Ginsenoside Rb1 induces a pro-neurogenic microglial phenotype via PPARγ activation in male mice exposed to chronic mild stress

Abstract

Background Anti-inflammatory approaches are emerging as a new strategy for the treatment of depressive disorders. Ginsenoside Rb1 (GRb1), a major component of Panax ginseng, can inhibit inflammatory cascade and alleviate depressive-like behaviors. Microglia can promote or inhibit adult hippocampal neurogenesis according to their functional phenotypes. Here, we examine whether GRb1 may exert antidepressant effects by promoting a pro-neurogenic phenotype of microglia and thereby increasing neurogenesis. Methods The antidepressant effects of GRb1 or the licensed antidepressant imipramine (IMI) were assessed in chronic mild stress (CMS)-exposed male mice. The depressive-like behaviors of mice were evaluated by sucrose preference test, forced swimming test (FST), and tail suspension test (TST). The microglial phenotypes were identified by pro- and anti-inflammatory cytokine expression and morphological properties, analyzed by RT-qPCR, western blotting, and immunofluorescence staining. The effect of GRb1-treated microglia on adult hippocampal neurogenesis in vivo and in vitro was detected using immunofluorescence staining. Results Behavioral assessment indicated that GRb1 or IMI treatment alleviated depressive-like behaviors in CMS-exposed mice. Immunofluorescence examination demonstrated that GRb1 induced a pro-neurogenic phenotype of microglia via activating PPARγ in vivo and in vitro, which were effectively reversed by the PPARγ inhibitor GW9662. In addition, GRb1-treated microglia increased the proliferation and differentiation of neural precursor cells. Conclusions These findings demonstrated that GRb1 alleviated depressive-like behaviors of CMS-exposed male mice mainly through PPARγ-mediated microglial activation and improvement of adult hippocampus neurogenesis.

Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression

“…In BV2 microglial cells, LPS exposure induced an imbalance between the pro-inflammatory and anti-inflammatory microglial phenotype [ 71 ], activated TLR4/nuclear factor-kappa B (NF-κB) pathway, and downregulated TREM2 expression [ 72 ]. In the HIP and cortex of CMS-exposed mice, immunofluorescence staining revealed that the activated microglia (Iba-1 positive cells), as well as increased pro-inflammatory microglial markers (IL-1β, TNF-ɑ, IL-6, INF-γ, and iNOS) and decreased anti-inflammatory markers (Ym1, IL-4, IL-10, and Arg-1), suggesting a transformation of the microglial phenotype [ 73 ]. The CSDS paradigm also produces mood alterations and microglial activation, as well as ROS elevation.…”

“…Direct and indirect evidence support that some ginsenosides (such as ginsenoside Rg3, Rb1, and Rg1) induce the anti-inflammatory actions of macrophages and microglia [ 195 ]. Ginsenoside Rb1 is a typical 20( S )-protopanaxadiol-type saponin and exerts significant antidepressive effects in chronic stress models [ 73 , 196 , 197 ]. It is known that Rb1 regulates microglial activation, protects neurons from inflammatory and oxidative damage, and promotes neurogenesis [ 198 , 199 ].…”

“…Recently, treatment with Rb1 (20 mg/kg/d, p.o. ) in CMS-treated mice for consecutive 4 weeks alleviated depressive-like behaviors in the SPT, TST, and FST mainly through PPARγ-mediated transitions in microglial phenotype (TNF-α, IL-1β, TGF-β, and Arg-1) in the HIP and cortex [ 73 ]. Rb1 attenuated a decrease in BDNF and the ratio of p-AKT/AKT expression, and increased IL-1β, TNF-α, and Iba-1 levels in the HIP in a CRS model.…”

Schisandra chinensis (Turcz.) Baill. essential oil exhibits antidepressant-like effects and against brain oxidative stress through Nrf2/HO-1 pathway activation

“…TST was conducted as described previously with slight modifications (Zhang et al 2021a ). In brief, the immobility time of each mouse was recorded for the last 4 min following 2 min habituation during a 6 min test period.…”

Ginsenosides Rb1 Attenuates Chronic Social Defeat Stress-Induced Depressive Behavior via Regulation of SIRT1-NLRP3/Nrf2 Pathways

“…Our recent work showed that Rb1 can significantly ameliorate depressive-like behavior induced by chronic social defeat stress and modulates the BDNF-Trkb signaling pathway ( 27 ). Ginsenoside Rb1 demonstrated substantial antidepressant effects in rats by modulation of amino-acidergic and monoaminergic receptors and their associated neurotransmitters, induced microglial activation, and improved adult hippocampal neurogenesis in mice subjected to chronic mild stress ( 28 ). Unfortunately, very little is known about Rb1's antidepressant-like effect on behavioral impairments caused by CSDS, or on the exact neuronal processes underlying, or about Rb1's significance to the neuroprotective effect of slowing the inflammatory process in depression.…”