Antidepressant effect of modified SuHeXiang Wan alone and in combination with fluoxetine in mice exposed to chronic immobilization stress by activating AMPK/AKT/CREB/BDNF signaling pathway

Abstract

SuHeXiang Wan and its constituents have been traditionally used to treat various central nervous system diseases. Although its neuroprotective effect has been demonstrated, studies on its antidepressant activity and mechanisms of action are limited. This study aimed to examine the antidepressant properties of a modified formulation of SuHeXiang Wan (termed “KSOP1009”) as a single treatment or in combination with fluoxetine and to elucidate the underlying mechanisms involved. The neuroprotective and anti-neuroinflammatory effects of KSOP1009 were demonstrated in in vitro models of depression. The antidepressant activities of KSOP1009 or KSOP1009 + fluoxetine were validated using an immobilization stress-induced depression mouse model. KSOP1009 pretreatment (200 mg/kg) significantly alleviated depression-like behaviors, reduced serum CORT, IL-6, and TNF-α levels, as well as restored AMPK/AKT/CREB/BDNF signaling pathway in the brain. Moreover, the combination of fluoxetine and KSOP1009 significantly improved stress-induced depression and anxiety behaviors by downregulating inflammation-related genes, upregulating neural circuit-related genes, and neurogenesis-related proteins. This study confirmed the antidepressant properties of KSOP1009 and demonstrated the synergistic effects of the combination of KSOP1009 and fluoxetine in a mouse model of depression by improving neurogenesis and reducing neuroinflammation, suggesting that KSOP1009 might hold promise as an alternative and integrative treatment for managing depression. © 2025