The antioxidant and immunomodulatory compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole attenuates depression-like behavior and cognitive impairment developed in a mouse model of breast tumor.

Psychiatric alterations are often found in patients with breast cancer even before the initiation of adjuvant therapy, resulting in a poor quality of life. It has become accepted that neuroinflammation and oxidative stress are involved in the pathophysiology of depression and cognitive impairment. Herein, we tested the hypothesis that treatment with the antioxidant and immunomodulatory selenium-containing compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI)could attenuate behavioral and neurochemical alterations in a mammary (4T1) tumor model. Female BALB/c mice were subcutaneously inoculated with 4T1 cancer cells (1 × 105 cells/mice) or PBS. From days 14 to 20, mice received daily gavage with canola oil or CMI. On day 21, mice were submitted to behavioral tests followed by euthanasia. We found that CMI did not alter tumor growth, body weight, and body temperature in tumor-bearing mice. Importantly, treatment with CMI abrogated tumor-induced depression-like behavior and cognitive impairment. By the time CMI improved the behavioral alterations, it had reduced tumor-induced neuroinflammation (altered expression of NFκB, IL-1ß, TNF-α, IL-10, IDO, and COX-2) and oxidative stress (altered expression of iNOS and Nrf2, and levels of reactive species, nitric oxide, lipid peroxidation, and superoxide dismutase activity) in the prefrontal cortices and hippocampi of mice. A molecular docking approach suggested the ability of CMI to inhibit the activity of iNOS and COX-2. Together, our results indicate that CMI treatment may attenuate depression and cognitive impairment in 4T1 tumor-bearing mice, and be a groundbreaking strategy for the treatment of cancer-related psychiatric symptoms to improve the quality of life of cancer patients.

Selanylimidazopyridine abolishes inflammation- and stress-induced depressive-like behaviors by modulating the oxido-nitrosative system.

The 3-[(4-methoxyphenyl)selanyl]-2-phenylimidazo[1,2-a] pyridine (MPI), a novel organic selenium compound, has been receiving increased attention due to its antioxidant effects and its ability to protect against depression-like behaviours. However, it remains elusive whether MPI is able to reverse depressive-like symptoms and biochemical alterations in mice. In the present work, we explored the ability of MPI (10 mg/kg, i.g.) to reverse inflammation- and stress-induced depression-like behaviours in mice injected with tumour necrosis factor (TNF-α) or submitted to acute restraint stress. Depression-like behaviours were evaluated by the tail suspension and splash test and the open field test was used to evaluate the locomotor activity of mice. The prefrontal cortex and hippocampus of mice were used for the evaluation of parameters of oxidonitrosative stress. Here, we showed that a single administration of MPI abolished the depressive-like behaviours induced by TNF-α and acute restraint stress. The oxidative and nitrosative stress presented in mice with depression-like behaviours were also decreased by MPI in the prefrontal cortex and hippocampus. Our findings suggest that MPI presents antidepressant-like activity which is associated with the biochemical regulation of oxidative stress in prefrontal cortex and hippocampus of mice, arising as a promising strategy for the management of depressive symptoms.

Depression-like behavior, hyperglycemia, oxidative stress, and neuroinflammation presented in diabetic mice are reversed by the administration of 1-methyl-3-(phenylselanyl)-1H-indole.

