Selanylimidazopyridine Prevents Lipopolysaccharide-Induced Depressive-Like Behavior in Mice by Targeting Neurotrophins and Inflammatory/Oxidative Mediators.

Micaela Domingues,Angela M Casaril,Beatriz Vieira,Paloma T Birmann,Tiago Collares,Fabiana K Seixas,Eder J Lenardão,Lucielli Savegnago,Karine Begnini,Darling De A Lourenço

doi:10.3389/fnins.2018.00486

Abstract

Inasmuch, as the major depressive disorder (MDD) has been characterized as a heterogeneous disease as the inflammatory processes, neurotrophic factors’ dysfunction and oxidative/nitrosative stress are believed to play a vital role in its establishment. Organoselenium compounds stand out due to their antioxidant, anti-inflammatory, neuroprotective, and antidepressant effects. In this sense, the present study investigated the effect of 3-((4-methoxyphenyl)selanyl)-2-phenylimidazo[1,2-a]pyridine (MPI; 20 and 50 mg/kg, intragastrically) pretreatment [30 min prior lipopolysaccharide (LPS) challenge (0.83 mg/kg)] on acute LPS induced depressive-like behavior, neuroinflammation, and oxidative stress. MPI was able to prevent the increased immobility time induced by LPS on the forced swimming test (FST), the increase in pro-inflammatory cytokines’ expression in the hippocampus (HC) of mice after LPS challenge via NFkB downregulation, and the increase of the reactive oxygen species generation and lipid peroxidation in the prefrontal cortex and HC of mice. It was observed that at the doses tested, MPI protected against reducing levels of BDNF in the cortex and HC of mice challenged with LPS. These observations suggest that the antidepressant-like effect of MPI depends on its capacity to modulate the inflammatory, antioxidant, and neurotrophic systems.

Highlights

Major depressive disorder (MDD) is a serious illness with great loss in quality of life, increased morbidity and mortality, and a high rate of recurrence and chronicity (Réus et al, 2016)
The monoaminergic systems are clearly involved in the etiology of depression, it is accepted that inflammatory processes, neurotrophic factors’ dysfunction, and oxidative/nitrosative stress might be involved in the establishment of this disorder (Maes et al, 2013)
We reported in this study that 3-((4-methoxyphenyl)selenyl)2-phenylimidazo[1,2-a]pyridine (MPI) mitigates the LPSinduced depressive-like behavior and investigated the mechanisms of this molecule in the biomarkers of oxidative stress, neuroinflammation, and neurotrophic factor

Summary

Introduction

Major depressive disorder (MDD) is a serious illness with great loss in quality of life, increased morbidity and mortality, and a high rate of recurrence and chronicity (Réus et al, 2016). The monoaminergic systems are clearly involved in the etiology of depression, it is accepted that inflammatory processes, neurotrophic factors’ dysfunction, and oxidative/nitrosative stress might be involved in the establishment of this disorder (Maes et al, 2013) Based on these observations, rodent models of inflammation-associated depression have been developed, such as administration of bacterial lipopolysaccharide (LPS), which is a potent activator of the immune system (Dantzer et al, 2008). In addition to the organoselenium compounds, the imidazopyridines have been found to possess interesting biological properties (Casaril et al, 2017) These molecules have been used to treat insomnia, and have shown promising antioxidant, anti-inflammatory, and neurotrophic effects (Parekh et al, 2013; Dyminska, 2015; Qian et al, 2016). Considering the pharmacological proprieties of organoselenium compounds and imidazopyridines, the combination of both molecules may be a relevant strategy for the development of more efficient drugs with multitarget profile for the treatment of depression

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