Previous studies have demonstrated a close association between an altered immune system and
major depressive disorders, and inhibition of
neuroinflammation may represent an alternative mechanism to treat depression. Recently, the anti-inflammatory activity of
ibrutinib has been reported. However, the effect of
ibrutinib on
neuroinflammation-induced depression and its underlying mechanism has not been comprehensively studied. Therefore, we aimed to elucidate the potential anti-depressive role and mechanism of
ibrutinib against
neuroinflammation-induced depression and synaptic defects. Our results showed that
ibrutinib treatment significantly reduced
lipopolysaccharide (LPS)-induced depressive-like behaviors and
neuroinflammation via inhibiting
NF-kB activation, decreasing proinflammatory
cytokine levels, and normalizing redox signaling and its downstream components, including Nrf2, HO-1, and SOD2, as well as glial cell activation markers, such as Iba-1 and GFAP. Further,
ibrutinib treatment inhibited LPS-activated
inflammasome activation by targeting NLRP3/P38/
Caspase-1 signaling. Interestingly, LPS reduced the number of dendritic spines and expression of
BDNF, and synaptic-related markers, including PSD95, snap25, and
synaptophysin, were improved by
ibrutinib treatment in the hippocampal area of the mouse brain. In conclusion, our findings suggest that
ibrutinib can alleviate
neuroinflammation and synaptic defects, suggesting it has
antidepressant potential against LPS-induced
neuroinflammation and depression.