6-Shogaol Attenuates Traumatic Brain Injury-Induced Anxiety/Depression-like Behavior via Inhibition of Oxidative Stress-Influenced Expressions of Inflammatory Mediators TNF-α, IL-1β, and BDNF: Insight into the Mechanism

Abstract

Anxiety and depression are among the major traumatic brain injury-induced psychiatric disorders in survivors. The present study was undertaken to investigate the beneficial effects of 6-Shogaol against depression-like behavior and anxiety, induced by traumatic brain injury (TBI), in mice. The mice were administered either fluoxetine, vehicle, or three different doses (10, 20 and 30 mg/kg/day, i.p.) of 6-Shogaol after 10 days of impact-accelerated TBI. The treatment was continued for 14 consecutive days. Elevated plus maze test, marble burying test, staircase test, and social interaction test were employed to investigate the effect of 6-Shogaol on anxiety-like behavior. The impact of treatment on depression-like behavior was assessed using hyper-emotionality behavior or open-field exploration test. The expressions of brain-derived neurotrophic factor (BDNF), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and malondialdehyde (MDA) levels in brain tissue and brain water were measured to elucidate possible mechanisms involved. 6-Shogaol treatment (higher dose) was able to attenuate anxiety/depression-like behaviors in mice with TBI. 6-Shogaol treatment also altered MDA formation and expressions of TNF-α and IL-1β that act as major inflammation-inducing cytokines in brain tissue. Additionally, brain BDNF levels were also affected by 6-Shogaol treatment. Although the lower dose of 6-Shogaol was able to rectify inflammation and BDNF expression in brain tissue, it was unable to improve anxiety/depression-like behaviors. 6-Shogaol treatment produced beneficial effects for TBI-induced anxiety/depression-like behaviors in mice, which could be attributed to the reduction of lipid peroxidation, inflammation, and enhanced BDNF expression.

Figure 1

Effect of 6-Shogaol on marble-burying behavior in TBI mice. Values are expressed as mean ± S.E.M. (n = 6). Values represent mean ± S.E.M. (n = 6). ^#P < 0.001 vs normal control and *P < 0.05 and ***P < 0.001 vs TBI control mice (one-way ANOVA followed by Tukey’s post hoc test).

Figure 2

Effect of 6-Shogaol on staircase test in TBI mice. Values are expressed as mean ± S.E.M. (n = 6). Values represent mean ± S.E.M. (n = 6). ^#P < 0.001 vs normal control and *P < 0.05 and ***P < 0.001 vs TBI control mice (one-way ANOVA followed by Tukey’s post hoc test).

Figure 3

Effect of 6-Shogaol on social interaction behavior in TBI mice. (A) Social interaction time and (B) number of passive interactions. Values represent mean ± S.E.M. (n = 6). ^#P < 0.001 vs normal control and *P < 0.05 and ***P < 0.001 vs TBI control mice (one-way ANOVA followed by Tukey’s post hoc test).

Figure 4

Effect of 6-Shogaol on hyper-emotionality behavior in TBI mice. (A) Struggle response and (B) fight response. Values represent mean ± S.E.M. (n = 6). ^#P < 0.001 vs normal control and *P < 0.05 and ***P < 0.001 vs TBI control mice (one-way ANOVA followed by Tukey’s post hoc test).

Figure 5

Effect of 6-Shogaol on brain water content (%) in TBI mice. Values represent mean ± S.E.M. (n = 6). ^#P < 0.001 vs normal control and *P < 0.05 and ***P < 0.001 vs TBI control mice (one-way ANOVA followed by Tukey’s post hoc test).

Figure 6

Effect of 6-Shogaol on malondialdehyde levels in TBI mice. Values are expressed as mean ± S.E.M. (n = 6). ^#P < 0.001 vs normal control and *P < 0.05 and ***P < 0.001 vs TBI control mice (one-way ANOVA followed by Tukey’s post hoc test).

Figure 7

Effect of 6-Shogaol on TNF-α levels in TBI mice. Values represent mean ± S.E.M. (n = 6). ^#P < 0.001 vs normal control and *P < 0.05 and ***P < 0.001 vs TBI control mice (one-way ANOVA followed by Tukey’s post hoc test).

Figure 8

Effect of 6-Shogaol on IL-1β levels in TBI mice. Values represent mean ± S.E.M. (n = 6). ^#P < 0.001 vs normal control and *P < 0.05 and ***P < 0.001 vs TBI control mice (one-way ANOVA followed by Tukey’s post hoc test).

Figure 9

Effect of 6-Shogaol on BDNF levels in TBI mice. Values represent mean ± S.E.M. (n = 6). ^#P < 0.001 vs normal control and *P < 0.05 and ***P < 0.001 vs TBI control mice (one-way ANOVA followed by Tukey’s post hoc test).