antioxidant response via activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like ECH-associated protein (keap 1) pathway in macrophage cells. In the present study, we investigated whether (PhSe) 2 counteracts hepatic oxidative stress induced by BPA in male and female Swiss mice. Three-week-old mice received by the intragastric (i.g.) route BPA (5 mg/kg) from 21st to 60th postnatal day (PND). At PND 61, the mice were treated with (PhSe) 2 (1 mg/kg, i.g.) for seven days. Parameters of hepatic damage and oxidative stress were determined in male and female mice. The results show that BPA increased the activity of aspartate aminotransferase in female mice, and in male mice the activity of alanine aminotranseferase was increased. Male and female mice had an increase in fat mass accumulation. Male mice showed an increase in hepatic oxidative damage of proteins and a decrease in non-enzymatic (ascorbic acid and non-protein thiol) and enzymatic (superoxide dismutase) defenses, which are consistent with oxidative stress status. Male mice were more susceptible than female mice to hepatic oxidative stress induced by BPA. BPA decreased Nrf2/Keap1 protein content in male mice. (PhSe) 2 reduced hepatic oxidative stress induced by BPA in male mice. Our results demonstrate that male mice were more susceptible to hepatic oxidative stress induced by BPA than female mice. (PhSe) 2 regulated Nrf2/Keap-1 signaling pathway and countered hepatic oxidative stress induced by BPA in male mice., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Organoselenium compounds and indoles have gained attention due to their wide range of pharmacological properties. Depression is a recurrent and disabling psychiatric illness and current evidences support that oxidative stress and neuroinflammation are mechanisms underlying the pathophysiology of this psychiatric condition. Here, we evaluated the effect of 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI) in lipopolysaccharide (LPS)-induced depressive-like behaviour, neuroinflammation and oxidative stress in male mice. CMI pre-treatment (20 and 50 mg/kg, intragastrically) significantly attenuated LPS (0.83 mg/kg, intraperitoneally)-induced depressive-like behaviour in mice by reducing the immobility time in the tail suspension test (TST) and forced swimming test (FST). CMI pre-treatment ameliorated LPS-induced neuroinflammation by reducing the levels of interleukin (IL)-1β, IL-4 and IL-6 in the hippocampus and prefrontal cortex, as well as markers of oxidative damage. Additionally, we investigated the toxicological effects of CMI (200 mg/kg, i.g.) in the liver, kidney and brain through determination of the activity of aspartate aminotransferase (AST), alanine aminotransferase (ALT), δ-aminolevulinate dehydratase (δ-ALA-D) and creatinine levels. These biomarkers were not modified, indicating the possible absence of neuro-, hepato- and nephrotoxic effects. Our results suggest that CMI could be a therapeutic approach for the treatment of depression and other neuropsychiatric disorders associated with inflammation and oxidative stress.

The organoselenium compounds have been reported for many biological properties, especially as potent antioxidants. The compound bis(phenylimidazoselenazolyl) diselenide (BPIS) is a novel diaryl diselenide derivative, which shows antinociceptive and anti-inflammatory properties in mice, but whose antioxidant activity has not been studied. The present study aimed to investigate the antioxidant and toxicological potential of BPIS in brain of rats in vitro, and the effect of BPIS against the oxidative damage induced by sodium nitroprusside (SNP) in mouse brain. BPIS, at low molecular range, reduced lipid peroxidation (LP) and protein carbonyl (PC) content in rat brain homogenates (IC50 values of 1.35 and 0.74 μM, respectively). BPIS also presented dehydroascorbate reductase-like and glutathione-S-transferase-like, as well as DPPH and NO-scavenging activities. Related to togicological assays, BPIS inhibited δ-ALA-D and Na(+), K(+)-ATPase activities in rat brain homogenates and [(3)H]glutamate uptake in synaptosomes in vitro, but these effects were observed at higher concentrations than it had antioxidant effect (IC50 values of 16.41, 26.44 and 3.29 μM, respectively). In vivo, brains of mice treated with SNP (0.335 μmol per site; i.c.v.) showed an increase in LP and PC and a reduction in non protein thiol content, however, it was not observed significant alterations in antioxidant enzyme activities. BPIS (10 mg/kg; p.o.) protected against these alterations caused by SNP. In conclusion, the results demonstrated the antioxidant action of BPIS in in vitro assays. Furthermore, BPIS protected against oxidative damage caused by SNP in mouse brain, strengthening the potential antioxidant effect of this compound., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: The excitotoxin 3-nitropropionic acid (3-NP) induces a suitable experimental model of Huntington's disease (HD). This compound induces neurodegeneration via glutamatergic activation and oxidative stress, suggesting that the metabotropic glutamate receptor blockage and free radical scavenging are potential therapeutic targets in HD. In this study, we evaluated the role of 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP), a selective mGlu5 receptor antagonist, in a 3-NP model of HD., Methods: We administered 3-NP (20 mg/kg, intraperitoneal) to rats for 4 days. MTEP at doses of 2·5 and 5 mg/kg was administered 30 min before 3-NP. Behavioral tests and biochemical experiments were performed to assess the effects of 3-NP and the ability of MTEP to ameliorate these changes., Results: 3-NP administration induced body weight loss, decreased locomotor activity, and inhibition of succinate dehydrogenase and Na(+)-K(+) adenosine triphosphate (ATP)ase activities in rat striatum. We also observed increases in reactive species (RS) levels and glutathione reductase activity, decreased non-protein thiol levels, and an inhibition of glutathione peroxidase activity in the striatum of rats treated with 3-NP. Notably, all of these effects were attenuated by MTEP treatment., Discussion: Our results demonstrate the neuroprotective effect of MTEP and reinforce the involvement of mGluR5 in 3-NP-induced oxidative stress in rat striatum.

