Urolithin A Exhibits Antidepressant-like Effects by Modulating the AMPK/CREB/BDNF Pathway

Urolithin A (UA), a gut-derived metabolite of ellagitannins or ellagic acid, has recently gained attention for its potential benefits to brain health. The present research aimed to assess the antidepressant-like properties of UA in both in vitro and in vivo models and explored the molecular mechanisms underlying these effects.

We investigated the antidepressant effects and mechanisms of UA in a model of corticosterone-induced damage to PC12 cells and in a model of chronic socially frustrating stress.

Our results demonstrate that UA treatment (5 and 10 μM) significantly alleviated cellular damage and inflammation in corticosterone (CORT)-treated PC12 cells. Furthermore, UA administration (50 and 100 mg/kg) significantly reduced immobility time in the mouse tail suspension test (TST) and forced swim test (FST), indicating its antidepressant-like activity. Additionally, treatment with UA led to the activation of the cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling cascade and triggered the activation of adenosine monophosphate-activated protein kinase (AMPK) during these processes. Importantly, pretreatment with AMPK-specific inhibitor Compound C abolished UA's cytoprotective effects in PC12 cells, as well as its behavioral efficacy in the FST and TST, and its neurotrophic effects, highlighting the critical role of AMPK activation in mediating these effects. Furthermore, in the chronic social defeat stress (CSDS) mouse model, UA treatment (50 and 100 mg/kg) significantly alleviated depression-like behaviors, including reduced sucrose preference in the sucrose preference test, increased social avoidance behavior in the social interaction test, and anxiety-like behaviors, including diminished exploration, in the elevated plus maze test, suggesting the antidepressant-like and anxiolytic-like activities of UA. Moreover, UA treatment reversed elevated serum stress hormone levels, hippocampal inflammation, and the decreased AMPK/CREB/BDNF signaling pathway in the hippocampus of CSDS mice.

Together, these results provide compelling evidence for UA as a viable dietary supplement or therapeutic option for managing depression.