AIMS: There is increasing evidence showing that mild traumatic brain injury 
(mTBI) is associated with increased depression-related disorders in humans. 
Recent studies suggest that dietary intake or supplementation of natural 
flavonoids like hesperidin can be used for therapy of patients with brain injury 
and depression. However, the exact mechanisms by which hesperidin indicates its 
neuroprotective effects are not fully understood. The purpose of this study was 
to explore the influence of hesperidin on depression-related symptoms in a mouse 
model of mTBI, and that what mechanisms are primarily involved in the 
antidepressant effects of this bioflavonoid.
MAIN METHODS: Ten days after mTBI-induction, mice received oral hesperidin 
treatment (50 mg/kg/14 days), then animals were subjected to different 
depression tests including sucrose preference test, forced swim test, 
novelty-suppressed feeding test, and tail suspension test. We also measured 
levels of tumor necrosis factor (TNF)-α, interleukin-(IL)-1β, malondialdehyde 
(MDA), and brain-derived-neurotrophic-factor (BDNF) in the hippocampus.
KEY FINDINGS: Our results show that mTBI induction induced depressive-like 
behaviors in mice by increasing inflammatory cytokines (IL-1β and TNF-α) and 
oxidative stress marker (MDA), and reducing BDNF levels in the hippocampus. 
Interestingly, hesperidin treatment was effective to significantly reduce 
depression-related symptoms in mTBI-induced mice. In addition, hesperidin 
decreased the levels of IL-1β, TNF-α and MDA, and increased BDNF levels in the 
hippocampus. The major strength of our study is that four behavioral tests gave 
similar results.
SIGNIFICANCE: This study suggests that the antidepressant-like effect of 
hesperidin may be mediated, at least in part, by decreased neuroinflammation and 
oxidative damage, and enhanced BDNF production in the hippocampus.