p-Chloro-diphenyl diselenide modulates Nrf2/Keap1 signaling and counteracts renal oxidative stress in mice exposed to repeated dexamethasone administrations.

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.

4,4'-Dichloro-diphenyl diselenide modulated oxidative stress that differently affected peripheral tissues in streptozotocin-exposed mice.

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.

Keap1/Nrf2/HO-1 signaling pathway contributes to p-chlorodiphenyl diselenide antidepressant-like action in diabetic mice.

RATIONALE: The association between depression and diabetes has been recognized for many years, but the nature of this relationship remains uncertain. OBJECTIVES: This study investigated the antidepressant-like effect of (p-ClPhSe)2 on mice made diabetic by streptozotocin (STZ) and the contribution of cerebral cortical Keap1/Nrf2/HO-1 signaling pathway for this effect. METHODS: Male adult Swiss mice received streptozotocin (STZ, 200 mg/kg, i.p.) to induce diabetes (glycemia ≥ 200 mg/dl) or citrate buffer (5 ml/kg, control group). The mice were treated with (p-ClPhSe)2 at the dose of 5 mg/kg, i.g., for 7 days. Mice performed behavior tests, tail suspension (TST), and forced swimming tests (FST), to evaluate depressive-like phenotype. RESULTS: Diabetic mice showed an increase in immobility time in the TST and FST when compared to the control group. The protein contents of Keap1/Nrf2/HO-1 pathway were decreased in the cerebral cortex of diabetic mice. Diabetic mice had an increase in the relative adrenal weight and a decrease in the protein content of glucocorticoid receptor. The levels of TBARS and RS and SOD activity were found altered in the cerebral cortex of diabetic mice. The number of FJC-positive cells was increased in the cerebral cortex of diabetic mice. Treatment with (p-ClPhSe)2 was effective against depressive-like phenotype, oxidative stress, and FJC-positive cells of diabetic mice. (p-ClPhSe)2 did not reverse the parameters of HPA axis evaluated in this study. (p-ClPhSe)2 modulated the cerebral cortical Keap1/Nrf2/HO-1 pathway in diabetic mice. CONCLUSIONS: This study demonstrates the contribution of cerebral cortical Keap1/Nrf2/HO-1 pathway in the (p-ClPhSe)2 antidepressant-like action in diabetic mice.

(p-ClPhSe)2 modulates hippocampal BDNF/TrkB signaling and reverses memory impairment induced by diabetes in mice.

Diabetes is a metabolic disease characterized by hyperglycemia because of insulin resistance and/or insufficient insulin release. The most common diabetic brain complications include cognitive decline and depression. The present study investigated whether the 4-4'-dichlorodiphenyl diselenide (p-ClPhSe)2 is effective against memory impairment induced by diabetes in mice and the role of hippocampal BDNF/TrkB signaling in this effect. Male adult Swiss mice received an injection of streptozotocin (STZ) (200 mg/kg, i.p.) to induce diabetes. The results revealed that STZ injection in mice resulted in resilience (glycemia <200 mg/dl) or diabetes (glycemia ≥200 mg/dl). The vehicle-control group received citrate buffer (5 ml/kg). The animals were subchronically treated with (p-ClPhSe)2 (1 or 5 mg/kg, i.g.) for 7 days. Mice performed a battery of well-validated behavior tests designated to evaluate memory, object recognition (ORT), object location (OLT), and Morris water maze (MWM). The hippocampal protein contents of the BDNF/TrkB pathway were determined in the samples of experimental groups. Fluoro Jade C (FJC) was used for staining degenerating neurons. The STZ administration resulted in memory impairment that was demonstrated in the mouse ORT, OLT, and MWM tests. The molecular findings indicate an increase in hippocampal protein levels of proBDNF and TrKB but a decrease in those of mBDNF and pCREB in diabetic mice. The number of FJC-positive cells was increased in the hippocampus of diabetic mice. (p-ClPhSe)2 at the dose of 5 mg/kg modulated the hippocampal BDNF/TrkB pathway, reduced FJC-positive cells and reversed memory impairment induced by STZ in mice. These findings demonstrate the effectiveness of (p-ClPhSe)2 against memory impairment caused by diabetes in mice. (p-ClPhSe)2 modulated the hippocampal BDNF/TrkB signaling pathway in diabetic mice.

Combined Therapy With Swimming Exercise and a Diet Supplemented With Diphenyl Diselenide Is Effective Against Age-Related Changes in the Hepatic Metabolism of Rats.

Aging is characterized by a widespread loss of homeostasis in biological systems and is accompanied by pathophysiological changes including the liver injury. The aim of the present study was to investigate the effects of the combined therapy with swimming exercise (20 min session, 5 days/week during 4 weeks) and a diet supplemented with 1 ppm of (PhSe)2 on the hepatic metabolic alterations caused by aging in rats. In this study, male old Wistar rats had an increase in the epididymal fat relative weight, disturbances in the activities of hepatic enzymes associated to the glucose homeostasis, higher hepatic triglyceride content and higher activity of the plasma alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The combined therapy normalized the activities of glucose-6-Pase and tyrosine aminotransferase, gluconeogenic enzymes, increased the hepatic glycogen content and was effective against the increase in the hepatic triglycerides content, without altering the activities of hexoquinase, and citrate synthase. Moreover, the combined therapy normalized the activities of AST and ALT, indicating a hepatoprotective effect. The combined therapy with swimming exercise and a diet supplemented with 1 ppm of (PhSe)2 contributed to the hepatic glucose homeostasis in old rats. Nevertheless, more studies are needed to investigate the possible mechanisms of action behind these effects. J. Cell. Biochem. 118: 1574-1582, 2017. © 2016 Wiley Periodicals, Inc.

p-Chloro-diphenyl diselenide reverses memory impairment-related to stress caused by corticosterone and modulates hippocampal [(3)H]glutamate uptake in mice.

