Work

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

Year: 2026

Type: article

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.

Source: Phytomedicine

DOI: 10.1016/j.phymed.2026.157866