Role of echinacoside in alleviating depressive-like symptoms in chronic unpredictable mild stressed mice via PI3K/AKT/Nrf2/HO-1 signaling pathwayOA

Background:Depression,a prevalent mental health disorder,benefits from traditional Chinese medicine(TCM).Echinacoside(ECH),a natural phenolic compound extracted from Cistanche tubulosa and Echinacea angustifolia,exhibits neuroprotective and antioxidant properties.However,research on the potential mechanism of ECH’s antidepressant activity is limited.This study explored the antidepressant potential of ECH in mice subjected to chronic unpredictable mild stress(CUMS)and its underlying molecular mechanisms.Methods:Mice received ECH(10,20,40 mg/kg/d,i.p.)during the last 14 days of a 28-day CUMS protocol.The therapeutic effect was assessed via the sucrose preference test(SPT),tail suspension test(TST)and forced swim test(FST).Hematoxylin-eosin(H&E)and Nissl staining were employed to evaluate the changes of neuronal injury in hippocampus.Network pharmacology was used to explore the potential targets and pathway enrichment in ECH-mediated antidepression.The expression changes of PI3K/AKT/Nrf2/HO-1 were evaluated by Western blotting.Furthermore,the neuroprotection effects of ECH were assessed on cultured primary neurons injured by corticosterone(CORT)using CCK-8 assay.Results:The results indicated that ECH significantly alleviated depression-like behaviors in CUMS mice characterized as the improved sucrose intake in SPT,reduced immobility duration in TST and FST,reversed weight loss and hippocampal neuronal injury induced after CUMS.PI3K/AKT was selected as core targets by network pharmacology and supported by molecular docking and dynamics simulations.WB results indicated that ECH administration offered neuroprotection by recovering the expression levels of p-PI3K,p-AKT,Nrf2,and HO-1 in CUMS mice hippocampus.Moreover,ECH rescued CORT-induced neuron death in vitro by activating PI3K/AKT/Nrf2/HO-1 pathway,which was abolished by PI3K inhibitor LY294002.Conclusion:These findings demonstrated that ECH alleviated depressive-like behaviors via PI3K/AKT/Nrf2/HO-1 activation,highlighting its potential as a novel antidepressant.