Protective Effects of Antioxidant Polyphenols against Hyperglycemia‐Mediated Alterations in Cerebral Endothelial Cells and a Mouse Stroke Model

Abstract

Scope Hyperglycemia alters cerebral endothelial cell and blood‐brain barrier functions, aggravating cerebrovascular complications such as stroke during diabetes. Redox and inflammatory changes play a causal role. This study evaluates polyphenol protective effects in cerebral endothelial cells and a mouse stroke model during hyperglycemia. Methods and results Murine bEnd.3 cerebral endothelial cells and a mouse stroke model are exposed to a characterized, polyphenol‐rich extract of Antirhea borbonica or its predominant constituent caffeic acid, during hyperglycemia. Polyphenol effects on redox, inflammatory and vasoactive markers, infarct volume, and hemorrhagic transformation are determined. In vitro, polyphenols improve reactive oxygen species levels, Cu/Zn superoxide dismutase activity, and both NAPDH oxidase 4 and nuclear factor erythroid 2‐related factor 2 (Nrf2) gene expression deregulated by high glucose. Polyphenols reduce Nrf2 nuclear translocation and counteract nuclear factor‐ĸappa B activation, interleukin‐6 secretion, and the altered production of vasoactive markers mediated by high glucose. In vivo, polyphenols reduce cerebral infarct volume and hemorrhagic transformation aggravated by hyperglycemia. Polyphenols attenuate redox changes, increase vascular endothelial‐Cadherin production, and decrease neuro‐inflammation in the infarcted hemisphere. Conclusion Polyphenols protect against hyperglycemia‐mediated alterations in cerebral endothelial cells and a mouse stroke model. It is relevant to assess polyphenol benefits to improve cerebrovascular damages during diabetes.

Medicinal Plant Polyphenols Attenuate Oxidative Stress and Improve Inflammatory and Vasoactive Markers in Cerebral Endothelial Cells during Hyperglycemic Condition

“…This experimental hyperglycemic condition was mimicked by treating cells with a high glucose concentration (33 mM) after a glucose starvation related to normoglycemia (5.5 mM). Similar treatments with high glucose level were reported to mimic hyperglycemia in in vitro cellular models and led to demonstrate high glucose-caused redox and pro-inflammatory alterations that are associated with endothelial dysfunctions, such as altered permeability and reduced NO production [ 40 , 42 , 45 , 46 ]. