Urolithin B ameliorates depressive-like behavior and hippocampal neuronal damage in depressed rats via regulation of the SLP2/PINK1/Parkin signaling pathway.

BACKGROUND

Depression is a highly prevalent mental disorder, with current medications often limited by delayed onset and insufficient efficacy, underscoring the urgent need to explore novel therapeutic strategies. Urolithin B (UB), a natural ellagitannin-derived metabolite, exhibits anti-inflammatory and antioxidant activities in neuroinflammation, yet its role in depression remains unclear.

OBJECTIVE

The present research aimed to uncover possible effects of UB on depressive-like behavior and hippocampal neuronal damage in a rat model of depression and to preliminarily elucidate its underlying molecular mechanisms.

METHODS

A rat model of depression was created using the chronic unpredictable mild stress (CUMS) paradigm, after which UB intervention was applied. To evaluate depressive-like behaviors, several behavioral tests were conducted, including sucrose preference test, forced swim test, tail suspension test, and open field test. Hippocampal pathological changes and related factor expression were evaluated using histopathology, immunofluorescence, and ELISA. Potential targets were screened via single-cell RNA sequencing (scRNA-seq) data obtained from the GEO database. Subsequently, the function of the identified target gene was validated through in vitro knockdown/overexpression experiments and an in vivo rescue experiment.

RESULTS

UB significantly ameliorated depressive-like behaviors in CUMS rats and alleviated hippocampal neuronal damage, synaptic loss, and neuroinflammation. scRNA-seq analysis revealed a significant upregulation of SLP2 expression in hippocampal neurons (HNs) from the treated group, along with the enrichment of mitophagy-related pathways. Functional experiments confirmed that SLP2 regulates the PINK1/Parkin pathway, promotes mitophagy, and maintains neuronal energy homeostasis. Conversely, knockdown of SLP2 reversed the antidepressant and neuroprotective effects of UB.

CONCLUSION

UB alleviates CUMS-induced depressive-like behavior and hippocampal neuronal damage by upregulating SLP2 and regulating the PINK1/Parkin-mediated mitophagy pathway. This study presents a new potential target and theoretical basis for developing natural compound-based therapies for depression.