Prophylactic administration of Xuesaitong soft capsule ameliorating depression-like behaviors in rats after ischemic stroke by modulating metabolic disturbance

Abstract

Background: Post-stroke depression (PSD) exacerbates neurological disability, elevates suicide risk, and severely compromises survivors' quality of life and long-term prognosis. Current antidepressants exhibit suboptimal efficacy in PSD, underscoring an urgent need for targeted therapeutic strategies. Although Xuesaitong soft capsules (XST, total saponin preparations of Panax notoginseng (Burk.) F.H. Chen) are clinically used during stroke recovery period, their efficacy for PSD remains unclear. This study aims to explore the therapeutic potential of XST for PSD.

Methods: A translational PSD rat model was established by integrating middle cerebral artery occlusion with chronic psychosocial stress. Following preventative administration of XST, behavioral phenotyping (sucrose preference test [SPT], tail suspension test [TST], locomotor activity test), neurotransmitter analysis (hippocampal serotonin [5-HT], norepinephrine [NE], dopamine [DA], and cortical/serum glutamate), and longitudinal serum metabolomics were performed; mechanistic insights were further explored through network pharmacology.

Results: Prophylactic XST administration prevented depression-like behaviors in PSD rats, dose-dependently improving sucrose preference (0.3, 0.6, 1.2 g/kg; p < 0.05, p < 0.01, p < 0.01), locomotor activity (horizontal/vertical: 0.3, 0.6 g/kg; p < 0.05, p < 0.01), and reducing immobility time (0.6, 1.2 g/kg; p < 0.01, p < 0.05). Compared to citalopram, XST demonstrated superior therapeutic kinetics and functional recovery, achieving higher response/remission rates for anhedonia (85.7 %/79.3 % vs. 66.7 %/54.0 %) and hypoactivity (87.5 %/146.2 % vs. 16.7 %/21.0 %). XST exerted dual neuromodulatory effects through hippocampal monoamine potentiation (5-HT, NE, DA; p < 0.01, p < 0.05, p < 0.05) and cortical/serum glutamate suppression (p < 0.001). Temporal metabolomics revealed stage-specific metabolic reprogramming: early-phase sulfur metabolism modulation (p < 0.05) may address oxidative stress post-ischemia, while chronic-phase regulation of riboflavin, phenylalanine, and galactose pathways (p < 0.05) may correct ischemia-induced energy dysregulation. Network pharmacology identified monoamine oxidase A (MAOA) inhibition by ginsenosides Rh1/F5 and notoinsenoside R2 as a key mechanism, corroborated by enzymatic and protein analyses.

Conclusions: This study systematically deciphers XST's polypharmacology in PSD prevention, characterized by multi-target synergy (monoamine-glutamate axis), temporal metabolic adaptation, and MAOA-dependent mechanisms. Our findings propose a novel therapeutic strategy for PSD management, emphasizing early intervention and pathophysiological conditioning. XST emerges as a promising candidate for this paradigm, offering a potential step forward in PSD treatment.

Keywords: Blood metabolomics; Network pharmacology; Post-stroke depression; Preventive treatment; Xuesaitong soft capsule.