This study was designed to investigate the protective effect of melatonin in a preclinical animal model of mania induced by ouabain (OUA). Male Wistar rats were pretreated with melatonin (5 or 20mg/kg; intraperitoneal, i.p.) for seven days or with the mood stabilizer lithium chloride (positive control) (45 mg/kg, per oral, p.o.). One day after the last dose, animals received an intracerebroventricular (i.c.v.) injection of OUA (5μl, 10(-5)M), a Na(+)K(+)ATPase-inhibiting compound. Locomotor activity was assessed in the open-field test (OFT). The levels of reactive species (RS), protein carbonyl (PC) and non-protein thiols (NPSH), as well as the activities of the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were measured in the cerebral cortex and hippocampus of rats. OUA markedly increased the locomotor activity in the OFT, and the pretreatment with melatonin or lithium chloride prevented this effect. Melatonin treatment (similar to lithium) was also effective in preventing the following alterations elicited by OUA: increase of RS and PC levels; depletion of NPSH levels; increase of SOD activity; and inhibition of CAT and GPx activities. Moreover, we found that brain oxidative stress and behavioural alterations elicited by OUA were significantly correlated. Our study showed that Melatonin, similarly to lithium, protected against OUA-induced brain oxidative stress and hyperlocomotion in rats. Thus, our findings reinforce the notion that oxidative stress may play an important role in the manic-like behavioural. Therefore, we indicate that melatonin has antimanic-like action, suggesting a potential role for this substance in the pharmacological management of Bipolar disorder., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Cerebrovascular diseases, including ischemic stroke, are associated with high mortality worldwide. Oxidative stress and inflammation are important pathophysiological mechanisms involved in post-ischemic cerebral injury. The present study was designed to investigate the potential protective effect of diphenyl diselenide (PhSe)(2), an organoselenium compound with antioxidant and anti-inflammatory properties, against ischemia/reperfusion (I/R) insult in rat brain. The experimental model adopted was that of surgically-induced brain ischemia, performed by means of bilateral common carotid artery occlusion in rats. The effect of a single oral dose of (PhSe)(2) (50 mg/kg), administered 30 min before the onset of ischemia, was investigated by assessing cerebral oxidative stress-related biochemical parameters and pro-inflammatory cytokines in plasma of rats. The results demonstrated an increase in the levels of malondialdehyde (MDA), reactive oxygen species (ROS) and nitrate/nitrite as well as the alteration in the non-enzymatic and enzymatic (catalase and superoxide dismutase) antioxidant defense system induced by I/R insult in rat brain. I/R insult increased the levels of IL-1β, IL-6, TNF-α and INF-γ in plasma of rats. The administration of (PhSe)(2) restored cerebral levels of MDA, ROS, nitrate/nitrite and antioxidant defenses of rats exposed to I/R insult. (PhSe)(2) markedly reduced pro-inflammatory cytokines in plasma of I/R rats. I/R insult increased the plasma levels of tissue damage markers, such as creatine kinase and α-1-acid glycoprotein. Pretreatment with (PhSe)(2) was effective in reducing the levels of these proteins. In addition, (PhSe)(2) attenuated cerebral histological alterations induced by I/R. This study showed for the first time the in vivo protective effect of (PhSe)(2) against oxidative stress and pro-inflammatory cytokines-induced by I/R insult in rats.

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)., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: In this study, we investigated the effect of diphenyl diselenide [(PhSe)(2)] on chlorpyrifos (CPF)-induced hepatic and hematologic toxicity in rats., Methods: Rats were pre-treated with (PhSe)(2) (5 mg/kg) via the oral route (oral gavage) once a day for 7 days. On the eighth and ninth days, rats were treated with (PhSe)(2) (5 mg/kg) 30 min prior to CPF (50 mg/kg, by subcutaneous route). The aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase activities were determined in plasma of rats. Lipid peroxidation, protein carbonyl, and non-protein thiol levels as well as catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase, and gluthatione S-transferase activities were determined in livers of rats. Hematological parameters were also determined., Results: The results showed that CPF caused hepatic oxidative damage, as demonstrated by an increase in lipid peroxidation and protein carbonyl levels which was associated with a decrease in antioxidant defenses. CPF exposure caused a reduction in the leukocyte, indicating hematologic toxicity. (PhSe)(2) was effective in attenuating these toxic effects caused by CPF exposure in rats., Conclusions: The results indicated that (PhSe)(2) was effective in protecting the hepatic and hematologic toxicity induced by acute CPF exposure in rats.