Oxidative stress and neuroinflammation are found both in diabetes mellitus and major depressive disorder (MDD). In addition to damage in peripheral organs, such as liver and kidney, diabetic patients have a higher risk of developing depression. In this sense, the objective of the present study was to characterize the antidepressant-like effect of a selenium-containing compound, the 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI), in streptozotocin (STZ)-induced diabetic mice. STZ (200 mg/kg, i.p.) was used to induce diabetes mellitus type I, and after seven days, the administration of MFSeI (10 mg/kg, i.g.) was initiated and followed for the next 14 days. Twenty-four hours after the last administration of MFSeI, the behavioral tests were performed, followed by euthanasia. The treatment with MFSeI was able to reverse the hyperglycemia induced by STZ. MFSeI also decreased the plasma levels of biomarkers of liver and kidney damage. Importantly, MFSeI reversed the depression-like behavior induced by STZ in the tail suspension test and forced swimming test without promoting locomotor alterations. Furthermore, MFSeI reversed the increased levels of reactive species and lipid peroxidation in the prefrontal cortex (PFC), hippocampus (HC), liver, and kidney of STZ-treated mice. Treatment with MFSeI also decreased the expression of tumor necrosis factor-alpha, inducible nitric oxide synthase and indoleamine 2,3-dioxygenase, while increasing the expression of interleukin-10, insulin receptor substrate-1 and glucose transport-4 in the PFC and HC of mice. Taken together, the results indicate the effectiveness of MFSeI against depression-like behavior and central and peripheral complications caused by diabetes in mice.

The selenocompound 1-methyl-3-(phenylselanyl)-1H-indole attenuates depression-like behavior, oxidative stress, and neuroinflammation in streptozotocin-treated mice.

Major depressive disorder (MDD) is a chronic mental illness affecting a wide range of people worldwide. The pathophysiology of MDD is not completely elucidated, but it is believed that oxidative stress and neuroinflammation are involved. In light with this, the aim of the present study was to investigate whether a single administration of the antioxidant 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI) was able to reverse the streptozotocin-induced depression-like behavior, oxidative stress, and neuroinflammation in mice. MFSeI (10 mg/kg) was administered intragastrically (i.g.) 24 h after the intracerebroventricular injection of STZ (0.2 mg/4 µL/per mouse). Thirty minutes after MFSeI administration, behavioral tests and neurochemical analyses were performed. Fluoxetine (10 mg/kg, i.g.) was used as a positive control. MFSeI and fluoxetine were able to reverse the STZ-induced depression-like behavior, as evidenced by decreased immobility time in the forced swimming test and increased grooming time in the splash test. Mechanistically, MFSeI reversed the increased levels of reactive species and lipid peroxidation in the prefrontal cortices and hippocampi of STZ-treated mice. Additionally, neuroinflammation (i.e. expression of NF-κB, IL-1ß, and TNF-α) and the reduced mRNA levels of BDNF in the and hippocampi of depressed mice were reversed by treatment with MFSeI. Fluoxetine did not improve the STZ-induced alterations at the levels of reactive species, NF-κB and BDNF in the prefrontal cortices neither the levels of TNF-α in both brain regions. Together, these data suggest that the MFSeI may be a promising compound with antidepressant-like action, reducing oxidative stress and modulating inflammatory pathways in the brain of depressed mice.

Repeated administration of a selenium-containing indolyl compound attenuates behavioural alterations by streptozotocin through modulation of oxidative stress in mice.

Although the pathophysiology of major depression disorder (MDD) is still poorly understood, mounting evidence suggests that the brains of depressed patients are under oxidative stress, leading to depressive symptoms that may include anxiety and cognitive impairment. This study aimed to investigate if the seleno-organic compound 1-methyl-3-(phenylselanyl)-1H-indole (MFSeI) reverses the depression- and anxiogenic-like behaviour, cognitive impairment and oxidative stress induced by the intra-cerebroventricular injection of streptozotocin (STZ; 0.2 mg/4 µl/per mouse) in Swiss male mice. Twenty-four hours after the STZ injection, mice were treated with MFSeI (10 mg/kg, intra-gastrically), or vehicle solution, once daily for seven days. The behavioural tests were performed 30 min after the final MFSeI administration, followed by euthanasia and collection of the cerebral cortex and hippocampus. Administration of MFSeI reversed the depression- and anxiogenic-like behaviour and cognitive impairment induced by STZ, in mice. Neurochemical analyses demonstrated that MFSeI reversed the STZ-increased levels of reactive species, nitrite, lipid peroxidation and acetylcholinesterase activity in the cerebral cortex and hippocampus of mice. Moreover, a single administration of MFSeI (300 mg/kg, intra-gastrically) did not cause acute toxicity in Swiss male mice. Altogether, our data suggest that MFSeI exhibits antidepressant- and anxiolytic-like effects and improves the cognition of STZ-treated mice, without any toxicity.

