Short- and Long-Term Repeated Forced Swim Stress Induce Depressive-Like Phenotype in Mice: Effectiveness of 3-[(4-Chlorophenyl)Selanyl]-1-Methyl-1H-Indole.

Exposure to stress highly correlates with the emergence of mood-related illnesses. Therefore, the present study was designed to characterize the acute and chronic effects of 3-((4-chlorophenyl)selanyl)-1-methyl-1H-indole (CMI) on depressive-like behavior induced by repeated forced swim stress (FSS) in male adult Swiss mice. In the repeated FSS, mice were placed in water to swim for a single trial during a 15-min period. Twenty-four hours after the first FSS, the animals were placed in water to swim through a series of four trials, and each of them swam for 6 min long; between each trial, mice were towel dried and returned to their home cage for 6 min. In addition, the oxidative stress in the prefrontal cortex and hippocampus and corticosterone levels of plasma of mice were investigated. The animals exposed to FSS were treated with CM in two different protocols. In protocol 1, CMI [1 and 10 mg/kg, intragastric (i.g.) route] or fluoxetine, a positive control (10 mg/kg, i.g. route), were administered 30 min before of sections of repeated FSS in both days of stress. After the last section of repeated FSS, the mice performed first the spontaneous locomotor activity and after the tail suspension test. In protocol 2, CMI or fluoxetine (1 mg/kg, i.g. route) was administered for 20 days after the exposition of repeated FSS. The spontaneous locomotor activity, tail suspension, and forced swimming tests were performed in this order after 24 h of last administration of CMI or fluoxetine. The euthanasia of animals was performed after the behavioral tests. CMI and fluoxetine abolished the depressive-like behavior induced by repeated FSS in mice in the two different treatments. CMI modulated the oxidative stress in the prefrontal cortices and hippocampi of mice subjected to repeated FSS. Mice subjected to repeated FSS had an increase in the corticosterone levels and CMI regulated the levels of this glucocorticoid. These findings demonstrate that CMI was effective to abolish the depressive-like behavior induced by repeated FSS, which was accompanied by changes in the corticosterone levels and oxidative stress of prefrontal cortices and hippocampi of mice.

Arylseleninic acid as a green, bench-stable selenylating agent: synthesis of selanylanilines and 3-selanylindoles.

Arylseleninic acids were used as an electrophilic selenium source in aromatic substitution reactions, using N,N-substituted anilines and indoles as nucleophiles at 70 °C for 6-15 h. A total of fourteen 4-selanylanilines and five 3-selanylindoles were selectively obtained in good to excellent yields. The starting benzeneseleninic acids are easily prepared from the respective diselenides, are bench stable and easy to handle, affording water as the only waste at the end of the reaction.

Depression- and anxiogenic-like behaviors induced by lipopolysaccharide in mice are reversed by a selenium-containing indolyl compound: Behavioral, neurochemical and computational insights involving the serotonergic system.

Major depression and anxiety are highly incapacitating psychiatric disorders often present simultaneously, and the causal relationship between these disorders and inflammation are under extensive investigation. The treatment for this comorbidity still relies on drugs acting on the serotonergic neurotransmission, but the modulation of immune-inflammatory pathways has attained an increasing interest in the drug discovery. We have previously demonstrated that the selenoorganic compound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) possess antioxidant, anti-inflammatory, antinociceptive and antidepressant-like effect in mice. Considering these pharmacological properties and the structural similarities between tryptophan, serotonin and CMI, the aim of the present study was to investigate whether CMI ameliorates depression- and anxiogenic-like behavior induced by lipopolysaccharide (LPS) in Swiss male mice by modulating the serotonergic system and reducing neuroinflammation. The administration of CMI (1 mg/kg, i.g) reversed the behavioral deficits induced by LPS (0.83 mg/kg, i.p) in the tail suspension test, splash test and elevated plus maze. The pre-treatment of mice with WAY100635 (5-HT1A receptor antagonist), ketanserin (5-HT2A/2C receptor antagonist) and ondansetron (5-HT3 receptor antagonist) prevented the antidepressant- and anxiolytic-like effect elicited by CMI treatment after the LPS challenge. The administration of CMI also counteracted the increased expression of pro-inflammatory cytokines and indoleamine 2,3-dioxygenase (IDO) in the prefrontal cortex and hippocampus of mice challenged with LPS. Additionally, a molecular docking analysis showed that CMI binds to the active site of the serotonin transporter and IDO. These findings suggest that CMI reversed behavioral and biochemical alterations in the depression-anxiety comorbidity induced by LPS, possibly by modulation of neuroinflammatory mediators and the serotonergic system.

