Abstract
BackgroundExperiences and inflammatory mediators are fundamental in the provocation of major depressive disorders (MDDs). We investigated the roles and mechanisms of inducible nitric oxide synthase (iNOS) in stress-induced depression.MethodsWe used a depressive-like state mouse model induced by unpredictable chronic mild stress (UCMS). Depressive-like behaviors were evaluated after 4 weeks of UCMS, in the presence and absence of the iNOS inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400 W) compared with the control group. Immunohistochemistry was used to check the loss of Nissl bodies in cerebral cortex neurons. The levels of iNOS mRNA expression in the cortex and nitrites in the plasma were measured with real-time reverse transcription PCR (RT-PCR) and Griess reagent respectively.ResultsResults showed that the 4-week UCMS significantly induced depressive-like behaviors, including decreased sucrose preference in a sucrose preference test, increased duration of immobility in a forced swim test, and decreased hole-searching time in a locomotor activity test. Meanwhile, in the locomotor activity test, UCMS had no effect on normal locomotor activities, such as resting time, active time and total travel distance. Furthermore, the levels of iNOS mRNA expression in the cortex and nitrites in the plasma of UCMS-exposed mice were significantly increased compared with that of the control group. Neurons of cerebral cortex in UCMS-exposed mice were shrunken with dark staining, together with loss of Nissl bodies. The above-mentioned stress-related depressive-like behaviors, increase of iNOS mRNA expression in the cortex and nitrites in the plasma, and neuron damage, could be abrogated remarkably by pretreating the mice with an iNOS inhibitor (1400 W). Moreover, neurons with abundant Nissl bodies were significantly increased in the 1400 W + UCMS group.ConclusionsThese results support the notion that stress-related NO (derived from iNOS) may contribute to depressive-like behaviors in a mouse model, potentially concurrent with neurodegenerative effects within the cerebral cortex.
Highlights
Experiences and inflammatory mediators are fundamental in the provocation of major depressive disorders (MDDs)
There are three genetically different isoforms of nitric oxide synthase (NOS) that account for Nitric oxide (NO) production: neuronal nitric oxide synthase being the isoform first identified in neurons, endothelial nitric oxide synthase being the isoform first identified in endothelial cells, and inducible nitric oxide synthase, which can be synthesized following induction by proinflammatory cytokines or endotoxins [5]
To explore whether and how depressive behavior was induced by unpredictable chronic mild stress (UCMS), mice were treated with UCMS for 4 weeks in the presence and absence of the inducible nitric oxide synthase (iNOS) inhibitor 1400 W
Summary
Experiences and inflammatory mediators are fundamental in the provocation of major depressive disorders (MDDs). We investigated the roles and mechanisms of inducible nitric oxide synthase (iNOS) in stress-induced depression. Nitric oxide (NO), a free gaseous signaling molecule, is involved in the regulation of the nervous and immune system. It has been suggested NO is involved in depression and stress [4]. Various studies suggest the involvement of nNOS in the pathophysiological mechanism of depression-like behavior in rodents [7,8,9,10]. INOS is inflammation inducible and plays no role in the brain under normal physiological conditions. We chose iNOS as our focus to identify whether and how NOS is involved in the pathogenesis of the depressive behavior induced by chronic stress exposure
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