2. Academic Validation
  3. Tongmai Yishen Formula alleviates post-stroke depression by restoring neuronal homeostasis in the lateral habenula via the ITPKA signaling pathway

Tongmai Yishen Formula alleviates post-stroke depression by restoring neuronal homeostasis in the lateral habenula via the ITPKA signaling pathway

  • Phytomedicine. 2026 Jan 21:153:157866. doi: 10.1016/j.phymed.2026.157866.
Zhen-Ling Liu 1,  Yu Wang 2,  Feng-Xian Hu 1,  Huai-Qian Bo 1,  Tao Xu 3,  Zong-Yan Yin 4,  Kai-Xin Zhang 1,  Yi-Ran Wang 1,  Heng-Ye Zhao 1,  Xiang-Qing Xu 5,  Xiang-Dong Xu 6,  Wen-Qiang Cui 7
Affiliations

Affiliations

  • 1 First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
  • 2 Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China.
  • 3 Department of Traditional Chinese Medicine, Qingdao West Coast New Area People's Hospital, Qingdao, China.
  • 4 Department of Laboratory, Qingdao West Coast New Area People's Hospital, Qingdao, China.
  • 5 First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China; Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China. Electronic address: [email protected].
  • 6 Department of Traditional Chinese Medicine Innovation and Transformation Research Institute, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China. Electronic address: [email protected].
  • 7 First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China; Department of Neurology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China. Electronic address: [email protected].
PMID: 41655549 DOI: 10.1016/j.phymed.2026.157866
Abstract

Background: Post-stroke depression (PSD) is a common and debilitating complication of stroke, characterized by persistent abnormalities in neuronal excitability and synaptic plasticity. The lateral habenula (LHb) has emerged as a key regulatory hub in the pathophysiology of PSD. Tongmai Yishen Formula (TMYSF) has demonstrated clinical efficacy in alleviating PSD symptoms, yet its mechanism in restoring the excitability-plasticity balance remains unclear.

Purpose: We aimed to determine whether TMYSF alleviates PSD by modulating the inositol-trisphosphate 3-kinase A (ITPKA)-mediated beta isoform of calcium/calmodulin-dependent protein kinase II/extracellular signal-regulated kinase/cyclic adenosine monophosphate response element-binding protein (βCaMKII/ERK/CREB) signaling pathway and restoring neuronal homeostasis within the LHb.

Methods: A PSD rat model was established using middle cerebral artery occlusion/reperfusion (MCAO/R) combined with chronic unpredictable mild stress (CUMS). Behavioral assessments, electrophysiological recordings, molecular analyses, and gene interference techniques were employed to evaluate changes in neuronal excitability, synaptic plasticity, and the therapeutic effects of TMYSF.

Results: TMYSF treatment significantly alleviated depressive-like behaviors, reduced neuronal hyperexcitability, and restored synaptic ultrastructure. Mechanistically, TMYSF suppressed the ITPKA-dependent βCaMKII/ERK/CREB signaling cascade, thereby normalizing neuronal excitability and synaptic plasticity. Conversely, overexpression of ITPKA or βCaMKII abolished the antidepressant effects of TMYSF by maintaining pathway activation and disrupting neuronal homeostasis.

Conclusion: Dual dysregulation of neuronal excitability and synaptic plasticity in the LHb represents a core pathological feature of PSD. TMYSF exerts potent neuroprotective and antidepressant effects by targeting the ITPKA-βCaMKII/ERK/CREB signaling axis.

Keywords

ITPKA signaling pathway; Lateral habenula; Neuronal excitability; Post-stroke depression; Synaptic plasticity; Traditional Chinese medicine.

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