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.

Selenium-containing indolyl compounds: Kinetics of reaction with inflammation-associated oxidants and protective effect against oxidation of extracellular matrix proteins.

Activated white blood cells generate multiple oxidants in response to invading pathogens. Thus, hypochlorous acid (HOCl) is generated via the reaction of myeloperoxidase (from neutrophils and monocytes) with hydrogen peroxide, and peroxynitrous acid (ONOOH), a potent oxidizing and nitrating agent is formed from superoxide radicals and nitric oxide, generated by stimulated macrophages. Excessive or misplaced production of these oxidants has been linked to multiple human pathologies, including cardiovascular disease. Atherosclerosis is characterized by chronic inflammation and the presence of oxidized materials, including extracellular matrix (ECM) proteins, within the artery wall. Here we investigated the potential of selenium-containing indoles to afford protection against these oxidants, by determining rate constants (k) for their reaction, and quantifying the extent of damage on isolated ECM proteins and ECM generated by human coronary artery endothelial cells (HCAECs). The novel selenocompounds examined react with HOCl with k 0.2-1.0 × 108M-1s-1, and ONOOH with k 4.5-8.6 - × 105M-1s-1. Reaction with H2O2 is considerably slower (k < 0.25M-1s-1). The selenocompound 2-phenyl-3-(phenylselanyl)imidazo[1,2-a]pyridine provided protection to human serum albumin (HSA) against HOCl-mediated damage (as assessed by SDS-PAGE) and damage to isolated matrix proteins induced by ONOOH, with a concomitant decrease in the levels of the biomarker 3-nitrotyrosine. Structural damage and generation of 3-nitroTyr on HCAEC-ECM were also reduced. These data demonstrate that the novel selenium-containing compounds show high reactivity with oxidants and may modulate oxidative and nitrosative damage at sites of inflammation, contributing to a reduction in tissue dysfunction and atherogenesis.

Ultrasound-promoted copper-catalyzed synthesis of bis-arylselanyl chrysin derivatives with boosted antioxidant and anticancer activities.

Herein we report the use of ultrasonic irradiation (US) in the synthesis of six new semi-synthetic selenium-containing chrysin derivatives by a simple and effective methodology utilizing CuI as catalyst, in good to excellent yields (60-89%). It was observed that US accelerates the reaction compared to conventional heating with excellent selectivity for diselenylated products. Compounds were tested for their antioxidant and anticancer activities in vitro and it was observed that the presence of selenium in the A-ring of chrysin enhanced both antioxidant and anticancer properties. Semi-synthetic 6,8-bis(o-tolylselanyl)-chrysin 3b has the best radical scavenging activity of DPPH (Imax: 39.79µM) and ABTS+ (IC50: 6.5µM) radicals. Similarly, in the Reactive Species (RS) assay, 3b showed high antioxidant activity in mice cortex (IC50: 5.67µM), whereas 6,8-bis(p-anisoylselanyl)-chrysin 3c was the more active in the hippocampus (IC50: 5.63µM). The Se-chrysins were effective in prevention of lipid peroxidation, highlighting 6,8-bis(p-fluorophenylselanyl)-chrysin 3d in cortex (IC50: 0.54µM) and 3b in hippocampus (IC50: 0.27µM). In addition, 3d was effective in inhibiting human lung adenocarcinoma (A549) cells growth, with a IC50 of 19.9µM after 72h of treatment, while 6,8-bis(p-anisoylselanyl)-chrysin 3c presented the higher antiproliferative activity after 48h of treatment (IC50 of 41.4µM).