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. (August 2019)

• Record Type: Journal Article
• Authors: Casaril, Angela Maria; Domingues, Micaela; de Andrade Lourenço, Darling; Birmann, Paloma Taborda; Padilha, Nathalia; Vieira, Beatriz; Begnini, Karine; Seixas, Fabiana Kommling; Collares, Tiago; Lenardão, Eder João; Savegnago, Lucielli
• Is Part Of: Journal of psychiatric research. Volume 115(2019)
• Page Start: 1
• Page End: 12
• Publication Date: 2019-08
• Subjects: Organoselenium -- Antidepressant -- Anxiolytic -- Serotonin -- Neuroinflammation -- Molecular docking; Psychiatry -- Periodicals; Mental Disorders -- Periodicals; Maladies mentales -- Périodiques; Psychiatry; Electronic journals; Periodicals; 616.89005
• DOI: 10.1016/j.jpsychires.2019.05.006
• Languages: English
• ISSNs: 0022-3956

Abstract

Abstract: 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-1 H -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. Graphical abstract: Image 1 Highlights: CMI reversed depression- and anxiogenic-like effect induced by LPS in mice. CMI reversed LPS-induced IL-1β, TNF-α and IDO mRNA expression in prefrontal cortex and hippocampus of mice. 5-HT1A, 5-HT2A/2C and 5-HT3 receptor antagonists blocked the behavioral effects of CMI. A molecular docking approach showed that CMI binds to the active site of SERT and IDO.