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.

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.…”

“… 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 …”

Roles of microglia in adult hippocampal neurogenesis in depression and their therapeutics

“…For instance, CMS exposure in mice was found to upregulate inflammatory factors and inhibit neuronal growth in the dentate gyrus region of the hippocampus, leading to depression-like behavior ( 156 ). Surprisingly, drug treatment reprogrammed Arg-1 + microglial cell phenotypes in the dentate gyrus region, suppressed neuronal inflammation, increased the quantification of hippocampal newborn neurons (BrdU + - DCX + cells), and improved depression-like behavior in CMS-exposed mice ( 156 ). Thus, the balance of cytokines participates in neurogenesis, thus influencing the occurrence of depression.…”

Adult hippocampal neurogenesis: pharmacological mechanisms of antidepressant active ingredients in traditional Chinese medicine

“…Patchouli alcohol, the principal active ingredient of Patchouli, inhibits NLRP3 inflammasomes and ameliorates microglia-mediated disturbances in neurogenesis ( He et al, 2023 ). Akebia saponin D, a triterpenoid saponin derived from the rhizome of Dipsacus asper ( Yang et al, 2021 ), reprograms neurogenic microglia via the peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathway, rescues hippocampal neurogenesis impaired by Chronic Mild Stress (CMS), and enhances AHN ( Zhang et al, 2023 ). Ginsenoside Rg1 and Ginsenoside Rb1, major components of Panax ginseng C.A.…”