Tuberostemonine produces antidepressant effects via the BDNF/TrkB/Erk/CREB signaling pathway

Depression is a highly prevalent, debilitating psychiatric disorder that imposes severe global public health and socioeconomic burdens, greatly compromising patients' quality of life and social function. Current clinical antidepressants suffer from several critical drawbacks, including delayed therapeutic onset, limited efficacy, high relapse rates, and widespread treatment resistance that affects over 30% of patients. This creates an urgent demand for novel, safe antidepressant drug candidates. Natural products, with favorable safety profiles and unique neuropharmacological activities, are promising resources for psychiatric drug development. Herein, we screened an in-house natural product library and identified tuberostemonine as a potential antidepressant agent, and systematically validated its therapeutic effects and molecular mechanisms through integrated in vitro and in vivo experiments. In corticosterone-injured PC12 cells, tuberostemonine effectively mitigated neuronal apoptosis and excessive reactive oxygen species accumulation. In a mouse depression model, tuberostemonine significantly rescued depressive-like behaviors, as evidenced by elevated sucrose preference and shortened immobility time in tail suspension and forced swim tests. Mechanistically, tuberostemonine exerted its antidepressant effects by restoring the corticosterone-induced downregulation of the BDNF/TrkB/ERK /CREB signaling pathway. In PC12 cells, ERK inhibitor treatment effectively abrogated its protective effects, confirming the involvement of this signaling cascade. In conclusion, tuberostemonine ameliorates corticosterone-induced neuronal injury and depressive behaviors via restoration of the BDNF/TrkB/ERK/CREB pathway. This study reveals a novel antidepressant role of tuberostemonine and provides preclinical evidence supporting further investigation of its potential as an innovative natural antidepressant candidate.