Gypenoside XVII, an Active Ingredient from Gynostemma Pentaphyllum, Inhibits C3aR-Associated Synaptic Pruning in Stressed Mice

Abstract

Gynostemma pentaphyllum is a herbal medicine widely used in Asian countries, and its saponin extracts have been shown to possess potent anti-inflammatory effects. Gypenoside XVII, an active ingredient isolated from Gynostemma pentaphyllum, has been found to alleviate the inflammation induced by LPS in the BV2 microglia, according to our preliminary study. This study aims to evaluate whether Gypenoside XVII could attenuate depression-like symptoms in vivo and tries to demonstrate the involvement of the complement regulation in its antidepressant-like effect. The results showed that Gypenoside XVII significantly attenuated depression-like behaviors in the forced swimming test, tail suspension test and sucrose preference test. It also alleviated the acute stress-induced hyperactivity of serum corticosterone levels. Additionally, Gypenoside XVII significantly inhibited the activation of microglia and the expression of C3 in mice exposed to chronic unpredictable mild stress (CUMS). Meanwhile, the activation of C3aR/STAT3 signaling and the expression of proinflammatory cytokines was reversed by Gypenoside XVII. Moreover, CUMS induced excessive synaptic pruning by activating microglia, while Gypenoside XVII restored it in the prefrontal cortex. Our data demonstrated that Gypenoside XVII, the active ingredient of Gynostemma pentaphyllum, produced the antidepressant-like effects in mice, which was mediated by the inhibition of complement C3/C3aR/STAT3/cytokine signaling in the prefrontal cortex.

Suppressive Effects of Isofraxidin on Depressive-like Behaviors Induced by Chronic Unpredictable Mild Stress in Mice

“…Then, we discovered that isofraxidin treatment could restore the impaired sucrose preference in CUMS-treated mice, indicating that indeed isofraxidin had antidepressant-like actions. The OFT is commonly used to examine locomotor activity and exploratory behaviors, whereas the FST and TST are used to assess immobility, the distinctive behavior index of behavioral despair observed in humans [ 18 , 19 ]. We demonstrated the antidepressant-like effects of isofraxidin in mice with CUMS-induced depression, based on the fact that isofraxidin improved locomotor activity in the OFT and decreased immobility lengths in the FST and TST.…”

“…The regulation of pro-inflammatory cytokines is a well-known function of NF-κB and NLRP3 inflammasomes [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Inactive NF-κB often binds to the IκB proteins and accumulates in the cytoplasm [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…The regulation of pro-inflammatory cytokines is a well-known function of NF-κB and NLRP3 inflammasomes [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Inactive NF-κB often binds to the IκB proteins and accumulates in the cytoplasm [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. The IκB kinase first phosphorylates and degrades IκB, which causes NF-κB to become dissociated from its complex and stimulates NF-κB translocation into the nucleus [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…Once NF-κB is activated, it induces transcription and expression of pro-inflammatory cytokines [ 13 , 14 , 15 ]. The NLR family of NLRP3 inflammasomes is mainly composed of NLRP3 and apoptosis-associated speck-like protein containing (ASC) [ 16 , 17 , 18 , 19 ]. NLRP3 is a component of the innate immune system, and its primary function is to regulate the activation of caspase-1 and IL-1β [ 16 , 17 , 18 , 19 ].…”

“…The NLR family of NLRP3 inflammasomes is mainly composed of NLRP3 and apoptosis-associated speck-like protein containing (ASC) [ 16 , 17 , 18 , 19 ]. NLRP3 is a component of the innate immune system, and its primary function is to regulate the activation of caspase-1 and IL-1β [ 16 , 17 , 18 , 19 ]. Consequently, modulating NF-κB/NLRP3 pathways represents an important strategy for the development of antidepressants.…”