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Ginsenoside Rg1 alleviates chronic stress-induced depression in rats by targeting Cx43-YAP axis
Hui-Qin Wang1,2, Rui-Fang Zheng3, Qi-di Ai1
1School of Pharmacy, Hunan University of Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha, 410208, China.
Acta Pharmacologica Sinica
|March 7, 2025
Summary
Ginsenoside Rg1 (Rg1) shows antidepressant effects by restoring brain connectivity and reducing inflammation. It targets connexin43 (Cx43) to regulate the Hippo pathway effector YAP, offering a new therapeutic avenue for depression.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Existing antidepressants are ineffective for many patients.
- Ginsenoside Rg1 (Rg1) demonstrates antidepressant properties but requires mechanistic understanding.
- Previous work linked Rg1 to astrocytic connexin43 (Cx43) in depression models.
Purpose of the Study:
- To investigate the brain-wide effects and molecular mechanisms of Rg1 in chronic unpredictable stress (CUS)-induced depression in rats.
- To identify the specific molecular targets and pathways involved in Rg1's antidepressant action.
Main Methods:
- Rats were subjected to CUS and treated with Rg1 for 8 weeks.
- Multimodal neuroimaging (fMRI, PET/CT) assessed brain function and inflammation.
- Proteomic profiling, molecular docking, and surface plasmon resonance identified molecular targets.
- Investigated the role of Cx43 and Yes-associated protein (YAP) in Rg1's mechanism.
Main Results:
- Rg1 restored functional connectivity and reduced neuroinflammation in CUS rats, particularly in the prelimbic area.
- Rg1's primary target is Cx43-mediated gap junctions, modulating the Hippo pathway effector YAP.
- Rg1 enhanced Cx43-YAP interaction, inhibiting YAP nuclear translocation and gene expression related to inflammation.
- Cx43 degradation and YAP nuclear translocation were identified as potential depression mechanisms.
Conclusions:
- Rg1 exerts antidepressant effects by targeting Cx43-mediated gap junctions and regulating YAP.
- The Cx43-YAP interaction represents a novel molecular mechanism underlying Rg1's therapeutic action.
- Targeting the Cx43-YAP pathway holds potential for developing new antidepressant treatments.