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

It is widely accepted that oxidative stress plays a central role in alcohol-induced pathogenesis. The protective effect of binaphthyl diselenide (NapSe)2 was investigated in ethanol (Etoh)-induced brain injury. Thirty male adult Wistar rats were divided randomly into five groups of six animals each and treated as follows: (1) The control group received the vehicle (soy bean oil, 1 mL/kg, p.o.). (2) Ethanol group of animals was administered with ethanol (70% v/v, 2 mL/kg, p.o.). (3) (NapSe)2 1 mg/kg, 1 mL/kg plus ethanol 70% (v/v, 2 mL/kg, p.o. (5) (NapSe)2 10 mg/kg, 1 mL/kg) plus ethanol 70% (v/v, 2 mL/kg, p.o). After acute treatment, all rats were sacrificed by decapitation. Evidence for oxidative stress in rat brain was obtained from the observed levels of thiobarbituric acid reactive species, of non-protein thiol (NPSH) groups, and of ascorbic acid, as well as from the activities of catalase (CAT) and of superoxide dismutase (SOD). (NapSe)2 compensated the deficits in the antioxidant defense mechanisms (CAT, SOD, NPSH, and ascorbic acid), and suppressed lipid peroxidation in rat brain resulting from Etoh administration. It was concluded that ethanol exposure causes alterations in the antioxidant defense system and induces oxidative stress in rat brain. (NaPSe)2 at 5 mg/kg restored the antioxidant defenses in rat brain and mitigated the toxic effects of alcohol, suggesting that could be used as a potential therapeutic agent for alcohol-induced oxidative damage in rat brain.

Here, we compare the influence of molecular structural modifications of diphenyl diselenide (DPDS) and diphenyl ditelluride (DPDT) with their naphthalene analogs, 1-dinapthyl diselenide (1-NapSe)2, 2-dinapthyl diselenide (2-NapSe)2, 1-dinapthyl distelluride (1-NapTe)2, and 2-dinapthyl ditelluride (2-NapTe)2. Fe(II)-induced hepatic thiobarbituric acid reactive species (TBARS) was in the order [(2-NapTe)2] > [(2-NapSe)2] > [(DPDS)] > [(1-NapSe)2] > [(1-NapTe)2]> [(DPDT)]. For sodium nitroprusside (SNP)-induced hepatic TBARS, the order was [(2-NapTe)2] > [(DPDT)] > [(1-NapSe)2] > [(2-NapSe)2] > [(1-NapTe)2] > [(DPDS)]. For Fe(II) and SNP-induced renal TBARS, the orders were [(2-NapTe)2] > [(1-NapTe)2] = [(DPDT)] > [(1-NapSe)2] > [(2-NapSe)2] > [(DPDS)] and [(2-NapTe)2] > [(1-NapTe)2] > [(1-NapSe)2] > [(2-NapSe)2] > [(DPDS)] > [(DPDS)], respectively. The present investigation shows that DPDS was less potent and the change in the organic moiety from an aryl to napthyl group dramatically changed the potency of diselenides. These results suggest that minor changes in the organic moiety of aromatic diselenides can profoundly modify their antioxidant properties. In view of the fact that the pharmacological properties of organochalcogens are linked, at least in part, to their antioxidant properties, it becomes important to explore the pharmacological properties of dinaphtyl diselenides and ditellurides.

Objectives: Ovarian hormone decline after menopause is linked to many pathophysiological reactions. Female rats submitted to ovariectomy are employed as a model of post-menopausal condition. This study investigated the effects of diphenyl diselenide (PhSe)(2) on body weight gain, intra-abdominal fat deposition, plasma lipid profile and hepatic oxidative stress in ovariectomized rats., Methods: Female adult Wistar rats were ovariectomized (OVX rats) or sham-operated and divided into four groups: (i) sham-operated, (ii) (PhSe)(2), (iii) OVX and (iv) OVX + (PhSe)(2). (PhSe)(2) (5 mg/kg; 5 ml/kg, p.o.) was administered once a day for 30 days to groups (ii) and (iv). After that, rats were anaesthetized for blood sample gathering and submitted to euthanasia., Key Findings: (PhSe)(2) (5 mg/kg) was effective in preventing the rise in body weight gain and intra-abdominal fat deposition induced in OVX rats. Although (PhSe)(2) was not effective in avoiding the increase in plasma total cholesterol and non-HDL levels induced in OVX rats, (PhSe)(2) reduced plasma triglycerides and augmented HDL levels in OVX rats. (PhSe)(2) also increased hepatic ascorbic acid levels, reduced glutathione content, glutathione S-transferase activity and restored catalase activity in liver of OVX rats., Conclusions: These findings suggest that (PhSe)(2) could be a promising alternative to minimize menopause related symptoms., (© 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.)

Delta-aminolevulinate dehydratase (δ-ALA-D) enzyme is sensitive to pro-oxidant agents, including molecular oxygen. Here, we tested whether hyperoxygenation after total intravenous (i.v.) anesthesia could interact with the type of anesthesia (dexmedetomidine, continuous infusion; 0.5 μg/kg/h or remifentanil, continuous infusion; 0.3 μg/kg/min) plus propofol using blood δ-ALA-D activity and thiobarbituric acid reactive substances (TBARS) levels as ending points of toxicity. In absence or presence of dithiothreitol (DTT), δ-ALA-D activity was reduced after hyperoxygenation in the group treated with remifentanil and was not modified in dexmedetomidine group. TBARS increased considerably in the blood of both groups of patients after oxygenation. The results obtained here suggest that the hyperoxygenation was associated with a marked increase in TBARS production regardless of the type of anesthesia. δ-ALA-D activity was only inhibited in remifentanil group, which indicates a possible interaction between oxygenation and the type of anesthetic. This is the first demonstration that dexmedetomidine may protect blood δ-ALA-D from oxidation. However, further studies are necessary to establish a possible antioxidant role of dexmedetomidine against hyperoxygenation in human blood.