Lipopolysaccharide-induced depressive-like, anxiogenic-like and hyperalgesic behavior is attenuated by acute administration of α-(phenylselanyl) acetophenone in mice.

The lipopolysaccharide (LPS) is an endotoxin derived from gram-negative bacteria, which induces inflammation. The aims of this study were to evaluate the possible α-(phenylselanyl) acetophenone (PSAP) activity in reducing comorbid hyperalgesia, depressive-like and anxiogenic-like symptoms induced by LPS in mice. In additional, investigated physical chemical properties of PSAP through in silico analysis by ADMET predictor software. The LPS (100 µg/kg, intraperitoneally) or saline were administered and after 4 h the treatment with PSAP (0.001-10 mg/kg, intragastric route [i.g.]) or FLX (10 mg/kg, i.g.) was performed, and after 30 min, the behavioral tests were carried out. LPS reduced the latency time for the first episode of immobility and increased the immobility time in the FST as well as decreased the grooming time in the splash test. PSAP reversed these alterations demonstrating an antidepressive-like effect. LPS also enhances the anxiogenic behavior in the elevated plus maze test (EPM). PSAP reversed these parameters, showing anxiolytic-like effect. LPS also decreased the latency time (s) on the hot plate and the treatment with PSAP at all doses significantly reversed the hyperalgesic effect of LPS. LPS increased the activation of p38MAPK and p-p65NF-κB pathways as well as the COX-2 levels in the cerebral cortex, which are indicative of an inflammatory response. Besides, it also reduced the levels of mBDNF, involved in neuroplasticity. Treatment with PSAP restored all these neurochemical alterations induced by LPS. The results demonstrated that PSAP presents antidepressive-like, anxiolytic-like and anti-hyperalgesic effects related to reduction in neuroinflammation.

Effects of a selanylimidazopyridine on the acute restraint stress-induced depressive- and anxiety-like behaviors and biological changes in mice.

In the last decades, selenium-containing compounds have received increasing attention due to their various biological and pharmacological properties. In the present study, we investigated the effects of 3-[(4-methoxyphenyl) selanyl]-2-phenylimidazo[1,2-a] pyridine (MPI; 1, 10 or 50 mg/kg, i.g.) on the acute restraint stress (ARS)-induced depressive- and anxiety-like behaviors in mice and its underlying mechanism of action. We used the open filed test, forced swimming test, and splash test to evaluate depressive-like behavior, and marble burying and elevated plus maze test to measure anxiety-like behavior. We found that MPI attenuated ARS-induced depressive- and anxiety-like behaviors in all behavioral tests, without having an effect in non-stressed mice. MPI prevented the increased in pro-inflammatory cytokines, indoleamine-2,3-dioxygenase (IDO) and inducible nitric oxide synthase (iNOS) expression in brain structures via canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) down-regulation. Additionally, MPI prevented ARS-induced downregulation of brain-derived neurotrophic factor (BDNF), increased reactive oxygen/nitrogen species generation and lipid peroxidation in prefrontal cortex and hippocampus of mice. In addition, MPI blocked the downregulation of glucocorticoid receptors in the prefrontal cortex and hippocampus and reduced the increased circulating level of corticosterone in stressed mice. These results suggested that MPI showed antidepressant- and anxiolytic-like properties and the effects might be associated with the biological changes in the prefrontal cortex and hippocampus.

The selenium-containing compound 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole reverses depressive-like behavior induced by acute restraint stress in mice: modulation of oxido-nitrosative stress and inflammatory pathway.

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.