2. Academic Validation
  3. Verbascoside reverses GABAergic deficits in the prefrontal cortex to alleviate chronic Stress-Induced depression

Verbascoside reverses GABAergic deficits in the prefrontal cortex to alleviate chronic Stress-Induced depression

  • Psychopharmacology (Berl). 2025 Sep 12. doi: 10.1007/s00213-025-06894-9.
Jin Pan # 1,  Liuxuan Huang # 2,  Peng Sun # 3,  Haoquan Tian 2,  Wenguang Yang 2,  Xinyu Fang 2,  Feng Li 4 5 6,  Ke Ma 7
Affiliations

Affiliations

  • 1 The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
  • 2 Shandong Co-Innovation Center of Classic Traditional Chinese Medicine Formula, Shandong University of Traditional Chinese Medicine, 4655 Daxue Road, Changqing District, Jinan, 250355, China.
  • 3 Innovation Research Institute of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
  • 4 Department of pancreatic Surgery, general surgery, Qi Lu Hospital of Shandong University, Jinan, 250012, China. 201062000137@sdu.edu.cn.
  • 5 Department of Gastroentero-pancreatic surgery, Cheeloo College of Medicine, Qilu Hospital (Qingdao), Shandong University, No.758, Hefei Road, Qingdao, 266035, Shandong, China. 201062000137@sdu.edu.cn.
  • 6 Department of pancreatic Surgery, general surgery, Department of Gastroentero-pancreatic surgery, Cheeloo College of Medicine, Qi Lu Hospital of Shandong University, Qilu Hospital (Qingdao), Shandong University, No.758, Hefei Road, Qingdao, 266035, Shandong, China. 201062000137@sdu.edu.cn.
  • 7 Shandong Co-Innovation Center of Classic Traditional Chinese Medicine Formula, Shandong University of Traditional Chinese Medicine, 4655 Daxue Road, Changqing District, Jinan, 250355, China. make@sdutcm.edu.cn.
  • # Contributed equally.
PMID: 40938419 DOI: 10.1007/s00213-025-06894-9
Abstract

Background: The dysregulation of prefrontal synaptic transmission accompanied by γ-aminobutyric acid (GABA) deficit, is crucial in depression. Previously, we have demonstrated that Baihe Dihuang decoction with verbascoside (VB) as one of the main active ingredients attenuates prefrontal interneurons deficits through synthesis and release of GABA negatively regulated by miR-144-3p, but the potential mechanism through which VB reverses the dysfunction of stress-induced aberrant prefrontal GABAergic neurons through miRNAs/Gad-67/VGAT signaling remains elusive.

Methods: The antidepressant effects and neuroprotective function of VB were observed by a chronic stress-induced depression and corticosterone (CORT)-stimulated nerve cell injury model, respectively. Specific changes in prefrontal GABAergic miR-144-3p expression were used to assess the action of VB acting on GABA release.

Results: High-expression prefrontal miR-144-3p was associated with depression-like behaviors caused by long time stress, reflected by altered GABA tone. Supplementation with VB attenuated chronic stress-induced prefrontal cortex neuron injury and prefrontal GABAergic deficit by downregulating miR-144-3p expression, as well as obviously improved the relative abundance of beneficial GABA-producing bacteria. However, antidepressant-like effects by VB were antagonized by overexpressed miR-144-3p in frontal cortex GABAergic neurons. Similarly, VB administration caused reduced expression of miR-144-3p against impaired GABA production. In the CORT-induced nerve cell injury model, The pharmacological effect of VB promoting GABA release ability and exerting neuroprotection is strongly reversed by overexpression of miR-144-3p.

Conclusion: This study elucidated that miR-144-3p down-regulated GABAergic neurons activation in the medial prefrontal cortex was sufficient and necessary for VB antidepressant responses.

Keywords

Depression; GABA deficits; Neuroprotection; Prefrontal cortex; Verbascoside.

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