Isoschaftoside improves white matter injury via TREM2-mediated phagocytosis and anti-inflammatory effects.

BACKGROUND: Ischemic white matter injury (WMI) is a core pathological mechanism underlying vascular cognitive impairment, for which effective clinical interventions are currently lacking. The natural flavonoid glycoside Isoschaftoside (ISO) has been reported to exhibit various pharmacological activities, but its effects and mechanisms on ischemic WMI remain unclear. METHODS: A mouse model of bilateral carotid artery stenosis (BCAS) was used to induce chronic ischemic white matter injury. ISO (5, 10, 20 mg/kg/day) was administered intraperitoneally for 28 days. Cognitive function was assessed using the Morris water maze, novel object recognition, and Y-maze tests. White matter injury was evaluated by Myelin Basic Protein (MBP) staining, Luxol Fast Blue (LFB) staining, transmission electron microscopy, and detection of MBP, myelin associated glycoprotein (MAG), and Proteolipid Protein 1 (PLP1) protein expression. Methods including qPCR, Western blot, immunofluorescence, flow cytometry, and transcriptome sequencing were employed to examine microglial phenotype, phagocytic capacity, and related signaling pathway molecules to explore the mechanism by which ISO ameliorates WMI. RESULTS: ISO dose-dependently improved cognitive function and attenuated demyelination in white matter regions of BCAS mice. Mechanistic studies revealed that ISO upregulated triggering receptor expressed on myeloid cells 2 (TREM2) expression, activated downstream spleen tyrosine kinase (SYK) phosphorylation, and enhanced the phagocytic clearance of myelin debris by microglia. Concurrently, ISO inhibited the phosphorylation of the PI3K/Akt/mTOR signaling pathway, reducing microglial activation and the release of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, iNOS). Following TREM2 functional blockade, the beneficial effects of ISO on cognitive improvement, myelin protection, microglial phagocytosis, and anti-inflammatory actions in BCAS mice were significantly attenuated or reversed. CONCLUSIONS: ISO upregulates TREM2 to enhance microglial phagocytosis and suppress neuroinflammation, thereby ameliorating chronic ischemic white matter injury and cognitive impairment. This study provides experimental evidence supporting ISO as a potential therapeutic agent for vascular cognitive impairment.