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Blood-brain barrier endothelial cells are the main targets of diabetes-related hyperglycemia that alters endothelial functions and brain homeostasis. Hyperglycemia-mediated oxidative stress may play a causal role. This study evaluated the protective effects of characterized polyphenol-rich medicinal plant extracts on redox, inflammatory and vasoactive markers on murine bEnd3 cerebral endothelial cells exposed to high glucose concentration. The results show that hyperglycemic condition promoted oxidative stress through increased reactive oxygen species (ROS) levels, deregulated antioxidant superoxide dismutase (SOD) activity, and altered expression of genes encoding Cu/ZnSOD, MnSOD, catalase, glutathione peroxidase (GPx), heme oxygenase-1 (HO-1), NADPH oxidase 4 (Nox4), and nuclear factor erythroid 2-related factor 2 (Nrf2) redox factors. Cell preconditioning with inhibitors of signaling pathways highlights a causal role of nuclear factor kappa B (NFκB), while a protective action of AMP-activated protein kinase (AMPK) on redox changes. The hyperglycemic condition induced a pro-inflammatory response by elevating NFκB gene expression and interleukin-6 (IL-6) secretion, and deregulated the production of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS), and nitric oxide (NO) vasoactive markers. Importantly, polyphenolic extracts from Antirhea borbonica, Ayapana triplinervis, Dodonaea viscosa, and Terminalia bentzoe French medicinal plants, counteracted high glucose deleterious effects by exhibiting antioxidant and anti-inflammatory properties. In an innovative way, quercetin, caffeic, chlorogenic and gallic acids identified as predominant plant polyphenols, and six related circulating metabolites were found to exert similar benefits. Collectively, these findings demonstrate polyphenol protective action on cerebral endothelial cells during hyperglycemic condition.