Tabersonine ameliorates depressive-like behavior by inhibiting NLRP3 inflammasome activation in a mouse model.

Depression, a common mental disorder, is intimately linked to neuroinflammation. In the central nervous system, microglia, the principal cells involved in immunity, are crucial in neuroinflammation and closely associated with the pathogenesis of depression. Several studies have demonstrated that depressive-like behaviors could be ameliorated by improving brain inflammation. Notably, natural products occupy a critical position in the study of antidepressants. Herein, we explored the antidepressant effects of tabersonine (Tab), a natural inhibitor of NLRP3. Tab significantly improved depressive-like behaviors and anxiety in lipopolysaccharide (LPS)-treated mice. To further elucidate mechanisms underlying the antidepressant actions of Tab, BV2 microglial cells were exposed to LPS and ATP in vitro. Tab effectively inhibited NLRP3 inflammasome activation, subsequent Caspase-1 cleavage, and interleukin-1β secretion both in the hippocampi of mice in vivo and BV2 cells in vitro. Additionally, Tab strongly decreased the concentrations of the proinflammatory cytokines interleukin-1β, tumor necrosis factor, and interleukin-6 in BV2 cell culture supernatants and sera of mice. Further studies indicated that Tab improved LPS-induced neuronal loss, as indicated by a significant rise in the quantity of Nissl-positive cells within the hippocampal regions CA1, CA3, and dentate gyrus. Importantly, Tab counteracted the LPS-induced microglial activation in the hippocampus. Our results indicate that Tab significantly improves LPS-triggered depressive-like behaviors and reverses injuries to hippocampal microglia and neurons, implying its potential as a therapeutic agent for depression.