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

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. We exposed C57BL/6 male mice to chronic mild stress (CMS) as a model of depressive-like behaviors, then gave them ASD (40 mg/kg) intraperitoneally once daily for 3 weeks. We investigated the effects of ASD on microglial phenotype, hippocampal neurogenesis, and animal behavior. We found that CMS upregulated pro-inflammatory factors and downregulated anti-inflammatory factors in dentate gyrus of mice, while decreasing sucrose preference and prolonging immobility time in the forced swimming test. CMS also inhibited hippocampal neurogenesis. ASD treatment induced Arg-1+ microglia and increases brain-derived neurotrophic factor (BDNF) expression in the dentate gyrus of CMS mice, and partially reversed all these stress effects. Conditioned medium from microglia treated with ASD and lipopolysaccharide (LPS) strongly increased levels of phospho-TrkB in neural stem/progenitor cells (NSPCs), while promoting their proliferation, survival and neuronal differentiation. An antagonist of TrkB blocked the pro-neurogenic, anti-depressant effects of ASD. Furthermore, ASD activated peroxisome proliferator-activated receptor-gamma (PPAR-γ) in dentate gyrus of CMS mice as well as in primary microglial cultures treated with LPS. 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. 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. Our results justify further studies of ASD as a potential treatment for depression and may inspire new lines of research targeting the PPAR-γ pathway in disorders involving impaired neurogegammnesis.

Oligodendrocyte‐derived exosomes‐containing SIRT2 ameliorates depressive‐like behaviors and restores hippocampal neurogenesis and synaptic plasticity via the AKT/GSK‐3β pathway in depressed mice

“…The hippocampus, recognized as a central hub for adult neurogenesis and mood regulation, is strongly linked to the onset of depression and the efficacy of antidepressant interventions 5 . Consistent with previous studies, we effectively established the CUMS‐induced mouse model of depression 49 . These behavioral changes in CUMS mice were associated with a decrease in newly developed hippocampal cells and synapse impairments 48 …”

“…5 Consistent with previous studies, we effectively established the CUMS-induced mouse model of depression. 49 These behavioral changes in CUMS mice were associated with a decrease in newly developed hippocampal cells and synapse impairments. 48 Exosomes can facilitate intercellular communication between various cell types, and they play a significant role in neuroplasticity in various pathophysiological conditions, including depression.…”