Abstract
Indole-3-carbinol (I3C), a phytochemical enriched in most cruciferous vegetables, has been shown to display various biological activities such as anti-oxidative stress, anti-inflammation, and anti-carcinogenesis. In this study, we investigated the regulatory effect of I3C on chronic stress-induced behavioral abnormalities in mice. Results showed that repeated I3C treatment at the dose of 10, 30, and 60 mg/kg prevented chronic social defeat stress (CSDS)-induced behavioral abnormalities in the tail suspension test, forced swimming test, sucrose preference test, and social interaction test in mice, and did not affect CSDS-induced behavioral abnormalities in the elevated plus maze, light-dark test, and open-field test, suggesting that the I3C treatment selectively prevents the onset of depression- but not anxiety-like behaviors in chronically stressed mice. Further analysis demonstrated that repeated I3C treatment (60 mg/kg, 10 days) prevented CSDS-induced increases in levels of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) mRNA and protein, but did not affect CSDS-induced decreases in levels of IL-4, IL-10, and Ym-1 mRNA and/or protein in the hippocampus and prefrontal cortex, suggesting that I3C can selectively prevent chronic stress-induced pro-inflammatory but not anti-inflammatory responses in the brain. Further analysis showed that repeated I3C treatment (60 mg/kg, 10 days) prevented CSDS-induced increases in levels of nitrite and malondialdehyde (MDA), decreases in contents of glutathione (GSH), and decreases in levels of brain derived neurotrophic factor (BDNF) protein in the hippocampus and prefrontal cortex. These results demonstrated that I3C selectively prevents chronic stress-induced depression-like behaviors in mice likely through suppressing neuroinflammation and oxido-nitrosative stress in the brain.
Highlights
Social stress exposure is a common phenomenon in the modern society, which can lead to the development of psychological disorders, such as depression and anxiety (Toyoda, 2017; Wang et al, 2021)
Post-hoc analysis revealed that I3C treatment during stress exposure at a dose of 10 mg/kg did not affect the chronic social defeat stress (CSDS)-induced increases in the immobility time in the TST (Figure 1B) and forced swimming test (FST) (Figure 1C), but at a dose of 30 or 60 mg/kg, I3C treatment caused a significant suppression of the CSDS-induced increases in the immobility time in the TST (Figure 1B) and FST (Figure 1C)
Post-hoc analysis showed that I3C treatment at the dose of 30 and 60 mg/kg induced a marked suppression of the CSDS-induced decrease in sucrose intake in the sucrose preference test (SPT) (Figure 1D)
Summary
Social stress exposure is a common phenomenon in the modern society, which can lead to the development of psychological disorders, such as depression and anxiety (Toyoda, 2017; Wang et al, 2021). Skewing the neuroinflammatory responses in the brain towards an anti-inflammatory state can prevent the progression of abnormal behaviors in animals stimulated with detrimental stress (Zhao et al, 2016; Duan et al, 2020; Jing Li et al, 2020; Wu et al, 2020; Kumar et al, 2021). Direct infusion of pro-inflammatory cytokines such as IL-1β and interferon-α (INF-α) into the brain in animals can induce behavioral abnormalities (Park et al, 2015; Zhifei Li et al, 2020), and clinically-available antidepressants such as fluoxetine can improve behaviors in depressed animals (Du et al, 2016) and patients suffering from generalized anxiety disorders (Hou et al, 2019) partially through suppression of inflammation. Searching drugs that can suppress neuroinflammation could be a potential strategy for the prevention of psychological disorders
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