In this study, the effects of caffeine (CAF) and SCH58261, a selective A(2A) receptor antagonist, on memory impairment and oxidative stress generated by aging in rats were investigated. Young and aged rats were treated daily per 10 days with CAF (30 mg/kg p.o.) or SCH58261 (0.5mg/kg, p.o.) or vehicle (1 ml/kg p.o.). Rats were trained and tested in a novel object recognition task. After the behavioral test, ascorbic acid and oxygen and nitrogen reactive species levels as well as Na(+)K(+) ATPase activity were determined in rat brain. The results demonstrated that the age-related memory deficit was reversed by treatment with CAF or SCH58261. Treatment with CAF or SCH58261 significantly normalized oxygen and nitrogen reactive species levels increased in brains of aged rats. Na(+)K(+) ATPase activity inhibited in brains of aged rats was also normalized by CAF or SCH58261 treatment. A decrease in basal ascorbic acid levels in brains of aged rats was not changed by CAF or SCH58261. These results demonstrated that CAF and SCH58261, modulators of adenosinergic receptors, were able to reverse age-associated memory impairment and to partially reduce oxidative stress., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The in vitro effect of (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD) was evaluated through iron/EDTA-induced thiobarbituric acid reactive species (TBARS) and reactive species (RS) determinations as well as of the scavenging 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical quantification. BPD at the concentrations of 10 and 50 μΜ decreased RS and TBARS levels, respectively. The antioxidant activity was not related to the scavenging DPPH radical mechanism. A second objective of this study was to investigate the hepatoprotective action of BPD, administered by oral route, against oxidative damage induced by 2-nitropropane (2-NP) (100 mg/kg of body weight) in liver of rats. At the dose of 50 mg/kg, BPD protected against the increase in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities induced by 2-NP. BPD (10 and 50 mg/kg) protected against the increase in TBARS levels and alkaline phosphatase (ALP) activity. Sections of liver from 2-NP-exposed rats presented intense infiltration of inflammatory cells and loss of cellular architecture. BPD (10 and 50 mg/kg) attenuated 2-NP-induced hepatic histological alterations. The inhibition of δ-aminolevulinic dehydratase (δ-ALA-D), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) activities and the decreased GSH levels caused by 2-NP were protected by BPD (50 mg/kg). Catalase activity and ascorbic acid levels were not altered by 2-NP. These results demonstrated the antioxidant and hepatoprotective effects of BPD in liver of rats., (© 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.)

Aim: This study investigated the in vitro antioxidant activity of (E)-2-benzylidene-4-phenyl-1,3-diselenole (BPD), the anticonvulsant effect of BPD on seizures induced by pilocarpine (PC), pentylenetetrazole (PTZ) and 4-aminopyridine (4-AMP) and the mechanism involved., Methods: BPD antioxidant activity in vitro was investigated using sodium nitroprusside (SNP) and malonate-induced thiobarbituric acid reactive species (TBARS) and sodium azide-induced reactive species (RS) production. Thiol peroxidase and oxidase as well as δ-aminolevulinate dehydratase (δ-ALA-D) activities were examined. Mice were pretreated via oral route (p.o.) with BPD (1-100 mg/kg) before intraperitoneal (i.p.) administration of PC (400 mg/kg), PTZ (80 mg/kg) or 4-AMP (12 mg/kg). To investigate the antioxidant effect of BPD on oxidative stress induced by PC, the activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST) and catalase (CAT) as well as the levels of RS and TBARS were determined in brains of mice. δ-ALA-D, acetylcholinesterase (AChE) and Na(+), K(+) ATPase activities were verified., Key Findings: BPD (5 μM) reduced RS production and lipid peroxidation induced by SNP and malonate. BPD (1-50 μM) did not show thiol peroxidase and oxidase activities and did not alter δ-ALA-D activity. BPD (5 mg/kg) increased the latency to the seizure onset on PTZ and 4-AMP models. BPD (100 mg/kg) abolished seizures and death induced by PC in mice. BPD protected against the increase in RS and TBARS levels. The activity of Na(+), K(+) ATPase and AChE inhibited by PC remained unaltered in the BPD group., Significance: BPD showed anticonvulsant and antioxidant effects on seizures induced by PC in mice., (Copyright © 2010 Elsevier Inc. All rights reserved.)

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.

Hypercholesterolaemia and oxidative stress are well-known risk factors in coronary artery diseases. Diphenyl diselenide is a synthetic organoselenium compound that has been shown to have in vitro and in vivo antioxidant properties. In this study, we investigated whether diphenyl diselenide could reduce the hypercholesterolaemia and diminish the tissue oxidative stress in cholesterol-fed rabbits. Twenty-four New Zealand white male rabbits were randomly divided into four groups. Each group was fed a different diet as follows: Control group--regular chow; Cholesterol group--1% cholesterol-enriched diet; diphenyl diselenide group--regular diet supplemented with 10 ppm diphenyl diselenide; and Chol/diphenyl diselenide group--the same cholesterol-rich supplemented with 10 ppm diphenyl diselenide. After 45 days of treatment, the rabbits were killed and the blood, liver, and brain were used for laboratory analysis. The results showed that the serum levels of total cholesterol were markedly increased in cholesterol-fed rabbits and the consumption of diphenyl diselenide decreased these levels approximately twofold in Chol/diphenyl diselenide rabbits (P < 0.05). The intake of diphenyl diselenide by hypercholesterolaemic rabbits diminished the serum and hepatic thiobarbituric acid reactive substances levels as well as the production of reactive oxygen species in the blood and brain (P < 0.05) when compared to the cholesterol group. In addition, diphenyl diselenide supplementation increased hepatic and cerebral delta-aminolevulinic dehydratase activity and hepatic non-protein thiol groups levels despite hypercholesterolaemia (P < 0.05). In summary, the results showed that diphenyl diselenide reduced the hypercholesterolaemia and the oxidative stress in cholesterol-fed rabbits.

