Asperosaponin VI inhibits LPS-induced inflammatory response by activating PPAR-γ pathway in primary microglia

Zhang, Jinqiang; Yi, Saini; Xiao, Chao; Li, Yahui; Liu, Chan; Jiang, Wei-Ke; Yang, Chun-Lin; Zhou, Tao

doi:10.1016/j.sjbs.2020.07.013

Cited by 14 publications

(9 citation statements)

References 25 publications

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“…62 Our previous research showed that ASD acts via PPARγ to switch activated microglia from a pro-inflammatory to anti-inflammatory phenotype in vitro. 33 In present study, we further demonstrated that ASD acts Taken together, these experiments strongly suggest that ASD acts via the PPARγ pathway to reprogramme a pro-neurogenic microglia in dentate gyrus of CMS mice that can increase BDNF expression and promote NSPC proliferation, survival, and neuronal differentiation (Figure 7).…”

Section: Discussionsupporting

confidence: 78%

Akebia saponin D acts via the PPAR‐gamma pathway to reprogramme a pro‐neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress

Zhang

Liu

et al. 2023

CNS Neurosci Ther

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Background Using drugs to modulate microglial function may be an effective way to treat disorders, such as depression, that involve impaired neurogenesis. Akebia saponin D (ASD) can cross the blood–brain barrier and exert anti‐inflammatory and neuroprotective effects, so we wondered whether it might influence adult hippocampal neurogenesis to treat depression. Methods We exposed C57BL/6 mice to chronic mild stress (CMS) as a model of depression and then gave them ASD intraperitoneally once daily for 3 weeks. We investigated the effects of ASD on microglial phenotype, hippocampal neurogenesis, and animal behavior. The potential role of the peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) or BDNF–TrkB pathway in the pro‐neurogenesis and anti‐depressant of ASD was identified using there inhibitors GW9662 and K252a, respectively. The neurogenic effects of ASD‐treated microglia were evaluated using conditioned culture methods. Results We found that CMS upregulated pro‐inflammatory factors and inhibited hippocampal neurogenesis in dentate gyrus of mice, while inducing depressive‐like behaviors. Dramatically, ASD (40 mg/kg) treatment reprogrammed an arginase (Arg)‐1+ microglial phenotype in dentate gyrus, which increased brain‐derived neurotrophic factor (BDNF) expression and restored the hippocampal neurogenesis, and partially ameliorated the depressive‐like behaviors of the CMS‐exposed mice. K252a or neurogenesis inhibitor blocked the pro‐neurogenic, anti‐depressant effects of ASD. Furthermore, ASD activated PPAR‐γ in dentate gyrus of CMS mice as well as in primary microglial cultures treated with lipopolysaccharide. Blocking the PPAR‐γ using GW9962 suppressed the ASD‐reprogrammed Arg‐1+ microglia and BDNF expression in dentate gyrus of CMS mice. Such blockade abolished the promoted effects of ASD‐treated microglia on NSPC proliferation, survival, and neurogenesis. The pro‐neurogenic and anti‐depressant effects of ASD were blocked by GW9962. Conclusion These results suggested that ASD acts via the PPAR‐γ pathway to induce a pro‐neurogenic microglia in dentate gyrus of CMS mice that can increase BDNF expression and promote NSPC proliferation, survival, and neurogenesis.

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Section: Discussionsupporting

confidence: 78%

Akebia saponin D acts via the PPAR‐gamma pathway to reprogramme a pro‐neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress

Zhang

Liu

et al. 2023

CNS Neurosci Ther

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“…PPAR-γ regulates the expression of anti-inflammatory cytokines [ 49 ], and the PPAR-γ agonists pioglitazone or rosiglitazone can switch activated microglia cells from a pro-inflammatory to anti-inflammatory state [ 50 , 51 ]. Previous research showed that asperosaponin VI acts via PPAR-γ to switch activated microglia from a pro-inflammatory to anti-inflammatory phenotype in vitro [ 52 ]. In present study, we further demonstrated that asperosaponin VI acts via PPAR-γ to induce a neuroprotective phenotype in hippocampal microglia of CMS-exposed mice and mitigate depressive-like mouse behaviors.…”

Section: Discussionmentioning

confidence: 99%

Asperosaponin VI ameliorates the CMS-induced depressive-like behaviors by inducing a neuroprotective microglial phenotype in hippocampus via PPAR-γ pathway

