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. 2025 Mar 25;40(4):158.
doi: 10.1007/s11011-025-01583-0.

Pharmacologically activating BDNF/TrkB signaling exerted rapid-acting antidepressant-like effects through improving synaptic plasticity and neuroinflammation

Si-Rui Sun  1 , Jia-Ning Zhao  2 , Peng-Wei Bi  3 , Hui-Ying Zhang  2 , Guang-Xiang Li  4 , Jiao-Zhao Yan  4 , Yun-Feng Li  5   6 , Yong-Yu Yin  7 , Hao Cheng  8
Affiliations

Pharmacologically activating BDNF/TrkB signaling exerted rapid-acting antidepressant-like effects through improving synaptic plasticity and neuroinflammation

Si-Rui Sun et al. Metab Brain Dis. .

Abstract

BDNF (Brain-derived neurotrophic factor)/TrkB (tropomyosin receptor kinase B) signaling has great therapeutic potential for depression, but the underlying mechanism remains unclear. This study aims to investigate the molecular mechanism underlying the BDNF/TrkB signaling-mediated antidepressant effects. Chronic Cort drinking for 4 weeks and a single injection of LPS for 24 h were used to induce depression-like behaviors; this study used 7,8-dihydroxyflavone (7,8-DHF, 10 mg/kg, i.p.), a selective TrkB receptor agonist, to activate the BDNF/TrkB signaling and examined its rapid-acting antidepressant-like effects; levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in BV2 microglial cells and synapse-related factors (BDNF, GluA1, Synapsin-1, and PSD95) in HT22 cells were examined by ELISA. Our behavioral results suggested that 7,8-DHF (10 mg/kg, i.p.) exerted rapid-acting antidepressant-like effects in Cort/LPS-treated mice; our immunofluorescence staining results suggested that Cort/LPS reduced the number of NeuN + HT22 cells and increased the number of Iba1 + BV2 microglial cells, which were completely reversed by 7,8-DHF pre-treatment. Our ELISA results suggested that 7,8-DHF significantly normalized the release of synapse-related factors (BDNF, GluA1, and PSD95) in HT22 cells and suppressed the production of inflammatory cytokines (IL-1β, IL-6, and TNF-α) in BV2 microglial cells. Taken together, this study suggested that pharmacologically activating the BDNF/TrkB signaling pathway exerted rapid-acting antidepressant-like effects through improving synaptic plasticity and inhibiting neuroinflammation, which provided new insights for developing next-generation rapid-acting antidepressants.

Keywords: 7,8-DHF; Antidepressant; BDNF/TrkB; Cort; LPS.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests.

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