Diankuang Mengxing Decoction exerts neuroprotective effects in post-stroke depression by mediating the activation of the Wnt/β-catenin pathway via TREM2

Ethnopharmacological relevance: Post-stroke depression (PSD) is a mood disorder that occurs subsequent to a stroke and is typified by a depressed mood and loss of interest. A traditional Chinese medicine (TCM) preparation, Diankuang Mengxing Decoction (DKMX), has demonstrated the potential to mitigate PSD in rats. However, the precise mechanism of action of this herbal preparation in the context of PSD remains to be elucidated.

Aim of study: This study aims to evaluate the therapeutic efficacy of DKMX extract in a rat model of PSD and its regulation of the TREM2/Wnt/β-catenin pathway.

Materials and methods: The high-performance liquid chromatography-ultraviolet (HPLC-UV) method was employed to quantify the active ingredients in DKMX extract. Following the establishment of the PSD rat model, a series of neurological function and depression-like behavior tests were conducted to evaluate the multifaceted therapeutic effects of DKMX extract, including its potential to alleviate depression-like symptoms, improve neurological function, regulate neuroinflammation, and promote neurogenesis. 3,5,37-Triphenyl tetrazolium chloride staining (TTC) was used to evaluate the extent of brain tissue damage. Nissl staining was used to visualise the morphological structure of nerve cells. Interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were detected via enzyme-linked immunosorbent assay (ELISA). The expression levels of microglia-specific markers Ionized Calcium Binding Adaptor Molecule 1 (Iba1) and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) were quantified by immunofluorescence staining, and alterations in hippocampal DCX expression were observed to assess the impact on neuroinflammation and nerve regeneration. Golgi staining was employed to facilitate the visualisation of dendritic spine density in neurons within the hippocampus. Western blot (WB) analysis was employed to detect the protein expression levels of glycogen synthase kinase-3β (GSK3β), p-GSK3β, Wnt family member 3a (Wnt3a), β-catenin and p-β-catenin in the hippocampus.

Results: The treatment with DKMX significantly improved behavioral and neurological outcomes in PSD rats by reducing cortical infarct volume, Longa score, and FST immobility time. Additionally, DKMX enhanced sucrose preference in the SPT. DKMX also attenuated neuroinflammation and promoted hippocampal neurogenesis in PSD rats. DKMX modulated TREM2 expression in microglia and activated the Wnt/β-catenin pathway to exert antidepressant and anti-neuroinflammatory effects.

Conclusions: The results of our study indicate that DKMX extracts exert their anti-neuroinflammatory effects primarily through the TREM2/Wnt/β-catenin pathway, thereby alleviating symptoms and enhancing functional outcomes in rats with PSD.

DKMX; PSD; TREM2; Wnt/β-catenin.