Chronic stress or chronically high levels of glucocorticoids can result in memory impairment. This study aimed to investigate if 4,4'-dichloro-diphenyl diselenide (p-ClPhSe)2 reverses memory impairment-related to stress caused by corticosterone administration in mice and its possible mechanism of action. Swiss mice received corticosterone (20µg/ml) in their drinking water during four weeks. In the last week, the animals were treated with (p-ClPhSe)2 (1 or 5mg/kg) by the intragastric route (i.g.) once a day for 7days. The cognitive performance of mice was assessed through the object recognition test (ORT), the object location test (OLT) and the step-down passive avoidance test (SDPA), some of predictive tests of memory. Biochemical parameters were determined and locomotor activity of mouse was performed to gain insight in (p-ClPhSe)2 toxicity. The findings demonstrated that treatment with (p-ClPhSe)2 in both doses was effective in reversing memory deficits in the ORT, the OLT and the SDPA caused by corticosterone exposure in mice. Treatment with (p-ClPhSe)2 at both doses reversed the increase in the [(3)H] glutamate uptake by hippocampal slices of mice treated with corticosterone. By contrast, [(3)H] glutamate uptake by brain cortical slices was not altered in mice exposed to corticosterone. The Na(+)K(+)ATPase activity was not altered in hippocampus and cerebral cortices of mice treated with corticosterone. There was no sign of toxicity in mice treated with (p-ClPhSe)2. This organoselenium compound reversed memory impairment-related to stress caused by corticosterone and modulated hippocampal [(3)H]glutamate uptake in mice.

Evidence for the contribution of multiple mechanisms in the feeding pattern of rats exposed to p-chloro-diphenyl diselenide-supplemented diets.

Preliminary findings suggest that food intake reduction induced by p-chloro-diphenyl diselenide [(p-ClPhSe)2] in rats is mediated by a satiating action; however, additional experiments are necessary to clarify its actions. The purpose of this study was to investigate the effects of diets supplemented with (p-ClPhSe)2 on feeding behavior of rats as well as the (p-ClPhSe)2 effectiveness in producing aversive reactions or specific flavor. The results demonstrated that behavioral satiety sequence (BSS) was preserved in animals exposed to (p-ClPhSe)2-supplemented diets (0.01 and 0.1%) and associated with a shift of the onset of resting to the left indicating a satiating action at the first contact. In addition, the frequency, the mean duration and the mean size of meals were decreased in rats exposed to a 0.1% (p-ClPhSe)2 diet. Alternatively, a second contact with a 0.01% (p-ClPhSe)2 diet caused disruption of BSS and pronounced changes in the meal pattern, suggesting that it produces aversiveness. In fact, rats developed a significant taste aversion to the saccharin solution after receiving the administration of (p-ClPhSe)2 (1 and 10mg/kg; i.p.). Lastly, a diet containing 0.1% of (p-ClPhSe)2 seems to alter the palatability of food given that rats had a preference for the control diet. The findings of the present study suggest that (p-ClPhSe)2 reduced the food intake of rats by inducing a satiating action at the first contact, but it also produced aversive reactions when rats were re-exposed to it. A specific flavor seems also to contribute to (p-ClPhSe)2 suppressant effects on feeding.

Effects of diphenyl and p-chloro-diphenyl diselenides on feeding behavior of rats.

RATIONALE: The searching for safe and effective antiobesity drugs has been the subject of intense research. Previous studies have shown several pharmacological applications of organoselenium compounds; however, their possible anorectic-like actions have not been investigated. OBJECTIVE: This study aims to investigate the effects of (PhSe)2 and (p-ClPhSe)2 on feeding behavior of rats and their potential as weight-reducing agents. METHODS: The effects of intraperitoneal administration of diselenides were investigated through the microstructural pattern of feeding behavior, behavioral satiety sequence (BSS), hypothalamic serotonin (5-HT) uptake, body weight, and epididymal fat content of male rats. RESULTS: Our findings demonstrated that food intake of fasted rats was reduced by both diselenides (1 and 10 mg/kg). Diphenyl diselenide [(PhSe)2] (1 mg/kg) and p-chloro-diphenyl diselenide [(p-ClPhSe)2] (10 mg/kg) decreased the frequency, mean duration, and mean size of meals compared with the control treatment. The BSS structure was preserved when organoselenium compounds (1 mg/kg) were administered, and it was associated to a displacement to the left when the resting period started indicating a satiating action. Inhibition of 5-HT uptake in the hypothalamus (∼20 %) was also found in rats treated with low doses of (PhSe)2 and (p-ClPhSe)2 (1 mg/kg). Treatments with a high dose of both diselenides (10 mg/kg) carried out for 7 days induced weight loss and epididymal fat reduction in sated rats. CONCLUSION: This study suggests that diselenides caused a satiating action in rats that could be partially explained by the inhibition of hypothalamic 5-HT uptake. These organoselenium compounds were potential weight-reducing agents when repeatedly administered.