NOD-like receptor protein 3 inhibitors in St. John's wort and their potential antidepressant effects

Depression is a chronic mental disorder characterized by persistent low mood and loss of interest, often associated with dysregulation of neuroinflammatory pathways. Inhibition of NOD-like receptor protein 3 (NLRP3), a key mediator of neuroinflammation, is a promising strategy for alleviating depressive symptoms by modulating inflammatory responses in the brain. Seven polycyclic polyprenylated acylphloroglucinols (PPAPs), including six new hyperioxides A-F (1-6) and furohyperforin (7) were isolated from St. John's wort and characterized via spectroscopic analyses. Compounds 2 and 7 exhibited neuroprotective effects at 10 μM in corticosterone (CORT)-injured SH-SY5Y cells. Furthermore, furohyperforin (7) was demonstrated potent antidepressant activity at 1.25 mg/kg in the forced swimming test (FST) of mice, which was equivalent to fluoxetine (10 mg/kg) and neurostan (78 mg/kg). Additionally, compound 7 was shown to reduce serum CORT levels in mice. Further studies highlighted its effects and potential mechanism through the NLRP3 inflammasome pathway and NLRP3 might be a protein target for the antidepressant effects of 7. Notably, this study provided the first evidence of furohyperforin (7)'s antidepressant properties in mice, highlighting its potential as a bioactive compound for antidepression.