Abstract
Hyperglycemia alters the function of cerebral endothelial cells from the blood-brain barrier, increasing the risk of cerebrovascular complications during diabetes. This study evaluated the protective effect of polyphenols on inflammatory and permeability markers on bEnd3 cerebral endothelial cells exposed to high glucose concentration. Results show that hyperglycemic condition increased nuclear factor kappa B (NFκB) activity, deregulated the expression of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-10 (IL-10) and endothelial-leukocyte adhesion molecule (E-selectin) genes, raised MCP-1 secretion and elevated monocyte adhesion and transendothelial migration. High glucose decreased occludin, claudin-5, zona occludens-1 (ZO-1) and zona occludens-2 (ZO-2) tight junctions production and altered the endothelial permeability. Characterized polyphenolic extracts from the French medicinal plants Antirhea borbonica, Ayapana triplinervis, Dodonaea viscosa and Terminalia bentzoe, and their major polyphenols quercetin, caffeic, chlorogenic and gallic acids limited the pro-inflammatory and permeability alterations caused by high glucose. Peroxisome proliferator-activated receptor gamma (PPARγ) agonist also attenuated these damages while PPARγ antagonist aggravated them, suggesting PPARγ protective action. Interestingly, polyphenols improved PPARγ gene expression lowered by high glucose. Moreover, polyphenols were detected at the intracellular level or membrane-bound to cells, with evidence for breast cancer resistance protein (BCRP) efflux transporter role. Altogether, these findings emphasize the ability of polyphenols to protect cerebral endothelial cells in hyperglycemic condition and their relevance for pharmacological strategies aiming to limit cerebrovascular disorders in diabetes.
Highlights
This study demonstrates the protective effect of polyphenol-rich extracts from four
French medicinal plants as well as quercetin, caffeic, chlorogenic and gallic acids on cerebral endothelial cells exposed to an experimental hyperglycemia
Polyphenols attenuated proinflammatory and permeability alterations, decreased monocyte recruitment and improved the deregulation of NFκB/PPARγ pathways caused by hyperglycemic condition
Summary
Zona occludens-2 (ZO-2) are important for connecting transmembrane proteins with the cytoskeleton at the intracellular level These multiprotein junctional complexes are essential to regulate paracellular permeability in order to maintain BBB tightness, and their production is strictly regulated via signaling pathways involving key transcriptional factors such as the nuclear factor kappa B (NFκB) and the peroxisome proliferator-activated receptor gamma (PPARγ) [3,4,5,6,7]. Cerebral endothelial cells express various families of drug efflux transport proteins and two major efflux transporters which are the P-glycoprotein (Pgp) and the breast cancer resistance protein (BCRP) that restrict substances penetrating the brain [8] These extra- and intracellular components limit permeability to low molecular mass molecules and increase barrier electrical resistance. Pro-inflammatory cytokine secretion leads to a reduction in
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