Prunus cerasoides extract and its active ingredient prunetin ameliorate neurovascular glial unit dysfunction via Akt pathway in vascular dementia mice

• PCE and PN improve cognition, reduce mortality, and prevent brain atrophy in VaD. • PCE and PN protect white matter and NVGU by suppressing neuroinflammation. • PCE and PN show neuroprotection via Akt activation, promising for VaD therapy. Vascular dementia (VaD) is increasingly prevalent in aging populations. However, its effective treatment remains limited. Although Prunus cerasoides extract (PCE) exhibits neuroprotective properties, its role in VaD is unknown. To investigate the potential of PCE and its active ingredient, prunetin (PN), for cognitive improvement and neuroprotection against neurovascular glia unit (NVGU) dysfunction in a mouse model of VaD. A mouse model of chronic VaD was established by surgically performing asymmetric bilateral common carotid artery stenosis (ACAS), followed by administration of ethanolic PCE (100 mg/kg, PO) and PN (10 mg/kg, PO) for six weeks. Cognitive and behavioral changes were assessed using passive avoidance, elevated plus maze, and open field tests at 4 weeks. Brain damage was analyzed by Luxol-fast-blue, immunofluorescence, and immunoblotting at 6 weeks. PCE or PN improved cognitive performance, decreased mortality, reduced cerebral ventricular enlargement, preserved white matter integrity, reduced blood-brain barrier leakage, and upregulated tight junction proteins (ZO-1, occludin). Increased glial fibrillary acidic protein of astrocyte in VaD was significantly reduced by PCE and PN. Decreased phosphorylation of Akt in VaD was restored by PCE and PN. Similarly, in primary neurons exposed to oxygen-glucose deprivation, the decrease of Akt phosphorylation was restored by PCE and PN. However, such effects of PCE and PN were blocked by co-treatment with Triciribine, a Akt inhibitor PCE and PN could enhance cognition through their neuroprotective effects on NVGU in an ACAS model of VaD by upregulating the Akt pathway. These findings highlight their potential as promising therapeutic candidates for VaD treatment.