Dataset Information

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.

ABSTRACT:

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.

SUBMITTER: Zhang J

PROVIDER: S-EPMC10401137 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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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.

Zhang Jinqiang J Liu Qin Q Su Dapeng D Li Liangyuan L Xiao Chenghong C He Hui H You Zili Z Zhou Tao T

CNS neuroscience & therapeutics 20230329 9

<h4>Background</h4>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.<h4>Methods</h4>We exposed C57BL/6 mice to chronic mild stress (CMS) as a model of depression and then gave them ASD intraperitone ...[more]

PMID: 36987659

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Project description:Given the ability of akebia saponin D (ASD) to protect various types of stem cells, in the present study, we hypothesized that ASD could promote the proliferation, differentiation, and survival of neural stem/precursor cells (NSPCs), even in a microglia-mediated inflammatory environment, thereby mitigating inflammation-related neuropsychopathology. We established a mouse model of chronic neuroinflammation by exposing animals to low-dose lipopolysaccharide (LPS, 0.25 mg/kg/d) for 14 days. The results showed that chronic exposure to LPS strikingly reduced hippocampal levels of PI3K and pAkt and neurogenesis in mice. In the presen of a microglia-mediated inflammatory niche, the PI3K-Akt signaling in cultured NSPCs was inhibited, promoting their apoptosis and differentiation into astrocytes, while decreasing neurogenesis. Conversely, ASD strongly increased the levels of PI3K and pAkt and stimulated NSPC proliferation, survival and neuronal differentiation in the microglia-mediated inflammatory niche in vitro and in vivo. ASD also restored the synaptic function of hippocampal neurons and ameliorated depressive- and anxiety-like behaviors and cognitive impairment in mice chronically exposed to LPS. The results from network pharmacology analysis showed that the PI3K-AKT pathway is one of the targets of ASD to against major depressive disorder (MDD), anxiety and Alzheimer's disease (AD). And the results from molecular docking based on computer modeling showed that ASD is bound to the interaction interface of the PI3K and AKT. The PI3K-Akt inhibitor LY294002 blocked the therapeutic effects of ASD in vitro and in vivo. These results suggested that ASD protects NSPCs from the microglia-mediated inflammatory niche, promoting their proliferation, survival and neuronal differentiation, as well as ameliorating depressive- and anxiety-like behaviors and cognitive impairment by activating the PI3K-AKT pathway. Our work suggests the potential of ASD for treating Alzheimer's disease, depression and other cognitive disorders involving impaired neurogenesis by microglia-mediated inflammation.

Project description:The first-generation precursors producing adult-born neurons in the crayfish (Procambarus clarkii) brain reside in a specialized niche located on the ventral surface of the brain. In the present work, we have explored the organization and ultrastructure of this neurogenic niche, using light-level, confocal and electron microscopic approaches. Our goals were to define characteristics of the niche microenvironment, examine the morphological relationships between the niche and the vasculature and observe specializations at the boundary between the vascular cavity located centrally in the niche. Our results show that the niche is almost fully encapsulated by blood vessels, and that cells in the vasculature come into contact with the niche. This analysis also characterizes the ultrastructure of the cell types in the niche. The Type I niche cells are by far the most numerous, and are the only cell type present superficially in the most ventral cell layers of the niche. More dorsally, Type I cells are intermingled with Types II, III and IV cells, which are observed far less frequently. Type I cells have microvilli on their apical cell surfaces facing the vascular cavity, as well as junctional complexes between adjacent cells, suggesting a role in regulating transport from the blood into the niche cells. These studies demonstrate a close relationship between the neurogenic niche and vascular system in P. clarkii. Furthermore, the specializations of niche cells contacting the vascular cavity are also typical of the interface between the blood/cerebrospinal fluid (CSF)-brain barriers of vertebrates, including cells of the subventricular zone (SVZ) producing new olfactory interneurons in mammals. These data indicate that tissues involved in producing adult-born neurons in the crayfish brain use strategies that may reflect fundamental mechanisms preserved in an evolutionarily broad range of species, as proposed previously. The studies described here extend our understanding of neurovascular relationships in the brain of P. clarkii by characterizing the organization and ultrastructure of the neurogenic niche and associated vascular tissues.

Dataset Information

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.

Background

Methods

Results

Conclusion

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.

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