The selective SIK2/3 inhibitor GLPG3970 exhibits antidepressant-like effects via the hippocampal SIK2-CRTC1-CREB-BDNF pathway in chronic stress models
- 1Department of Pharmacology, School of Pharmacy, Nantong University , , ,
- 2Office of Research and Innovation, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology , , ,
Abstract
Introduction: Depression is a common mental disorder driven by biopsychosocial factors. Although traditional antidepressants serve as first-line therapies, they face clinical challenges, underscoring the need for novel therapeutic agents with improved efficacy. Our previous studies have identified hippocampal SIK2 as a key regulator in the pathogenesis of depression, acting through the cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1)-CREB-brain derived neurotrophic factor (BDNF) signaling pathway. In this study, we investigated the antidepressant-like effects of GLPG3970, a novel selective inhibitor of SIK2/3, in male C57BL/6J mice.
Methods: Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression were employed, combined with behavioral tests, virus-mediated gene transfer, Western blotting, co-immunoprecipitation, and immunofluorescence.
Results: It was found that repeated administration of GLPG3970 significantly suppressed depressive-like behaviors in both CSDS and CUMS model mice, blocked stress-induced increases in hippocampal SIK2 expression and CRTC1 cytoplasmic translocation, and consequently restored the hippocampal BDNF signaling cascade and neurogenesis. More importantly, by using adeno-associated virus (AAV)-mediated overexpression of SIK2 or silencing of CRTC1/CREB/BDNF in the hippocampus, the antidepressant-like effects of GLPG3970 in mice were notably eliminated.
Discussion: Collectively, these findings together demonstrate that the antidepressant-like actions of GLPG3970 in mice depend on the hippocampal SIK2-CRTC1-CREB-BDNF signaling pathway, highlighting its potential as a novel candidate for antidepressant therapy.
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BibTeX
@article{shen2026selective,
title = {{The selective SIK2/3 inhibitor GLPG3970 exhibits antidepressant-like effects via the hippocampal SIK2-CRTC1-CREB-BDNF pathway in chronic stress models}},
author = {Jia-Yi Shen and Lu Chen and Fei-Yang Jin and Jun-Jie Qian and Feng Zhang and Ruo-Jia Wang and Meng-Jing Qi and Bo Jiang and Hua Fan},
journal = {Frontiers in pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1895911},
url = {https://europepmc.org/article/PMC/PMC13668743},
note = {CC BY},
}
RIS
TY - JOUR
TI - The selective SIK2/3 inhibitor GLPG3970 exhibits antidepressant-like effects via the hippocampal SIK2-CRTC1-CREB-BDNF pathway in chronic stress models
AU - Jia-Yi Shen
AU - Lu Chen
AU - Fei-Yang Jin
AU - Jun-Jie Qian
AU - Feng Zhang
AU - Ruo-Jia Wang
AU - Meng-Jing Qi
AU - Bo Jiang
AU - Hua Fan
PY - 2026
DA - 2026/10/01
JO - Frontiers in pharmacology
DO - 10.3389/fphar.2026.1895911
UR - https://europepmc.org/article/PMC/PMC13668743
AB - Introduction: Depression is a common mental disorder driven by biopsychosocial factors. Although traditional antidepressants serve as first-line therapies, they face clinical challenges, underscoring the need for novel therapeutic agents with improved efficacy. Our previous studies have identified hippocampal SIK2 as a key regulator in the pathogenesis of depression, acting through the cAMP response element-binding protein (CREB)-regulated transcription coactivator 1 (CRTC1)-CREB-brain derived neurotrophic factor (BDNF) signaling pathway. In this study, we investigated the antidepressant-like effects of GLPG3970, a novel selective inhibitor of SIK2/3, in male C57BL/6J mice. Methods: Chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression were employed, combined with behavioral tests, virus-mediated gene transfer, Western blotting, co-immunoprecipitation, and immunofluorescence. Results: It was found that repeated administration of GLPG3970 significantly suppressed depressive-like behaviors in both CSDS and CUMS model mice, blocked stress-induced increases in hippocampal SIK2 expression and CRTC1 cytoplasmic translocation, and consequently restored the hippocampal BDNF signaling cascade and neurogenesis. More importantly, by using adeno-associated virus (AAV)-mediated overexpression of SIK2 or silencing of CRTC1/CREB/BDNF in the hippocampus, the antidepressant-like effects of GLPG3970 in mice were notably eliminated. Discussion: Collectively, these findings together demonstrate that the antidepressant-like actions of GLPG3970 in mice depend on the hippocampal SIK2-CRTC1-CREB-BDNF signaling pathway, highlighting its potential as a novel candidate for antidepressant therapy.
SN - 1663-9812
ER -