Jiang

Liu

et al. 2022

J Neuroinflammation

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Background The natural compound asperosaponin VI has shown potential as an antidepressant, but how it works is unclear. Here, we explored its effects on mice exposed to chronic mild stress (CMS) and the underlying molecular pathways. Methods Mice were exposed to CMS for 3 weeks followed by asperosaponin VI (40 mg/kg) or imipramine (20 mg/kg) for another 3 weeks. Depression-like behaviors were assessed in the forced swimming test (FST), sucrose preference test (SPT), tail suspension test (TST). Microglial phenotypes were evaluated using immunofluorescence staining, real-time quantitative PCR and enzyme-linked immunosorbent assays in hippocampus of mice. In some experiments, stressed animals were treated with the PPAR-γ antagonist GW9662 to examine its involvement in the effects of asperosaponin VI. Blockade of PPAR-γ in asperosaponin VI-treated primary microglia in the presence of lipopolysaccharide (LPS) was executed synchronously. The nuclear transfer of PPAR-γ in microglia was detected by immunofluorescence staining in vitro and in vivo. A co-cultured model of neuron and microglia was used for evaluating the regulation of ASA VI on the microglia–neuron crosstalk molecules. Results Asperosaponin VI ameliorated depression-like behaviors of CMS mice based on SPT, TST and FST, and this was associated with a switch of hippocampal microglia from a pro-inflammatory (iNOS+-Iba1+) to neuroprotective (Arg-1+-Iba1+) phenotype. CMS reduced the expression levels of PPAR-γ and phosphorylated PPAR-γ in hippocampus, which asperosaponin VI partially reversed. GW9662 treatment prevented the nuclear transfer of PPAR-γ in asperosaponin VI-treated microglia and inhibited the induction of Arg-1+ microglia. Blockade of PPAR-γ signaling also abolished the ability of asperosaponin VI to suppress pro-inflammatory cytokines while elevating anti-inflammatory cytokines in the hippocampus of CMS mice. The asperosaponin VI also promoted interactions between hippocampal microglia and neurons by enhancing CX3CL1/CX3CR1 and CD200/CD200R, and preserved synaptic function based on PSD95, CamKII β and GluA levels, but not in the presence of GW9662. Blockade of PPAR-γ signaling also abolished the antidepressant effects of asperosaponin VI in the SPT, TST and FST. Conclusion CMS in mice induces a pro-inflammatory microglial phenotype that causes reduced crosstalk between microglia and neuron, inflammation and synaptic dysfunction in the hippocampus, ultimately leading to depression-like behaviors. Asperosaponin VI may ameliorate the effects of CMS by inducing microglia to adopt a PPAR-γ-dependent neuroprotective phenotype.

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“…Studies showed that interferon regulatory factor 8 (IRF8) is a key constitutive determinant of the morphological and molecular properties and motility of microglia in the central nervous system ( Horiuchi et al, 2012 ; Masuda et al, 2014 ). While the nuclear receptor PPAR-γ, a critical transcription factor for transforming microglia into a neuroprotective phenotype, alleviating a variety of brain diseases, such as depression, stroke, Alzheimer’s disease, and so on ( Pan et al, 2015 ; Zhao et al, 2016 ; Xie et al, 2020 ; Zhang et al, 2020b ). These findings support emerging strategies able to redirect microglia from detrimental to beneficial functions, and open novel approaches to target microglia therapeutically.…”

Section: Discussionmentioning

confidence: 99%

Mapping the Plasticity of Morphology, Molecular Properties and Function in Mouse Primary Microglia

Jiang

et al. 2022

Front. Cell. Neurosci.

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Microglia exert diverse functions by responding in diverse ways to different stimuli, yet little is known about the plasticity of various phenotypes that microglia display. We used interferon (IFN)-γ, interleukin (IL)-4 and IL-10 to induce different phenotypes in mouse primary microglia. RNA sequencing was used to identify genes differentially expressed in response to stimulation, and the different stimulated populations were compared in terms of morphology, proliferative capacity, phagocytic ability and neurotoxicity. IFN-γ induced an “immunodefensive” phenotype characterizing both induction of filopodia and upregulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor α. Microglia with this phenotype mediated an acute inflammatory response accompanied by excellent proliferative capacity and neurotoxicity, and remained susceptible to remodeling for up to 48 h after initial stimulation. IL-4 induced an enduring “neuroimmunoregulatory” phenotype involving induction of lamellipodium and persistent upregulation of arginase (Arg)-1 and YM-1 expression. Microglia with this phenotype remained susceptible to remodeling for up to 24 h after initial stimulation. IL-10 induced an “immunosuppressive” phenotype involving induction of ameba-like morphology and upregulation of transforming growth factor β and IL-10 as well as inhibition of inflammation. This phenotype was accompanied by inhibition of self-proliferation, while its morphology, molecular properties and function were the least susceptible to remodeling. IFN-γ, IL-4, or IL-10 appear to induce substantially different phenotypes in microglia. The immunodefensive microglia induced by IFN-γ showed remarkable plasticity, which may help repair CNS inflammation damage under pathological condition. Chronic activation with IL-10 decreases microglial plasticity, which may help protect the brain form the immune response. Our research justifies and guides further studies into the molecular pathways that operate in each phenotype to help multitasking microglia regulate homeostasis in the brain.

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Asperosaponin VI inhibits LPS-induced inflammatory response by activating PPAR-γ pathway in primary microglia

Cited by 14 publications

References 25 publications

Akebia saponin D acts via the PPAR‐gamma pathway to reprogramme a pro‐neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress

Akebia saponin D acts via the PPAR‐gamma pathway to reprogramme a pro‐neurogenic microglia that can restore hippocampal neurogenesis in mice exposed to chronic mild stress

Asperosaponin VI ameliorates the CMS-induced depressive-like behaviors by inducing a neuroprotective microglial phenotype in hippocampus via PPAR-γ pathway

Mapping the Plasticity of Morphology, Molecular Properties and Function in Mouse Primary Microglia

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