The aim of this study was to assess the toxic effects of chronic exposure to fluphenazine in liver and kidney of rats, as well as the possible protective effect of diphenyl diselenide on the fluphenazine-induced damage. Long-term treatment with fluphenazine caused an increase in lipid peroxidation levels in liver and kidney homogenates. Diphenyl diselenide treatment did not affect delta-aminolevulinate dehydratase (delta-ALA-D) activity, but fluphenazine alone or in combination with diphenyl diselenide showed an inhibitory effect on delta-ALA-D activity in liver. Diphenyl diselenide plus fluphenazine treatment increased the reactivation index of hepatic delta-ALA-D by approximately 80%. Superoxide dismutase activity decreased in liver of rats treated with fluphenazine alone. The combined treatment with fluphenazine and diphenyl diselenide was able to ameliorate superoxide dismutase activity in liver of rats. Catalase activity was augmented in liver from rats treated with fluphenazine, and this increase was prevented when diphenyl diselenide was co-administered. Taken together, these results indicate that the association of diphenyl diselenide with fluphenazine could protect the liver from lipid peroxidation and ameliorate superoxide dismutase and catalase activities. Moreover, our data point to the relationship between the oxidative stress and fluphenazine treatment in liver and kidney of rats.

This study was designed to examine if diphenyl diselenide (PhSe)(2), an organoselenium compound, attenuates oxidative stress caused by acute physical exercise in skeletal muscle and lungs of mice. Swiss mice were pre-treated with (PhSe)(2) (5 mg kg(-1) day(-1)) for 7 days. At the 7th day, the animals were submitted to acute physical exercise which consisted of continuous swimming for 20 min. The animals were euthanized 1 and 24 h after the exercise test. The levels of thiobarbituric acid reactive species (TBARS), non-protein thiols (NPSH) and ascorbic acid and the activity of catalase (CAT) were measured in the lungs and skeletal muscle of mice. Glycogen content was determined in the skeletal muscle of mice. Parameters in plasma (urea and creatinine) were determined. The results demonstrated an increase in TBARS levels induced by acute physical exercise in the skeletal muscle and lungs of mice. Animals submitted to exercise showed an increase in non-enzymatic antioxidant defenses (NPSH and ascorbic acid) in the skeletal muscle. In lungs of mice, activity of CAT was increased. (PhSe)(2) protected against the increase in TBARS levels and ameliorated antioxidant defenses in the skeletal muscle and lungs of mice submitted to physical exercise. These results indicate that acute physical exercise caused a tissue-specific oxidative stress in the skeletal muscle and lungs of mice. (PhSe)(2) protected against oxidative damage induced by acute physical exercise in mice., (2009 John Wiley & Sons, Ltd.)

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).

Oxidative stress has been pointed out as an important molecular mechanism in methylmercury (MeHg) intoxication. At low doses, diphenyl diselenide ((PhSe)2), a structurally simple organoselenium compound, has been shown to possess antioxidant and neuroprotective properties. Here we have examined the possible in vivo protective effect of diphenyl diselenide against the potential pro-oxidative effects of MeHg in mouse liver, kidney, cerebrum and cerebellum. The effects of MeHg exposure (2 mg/(kg day) of methylmercury chloride 10 ml/kg, p.o.), as well as the possible antagonist effect of diphenyl diselenide (1 and 0.4 mg/(kg day); s.c.) on body weight gain and on hepatic, cerebellar, cerebral and renal levels of thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), ascorbic acid content, mercury concentrations and activities of antioxidant enzymes (glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD)) were evaluated after 35 days of treatment. MeHg caused an increase in TBARS and decreased NPSH levels in all tissues. MeHg also induced a decrease in hepatic ascorbic acid content and in renal GPx and CAT activities. Diphenyl diselenide (1 mg/kg) conferred protection against MeHg-induced hepatic and renal lipid peroxidation and at both doses prevented the reduction in hepatic NPSH levels. Diphenyl diselenide also conferred a partial protection against MeHg-induced oxidative stress (TBARS and NPSH) in liver and cerebellum. Of particular importance, diphenyl diselenide decreased the deposition of Hg in cerebrum, cerebellum, kidney and liver. The present results indicate that diphenyl diselenide can protect against some toxic effects of MeHg in mice. This protection may be related to its antioxidant properties and its ability to reduce Hg body burden. We posit that formation of a selenol intermediate, which possesses high nucleophilicity and high affinity for MeHg, accounts for the ability of diphenyl diselenide to ameliorate MeHg-induced toxicity.

