2. Academic Validation
  3. 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

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

  • Eur J Pharmacol. 2023 Dec 22:176288. doi: 10.1016/j.ejphar.2023.176288.
Cheng Zhao 1,  Ruiting Shi 2,  Xu Lu 3,  Rongrong Yang 4,  Zhuo Chen 5,  Bingran Chen 3,  Wenfeng Hu 6,  Jie Ren 3,  Jie Peng 3,  Tao Zhu 3,  Haojie Zhu 3,  Chao Huang 7
Affiliations

Affiliations

  • 1 Department of Pharmacy, Affiliated Hospital of Nantong University, #20 Xisi Road, Nantong 226001, Jiangsu, China. Electronic address: [email protected].
  • 2 Faculty of Humanities and Social Sciences, City University of Macau, Av. Parde Tomas Pereira, Macau, Taipa, 999078, China.
  • 3 Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China.
  • 4 Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226001, China.
  • 5 Invasive Technology Department, The Second Affiliated Hospital of Nantong University, First People's Hospital of Nantong City, #666 Shengli Road, Nantong 226006, China.
  • 6 Department of Pharmacy, Affiliated Maternal and Child Health Hospital of Nantong University, #399 Shijidadao, Nantong 226007, China.
  • 7 Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China. Electronic address: [email protected].
PMID: 38142848 DOI: 10.1016/j.ejphar.2023.176288
Abstract

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.

Keywords

BDNF; CREB; Microglia; Prophylactic effect; β-glucan.

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