Fucosterol ameliorates depressive-like behaviours by suppressing microglial activation and neuroinflammation via inhibition the MAPK/ERK1/2 signaling pathway.

In this study, we investigated the beneficial effect of Fucosterol on lipopolysaccharide (LPS) and chronic unpredictable mild stress (CUMS) induced depressive symptoms, elucidating the potential molecular mechanism by which Fucosterol regulates microglial phenotypes and neuroinflammation in the prefrontal cortex (PFC) of mice with depressive-like behaviours. Behavioural tests, including the tail suspension test (TST), forced swimming test (FST) and open field test (OFT), revealed that Fucosterol treatment attenuated depressive behaviours in LPS-treated and CUMS-induced mice. Further analysis of RNA sequencing (RNA-seq) data from CUMS-induced mice was performed to identify the potential pathways by which Fucosterol exerts antidepressant effects. Fucosterol suppressed microglial activation by inhibiting MAPK and ERK1/2 signaling, thereby reducing neuroinflammatory cytokine release in CUMS-induced mice. Furthermore, Fucosterol attenuated LPS-induced oxidation, proliferation and inflammation in primary microglial culture, and PD98059 (an ERK1/2 inhibitor) alleviated inflammation in primary microglial culture by inhibiting ERK1/2 activation. To further investigate whether Fucosterol exerts its anti-inflammatory effects through an ERK1/2-dependent pathway, we used an ERK1/2 agonist (Ro67-7476) in our study. The findings of this study demonstrated that Fucosterol alleviated depressive-like behaviours in CUMS-induced mice by inhibiting microglial hyperactivation through MAPK/ERK1/2 signaling suppression. These results suggested that Fucosterol may be effective in preventing depression, offering a potential strategy for developing antidepressant treatments based on natural compounds.