Aims: The effect of telluroacetylenes a-d on pharmacological assays was investigated in vitro. A second objective of this study was to investigate the antioxidant action of compound b against the oxidative damage induced by sodium nitroprusside (SNP) in mouse brain., Main Methods: In in vitro experiments, lipid peroxidation (LP) and protein carbonyl (PC) levels and delta-aminolevulinate dehydratase (delta-ALA-D) activity were carried out in rat brain homogenate. The thiol peroxidase-like activity and DPPH radical scavenging of telluroacetylenes a-d were investigated. In in vivo experiments, mice received SNP (0.335 micromol per site) intra cerebroventricular (i.c.v.) thirty minutes after oral administration of telluroacetylene b (10 mg/kg). After 1 h, animals were euthanized. The levels of LP and delta-ALA-D, catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST) activities were carried out in mouse brain homogenate., Key Findings: Telluroacetylenes a-d, at low muM range, reduced LP and PC levels in rat brain homogenate. Telluroacetylenes a-d showed effect of scavenging DPPH radicals. delta-ALA-D activity was inhibited by telloruacetylenes a-d, at high muM range, in rat brain homogenate. Brains of mice treated with SNP showed an increase in LP and the reduction in delta-ALA-D, GR and GST activities. Telluroacetylene b protected against the oxidative stress caused by SNP in brain of rats., Significance: The results support an antioxidant effect of telluroacetylenes a-d in vitro. Telluroacetylene b protected against oxidative damage caused by SNP in mouse brain, suggesting an antioxidant effect of this compound.

Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been pointed as two key mechanisms in methylmercury-toxicity. Thus, here we investigate the involvement of glutamatergic system in methylmercury (MeHg) neurotoxicity and whether diphenyl diselenide, ebselen and guanosine could protect cortical rat brain slices from MeHg-induced ROS generation. MeHg (100 and 200 microM) increased 2',7'-dichlorodihydrofluorescin (DCFH) oxidation after 2h of exposure. At 50 microM, MeHg increased DCFH oxidation only after 5h of exposure. Guanosine (1 and 5 microM) did not caused any effect per se; however, it blocked the increase in DCFH caused by 200 or 50 microM MeHg. Ebselen (5 and 10 microM) decreased significantly the DCFH oxidation after 2 and 5h of exposure to MeHg. Diphenyl diselenide (5 microM) did not change the basal DCFH oxidation, but abolished the pro-oxidant effect of MeHg. MK-801 also abolished the pro-oxidant effect of MeHg. These results demonstrate for the first time the potential antioxidant properties of organoseleniun compounds and guanosine against MeHg-induced ROS generation after short-term exposure in a simple in vitro model. In conclusion, endogenous purine (guanosine) and two synthetic organoselenium compounds can modulate the pro-oxidant effect of MeHg in cortical brain slices.

Unsymmetrical dichalcogenides, a class of organoselenium compounds, were screened for antioxidant activity in rat brain homogenates in vitro. Unsymmetrical dichalcogenides (1-3) were tested against lipid peroxidation induced by sodium nitroprusside (SNP) or malonate, and reactive species (RS) production induced by sodium azide in rat brain homogenates. Compounds 1 (without a substituent at the phenyl group), 2 (chloro substituent at the phenyl group bounded to the sulfur atom) and 3 (chloro substituent at the phenyl group bounded to the selenium atom) protected against lipid peroxidation induced by SNP. The IC50 values followed the order 3<2<1. Lipid peroxidation induced by malonate was also reduced by dichalcogenides 1, 2 and 3. The IC50 values were 3

The aim of the present study was to evaluate if diphenyl diselenide administered by oral route was effective in restoring gastric lesions induced by ethanol. The possible involvement of oxidative stress in diphenyl diselenide antiulcer effect was also evaluated. Different doses of diphenyl diselenide (dissolved in soya bean oil, 1mL/kg) were administered orally 1h before (pre-treatment study) or 1h after ethanol (70%, v/v, 2mL/kg, post-treatment study). Ulcer lesions were quantified 1h after ethanol administration (pre-treatment protocol) or 1h after diphenyl diselenide study (post-treatment protocol). Diphenyl diselenide (0.1-10mg/kg or 0.32-32micromol/kg), when administered previously or posteriorly prevented and reversed respectively, the development of gastric lesions induced by ethanol in rats. A number of markers of oxidative stress were examined in rat stomach including thiobarbituric acid reactive species (TBARS), catalase (CAT), superoxide dismutase (SOD), non-protein thiol groups (NPSH) and ascorbic acid. In addition to attenuating the gastric lesions, low doses of diphenyl diselenide prevented (pre-treatment) or reversed (post-treatment) the ethanol-induced changes in TBARS, SOD activity and ascorbic acid content. In conclusion, the present data reveal that diphenyl diselenide, administered by oral route, possesses an antiulcer effect by modulating antioxidant mechanisms.

Objectives: To evaluate the possible relationship between aminotransferases levels and markers of oxidative stress in chronic hepatitis C patients., Design and Methods: Patients without treatment for hepatitis were divided in to group I (15-39 U/L); group II (41-76 U/L) and group III (81-311 U/L) of activity alanine aminotransferase (ALT). Blood markers of oxidative stress [catalase (CAT), glutathione peroxidase (GPx), thiobarbituric acid-reactive species (TBARS), nonprotein and protein thiol (NP-SH and P-SH) groups and vitamin C] were determined., Results: P-SH and NP-SH levels, TBARS, GPx and CAT were not different between groups. Vitamin C was significantly decreased in groups II (P=0.03) and III (P=0.001) when compared with group I and correlated negatively with aspartate aminotransferase (AST; r=-0.29, P=0.042)., Conclusion: Vitamin C levels were negatively associated with AST, suggesting that vitamin C could be an additional indicator of hepatitis C severity.

