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: 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.