SRT1720 ameliorates LPS-induced depressive-like behaviors in mice and activates Parkin-mediated mitophagy.

Abstract

Background: Emerging evidence suggests a connection between mitophagy-a key mitochondrial quality control mechanism-and depression. Furthermore, sirtuin 1 (SIRT1), a NAD⁺-dependent deacetylase, has been implicated in the pathophysiology of depression, though its precise role remains elusive. This study aimed to investigate how SIRT1 modulates depressive-like behaviors in mice and to determine whether mitophagy mediates this process.

Methods: Male BALB/c mice were administered lipopolysaccharide (LPS) to mimic depressive-like behaviors. The treatment group received a pre-administration of SRT1720 (50 mg/kg, i.p.), a specific SIRT1 activator. Depressive-like behaviors were assessed by sucrose preference test (SPT) and forced swimming test (FST). Additionally, hippocampal neuronal and mitochondrial ultrastructure was detected via transmission electron microscopy (TEM), and mitophagy-related protein expression was examined by western blotting.

Results: Results demonstrated that activation of SIRT1 significantly mitigated LPS-induced depressive-like behaviors in mice. Moreover, it was observed that SIRT1 activation protected against LPS-induced neuronal and mitochondrial damage in the hippocampus. TEM analysis revealed a marked increase in hippocampal autophagosomes following SIRT1 activation, accompanied by significantly elevated expression of LC3II and Parkin, suggesting enhanced mitophagy. In vitro experiment using HT-22 cells provided additional evidence that SIRT1 activation ameliorated LPS-induced mitochondrial dysfunction and promoted mitophagy via Parkin-mediated pathway.

Conclusions: These findings suggested that activation of SIRT1 could alleviate depressive-like behaviors in mice following LPS challenge, potentially through a Parkin-dependent mitophagy mechanism.