This study was designed to examine if diphenyl diselenide (PhSe)(2), an organoselenium compound, attenuates pulmonar and cerebral oxidative stress caused by sub-chronic exposure to CdCl(2). Male adult Swiss albino mice received CdCl(2) (10 micromol/kg, subcutaneously), 5 times/week, for 4 weeks. (PhSe)(2) (10 micromol/kg or 20 micromol/kg, orally) was given concomitantly with CdCl(2) to mice. A number of toxicological parameters in lung and brain of mice were examined including delta-aminolevulinic acid dehydratase (delta-ALA-D), superoxide dismutase (SOD) and catalase activities, lipid peroxidation, non-protein thiols (NPSH) and ascorbic acid content. Na(+),K(+)-ATPase activity, acetylcholinesterase (AChE) activity, [(3)H]glutamate uptake and [(3)H]glutamate release were also carried out in brain. Cadmium concentration and histopathological analysis were carried out in lung tissue. (PhSe)(2) at the dose of 20 micromol/kg protected the inhibition of delta-ALA-D, SOD and CAT activities, the reduction of vitamin C content and the increase of lipid peroxidation levels caused by CdCl(2) in lungs. At 10 micromol/kg, (PhSe)(2) protected cerebral AChE and CAT activities inhibited by CdCl(2). There were no histopathological alterations in the lung of mice after CdCl(2) exposure. The pulmonary cadmium concentration was higher (2.8-fold) in the group exposed to CdCl(2) than in control mice. (PhSe)(2) at dose of 20 micromol/kg reduced cadmium concentration towards the control level. The results suggest that oral administration of (PhSe)(2) attenuated the oxidative damage induced by CdCl(2) in lung and brain of mice.

In the present study the potential neurotoxicity of diphenyl diselenide, as measured by the manifestation of seizures in rat pups (postnatal days, PND, 12-14) was evaluated. The results suggest that the latency for the appearance of tonic-clonic seizures, characterized by rearing and falling of rat pups body, was dependent of the dose tested. Diphenyl diselenide at high doses induced seizure episodes in rat pups. The highest dose of diphenyl diselenide (500 mg/kg) increased the levels of lipid peroxidation and catalase activity as well as decreased delta-ALA-D (delta-aminolevulinate dehydratase) and Na(+), K(+) ATPase activity in the brain of rat pups. Our results indicate the possible involvement of free radical oxygen injury in diphenyl diselenide-induced seizures. The data obtained with the dose of 150 mg/kg in the brain of rats that exhibited seizures are: an increase in lipid peroxidation levels; the lack of effect on catalase activity; an inhibition of delta-ALA-D activity, supporting that the enzyme activity is more sensitive than other parameters analyzed as an indicator of oxidative stress. The lowest dose of diphenyl diselenide emphasizes the relationship between the appearance of seizures and the latency for the onset of the first episode. Taken together, this paper could add to our understanding of diphenyl diselenide neurotoxic effect demonstrated by the appearance of seizures which are, at least in part, related to the oxidative stress.

This study was designed to determine the effect of diphenyl diselenide and ebselen, synthetic organoselenium compounds with antioxidant properties, in diabetic rats. Diabetes was induced by the administration of streptozotocin (STZ) (45mg/kg, intravenous). In experimental trials, diphenyl diselenide, but not ebselen, caused a significant reduction in blood glucose levels of STZ-treated rats. This effect of diphenyl diselenide was accompanied by a reduction in the levels of glycated proteins. Diphenyl diselenide ameliorate superoxide dismutase activity (liver and erythrocytes) and Vitamin C levels (liver, kidney and blood), which were decreased in STZ-treated rats. In normal rats, diphenyl diselenide caused per se an increase in hepatic, renal and blood GSH levels. Similarly, treatment with diphenyl diselenide restored hepatic and renal GSH levels in STZ-treated rats. TBARS and protein carbonyl levels were not modified by STZ and/or diphenyl diselenide and ebselen treatments. Our findings suggest that diphenyl diselenide can be considered an anti-diabetogenic agent by exhibiting anti-hyperglycemic and antioxidant properties.

Objectives: To evaluate the potential role of oxidative stress in the evolution of cervical cancer, including its pre-malignant states., Design and Methods: Erythrocytes thiobarbituric acid reactive substances (TBARS) levels, plasma vitamin C and thiol content and total blood delta-ALA-D levels were estimated in 46 untreated cervical cancer and pre-malignant patients and in 46 age-sex-matched controls., Results: Erythrocytes from patients, regardless of disease state, pre-malignant (low squamous intraepithelial lesion--LSIL and high squamous intraepithelial lesion--HSIL) or cancer, showed a significant 2-3 times increase in TBARS levels (P<0.01). Plasma vitamin C was lower in the carcinoma group (P<0.01). The reactivation index of delta-aminolevulinate dehydratase (delta-ALA-D) was higher in the patient group, when compared to control (P<0.01)., Conclusion: LSIL, HSIL or cervical cancer can be associated with changes in 3 indicators of oxidative stress: increase in erythrocyte TBARS, ALA-D reactivation index and a decrease in vitamin C content, that may play an important role in carcinogenesis.

