Exploring the intervention mechanism of Acori Tatarinowii Rhizoma-Polygalae Radix herb pair on post-stroke depression...

The herb pair of Acori Tatarinowii Rhizoma (Shi Chang Pu) and Polygalae Radix (Yuan Zhi) is a classic combination in Traditional Chinese Medicine for "opening the orifices to revive the mind, and relieving depression to calm the spirit". Acori Tatarinowii Rhizoma-Polygalae Radix Herb Pair (APHP) has been widely used in treating post-stroke depression (PSD) and has shown promising results. However, its underlying combined mechanism of action remains unclear.

This study is aimed to evaluate the therapeutic effect of APHP on PSD and elucidate its mechanism through transcriptome and metabolomic approaches.

A PSD rat model was developed using middle cerebral artery occlusion (MCAO) coupled with chronic unpredictable mild stress (CUMS). Subsequently, the therapeutic efficacy of APHP on PSD were assessed through behavioral experiments, hematoxylin-eosin (HE) staining, Nissl staining, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. Then a systematic study was conducted on its mechanism using network pharmacology, transcriptomics and metabolomics.

APHP effectively alleviated depressive-like behaviors and restrained neuroinflammation in PSD rats. Specifically, APHP reversed anhedonia and despair-like states, ameliorated pathological brain damage and neuronal loss, inhibited inflammation, and regulated neurotransmitter levels. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis and network pharmacology indicated that kaempferol and α-Asarone might be the effective candidate ingredients ameliorating PSD via the modulation of inflammatory signaling pathways. Transcriptomic analysis revealed that compared to the model group, there were 80 genes upregulated and 167 genes downregulated in the APHP group. Metabolomic analysis identified upregulation of theobromine and 3-methylxanthine in the model group, which were downregulated following APHP treatment. Further analyses suggested that APHP may regulate the inflammatory response via the PI3K/AKT/NF-κB signaling pathway, inhibit the gene expression of CCL4 and IL-1 β in brain tissue, ameliorate metabolic disorders, and modulate the caffeine metabolism pathway, thereby exerting a protective effect.

APHP exhibited significant anti-PSD effects, potentially improving depressive symptoms and alleviating neuroinflammation by regulating the PI3K/AKT/NF-κB signaling cascade and modulating the caffeine metabolism pathway. This research establishes a solid basis for the clinical use of APHP in PSD management and paves the way for developing safer and more effective drugs derived from this herb pair.