Zingiberis Rhizoma Ethanol Extract Attenuates Recognition Memory Deficits and Neuroinflammation in a Mouse Model of Bilateral Common Carotid Artery Stenosis

Abstract

Chronic cerebral hypoperfusion (CCH), a key contributor to vascular dementia (VaD), causes white matter injury and neuroinflammation. We evaluated the neuroprotective effects of 6-gingerol-rich Zingiberis Rhizoma ethanol extract (ZRex) in a mouse bilateral common carotid artery stenosis (BCAS) model. BCAS-operated C57BL/6 mice received oral ZRex (30, 100, or 300 mg/kg, three times weekly). Spatial working memory, recognition memory, glial activation, oligodendrocyte and myelin markers, RNA sequencing (RNA-seq), and 6-gingerol molecular docking were evaluated. ZRex partially restored recognition memory in the novel object recognition test without altering Y-maze spatial working memory. BCAS significantly increased platelet-derived growth factor receptor alpha-positive cell counts, which ZRex restored toward sham levels. ZRex also markedly attenuated cluster of differentiation 68 immunoreactivity. RNA-seq identified 479 BCAS-responsive candidate genes (fold-change-filtered) and demonstrated that ZRex selectively restored downregulated transcripts. Molecular docking revealed the strongest predicted binding of 6-gingerol to Mup19 (Vina score: −9.4 kcal/mol), followed by Serpina3, Saa2, Mup1, and F10. Overall, ZRex attenuated BCAS-induced recognition memory deficits and neuroinflammation by modulating metabolic and inflammatory pathways, potentially mediated by direct 6-gingerol interactions with candidate targets. These findings support ZRex as a promising botanical candidate for VaD.