Haloperidol-induced orofacial dyskinesia (OD) is a putative animal model of tardive dyskinesia (TD) whose pathophysiology has been related to free radical generation and oxidative stress. Schizophrenic patients have been reported to eat a diet higher in fat than the general population and dietary fat intake can lead to an increase in oxidative stress in animal models. The objective of this study was to determine whether association of ingestion of a high fat diet with prolonged haloperidol treatment could lead to OD and oxidative stress in the rat brain. Haloperidol decanoate administration (38 mg/kg, IM, which is equivalent to 1 mg/kg/day) monthly for a period of 6 months to rats fed previously with a high fat and normo fat diets (6 months) caused a increase in vacuous chewing (VCM) and duration of facial twitching (FT). Haloperidol caused a reduction in body weight gain and the loss of body weight occurred after 4 months of treatment with haloperidol. The effects on body weight were more accentuated in HF diet group. HF diet ingestion was associated with an increase in TBARS levels in cerebellum and cerebral cortex (regardless of haloperidol treatment). A significant dietxhaloperidol treatment interaction in striatum, subcortical parts and the region containing the substantia nigra was observed for TBARS. In fact, haloperidol caused an increase in TBARS levels of these regions only in rats fed with the HF. These results indicate that a high fat diet caused a transitory increase in haloperidol-induced OD in rats and this in part can be related to the haloperidol-induced oxidative stress in brain structures involved with OD.

Oxidative stress plays a significant role in the neurotoxicity of a variety of agents that interact with the N-methyl-D-aspartate (NMDA) receptors. Here we investigated in a comparative way the pro-oxidative effects of quinolinic acid (QA) and malonate, two neurotoxic substances that act through distinct primary molecular mechanisms on the production of thiobarbituric acid reactive species (TBARS) by brain homogenates. In fact, QA is thought to activate directly the NMDA receptor, whereas malonate seems to act primarily by inhibiting oxidative metabolism. The malonate-induced TBARS formation was not modified by cyanide (CN-) or 2,4-dinitrophenol. MK-801 did not reduce basal or malonate induced-TBARS production in fresh tissues preparations. However, in heat-treated preparations a significant effect of MK-801 against basal TBARS production was observed, but not on the malonate induced-TBARS production. QA induced-TBARS production was significantly prevented by MK-801 either in fresh or heat-treated preparations. The antioxidant effect of MK-801 on basal and QA-induced TBARS production increased as the temperatures used to treat S1 were increased. Succinate dehydrogenase (SDH) was inhibited by malonate but not by QA. Malonate was able to chelate iron(II) and the malonate-iron complex(es) is(are) active as measured by its(their) activity on deoxyribose degradation assay. These findings indicate that direct interactions of malonate with NMDA receptors are not involved in malonate pro-oxidative activity in vitro. QA pro-oxidative activity in vitro was related, at least in part, to its capability in stimulate NMDA receptors. Taken together, these findings indicated that malonate pro-oxidative activity in vitro could be attributed to its capability of changing the ratio Fe2+/Fe3+, which is essential to TBARS production.

The concept that selenium-containing molecules may be better antioxidants than classical antioxidants, has led to the design of synthetic organoselenium compounds. In the present investigation subchronic deleterious effects of cadmium-intoxication in mice and a possible protective effect of diphenyl diselenide (PhSe)2 (5 micromol/kg) were studied. Male adult Swiss albino mice (25-35 g) received CdCl2 (10 micromol/kg, subcutaneously), five times/week, for 4 weeks. A number of toxicological parameters in blood, liver, kidney, spleen and brain of mice were examined including delta-aminolevulinic acid dehydratase (delta-ALA-D) activity, lipid peroxidation and ascorbic acid content, the parameters that indicate tissue damage such as plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, creatinine and lactate dehydrogenase (LDH) were also determined. The results demonstrated that cadmium caused inhibition of delta-ALA-D activity in liver (24%), kidney (33%) and spleen (73%) and (PhSe)2 therapy was effective in restoring enzyme activity in all tissues. A reduction in ascorbic acid content was observed in kidney (11%) and spleen (10.7%) of cadmium-treated mice and (PhSe)2 was only effective in improving this reduction in kidney. An increase of lipid peroxidation induced by cadmium was noted in liver (29%) and brain (28%) tissues and (PhSe)2 therapy was effective in restoring TBARS levels in both tissues. We also observed an increase on plasma LDH (1.99-times), AST (1.93-times) and ALT (4.24-times) activities. (PhSe)2 therapy was effective in restoring AST activity at control level. (PhSe)2 did not present toxic effects when plasma parameters were evaluated. The results suggest that the administration of an antioxidant (PhSe)2, during cadmium intoxication may provide beneficial effects by reducing oxidative stress in tissues.

Reserpine-induced orofacial dyskinesia is an alleged animal model of tardive dyskinesia whose pathophysiology has been related to striatal oxidative stress. In the present investigation, the authors examined whether ebselen, an antioxidant organochalcogen with glutathione peroxidase-like activity, changes the behavioral and neurochemical effect of acute reserpine administration. Reserpine injection for 3 days every other day caused a significant increase on the tongue protrusion frequency and ebselen (30 mg/kg ip for 4 days, starting 1 day before reserpine) reversed partially the effect of reserpine (P<.05). Reserpine- and reserpine+ebselen-treated groups displayed an increase in vacuous chewing frequency when compared to control and ebselen-treated groups (P<.05) Reserpine increased the duration of facial twitching and ebselen reversed partially the effect of reserpine (P<.01). Reserpine increased significantly the thiobarbituric acid-reactive species (TBARS) levels, and ebselen reversed the effect of reserpine on TBARS production in rat striatum. The results of the present study clearly indicated that ebselen has a protective role against reserpine-induced orofacial dyskinesia and reversed the increase in TBARS production caused by reserpine administration. Consequently, the use of ebselen as a therapeutic agent for the treatment of tardive dyskinesia should be considered.