Obligatory role of microglia-mobilized hippocampal CREB-BDNF signaling in the prophylactic effect of β-glucan on chronic stress-induced depression-like behaviors in mice

Article

作者: Shi, Ruiting ; Chen, Zhuo ; Chen, Bingran ; Yang, Rongrong ; Zhu, Haojie ; Lu, Xu ; Huang, Chao ; Zhu, Tao ; Peng, Jie ; Zhao, Cheng ; Hu, Wenfeng ; Ren, Jie

Our previous studies have reported that pre-stimulation of microglia before stress stimulation is a possible strategy to prevent depression-like phenotypes; however, the molecular mechanisms underlying this effect are still unclear. Here, we used β-glucan, a polysaccharide from Saccharomyces cerevisiae with immunomodulatory activities that cannot elicit pro-inflammatory responses in microglia, to address this issue. Our results showed that a single injection of β-glucan one day before stress exposure dose-dependently prevented the depression-like behaviors triggered by chronic unpredictable stress (CUS), which peaked at 20 mg/kg and prevented the impairment of hippocampal brain-derived neurotrophic factor (BDNF) signaling, a pathological process critical for the progression of depression-like phenotypes. Inhibition of BDNF signaling by infusion of an anti-BDNF antibody into the hippocampus, knock-in of the mutant BDNF Val68Met allele, or blockade of the BDNF receptor in the hippocampus abolished the preventive effect of β-glucan on CUS-induced depression-like behaviors. Further analysis showed that cAMP-response element binding protein (CREB)-mediated increase of BDNF expression in the hippocampus was essential for the prevention of depression-like phenotypes by β-glucan. Pretreatment with minocycline or PLX3397 before β-glucan injection to suppress microglia abolished the preventive effect of β-glucan on impaired CREB-BDNF signaling in the hippocampus and depression-like behaviors in CUS mice. These results suggest that an increase in hippocampal BDNF following CREB activation triggered by β-glucan-induced microglia stimulation and subsequent TrkB signaling mediates the preventive effect of β-glucan on depression. β-Glucan may be a more suitable immunostimulant for the prevention of depression due to its inability to promote pro-inflammatory responses in microglia.

2022-11-01·Brain, Behavior, and Immunity

ERK1/2-dependent BDNF synthesis and signaling is required for the antidepressant effect of microglia stimulation

Article

作者: Lu, Xu ; Huang, Chao ; Lu, Qun ; Liu, Huijun ; Shen, Zhongxia ; Wang, Yue ; Shen, Xinhua ; Wang, Dan ; Cai, Zixuan ; Ye, Minxiu ; Hu, Zhichao ; Gu, Yue

Depressed mice have lower numbers of microglia in the dentate gyrus (DG). Reversal of this decline by a single low dose of lipopolysaccharide (LPS) may have antidepressant effects, but there is little information on the molecular mechanisms underlying this effect. It is known that impairment of brain-derived neurotrophic factor (BDNF) signaling is involved in the development of depression. Here, we used a combination of neutralizing antibodies, mutant mice, and pharmacological approaches to test the role of BDNF-tyrosine kinase receptor B (TrkB) signaling in the DG in the effect of microglial stimulation. Our results suggest that inhibition of BDNF signaling by infusion of an anti-BDNF antibody, the BDNF receptor antagonist K252a, or knock-in of the mutant BDNF Val68Met allele abolished the antidepressant effect of LPS in chronically stressed mice. Increased BDNF synthesis in DG, mediated by extracellular signal-regulated kinase1/2 (ERK1/2) signaling but not protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling, was essential for the antidepressant effect of microglial stimulation. These results suggest that increased BDNF synthesis through activation of ERK1/2 caused by a single LPS injection and subsequent TrkB signaling are required for the antidepressant effect of hippocampal microglial stimulation.

2021-07-01·Neuroscience Letters4区 · 医学

Xanthoceraside administration produces significant antidepressant effects in mice through activation of the hippocampal BDNF signaling pathway

4区 · 医学

Article

作者: Liu, Yue ; Ji, Chun-Hui ; Jiang, Bo ; Gu, Jiang-Hong ; Tang, Wen-Qian ; Wang, Yao ; Guan, Wei

Current available antidepressants have various adverse reactions and slow pharmacodynamics, so it is necessary to find novel antidepressants for effective treatment. Xanthoceraside (XAN), a novel triterpenoid saponin extracted from the fruit husks of Xanthoceras sorbifolium Bunge, has anti-amnesic and neuroprotective properties. The purpose and significance of this study is to assess whether XAN has antidepressant effects in mice using the forced swim test (FST), tail suspension test (TST) and chronic unpredictable mild stress (CUMS) model of depression. The effects of XAN treatment on the hippocampal brain-derived neurotrophic factor (BDNF) signaling pathway and neurogenesis were examined. The antidepressant mechanism of XAN was explored using a BDNF inhibitor (K252a) and an anti-BDNF antibody. It was found that XAN administration significantly reversed the depressive-like behaviors of CUMS-treated mice. XAN treatment also significantly prevented the decreasing effects of CUMS on the hippocampal BDNF signaling and neurogenesis. The antidepressant effects of XAN in mice were blocked by both administration of K252a and anti-BDNF antibody. Collectively, these findings indicate that XAN possesses antidepressant effects in mice which are mediated by activation of hippocampal BDNF signaling pathway, thus providing the first evidence that XAN can be a potential antidepressant candidate.

100 项与抗TRAIL抗体(三诺佳邑) 相关的药物交易

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