Magnolol Ameliorates Depression Through Modulating the TREM2-DOK3-ERK Pathway.

Depression is a mental disorder with a high incidence and high clinical cure rate but a low treatment acceptance rate and a high recurrence rate. Depression is often accompanied by neuroinflammation. Magnolol (MA), a pharmacologically active compound in Magnolia officinalis, has an antidepressant effect. The aim of this study was to investigate the molecular mechanism of the antidepressant effect of MA in mice and BV2 microglia. MA increased sugar water preference in the sucrose preference test (SPT) and inhibited immobility time in the forced swim test (FST) but did not affect distance travelled in the open field test (OFT). MA reduced the levels of proinflammatory cytokines (IL-6, TNF-α and IL-1β) and increased the expression levels of BDNF and IL-10 to promote neuronal survival. MA inhibited not only the amoeba-like morphology of hippocampal microglia but also iNOS expression in BV2 microglia. MA increased the expression of TREM2 and the p-DOK3/DOK3 ratio but decreased the p-ERK/ERK ratio. The knockdown of TREM2 led to a decrease in the p-DOK3/DOK3 ratio and an increase in the p-ERK/ERK ratio while also inducing microglial activation, promoting the production of inflammatory factors, and abrogating the protective effects of MA. Our study suggested that MA attenuated CUMS-induced depression-like behaviour and microglial activation by reducing ERK phosphorylation through increased TREM2 expression and DOK3 phosphorylation, which may provide new approaches for the treatment of depression.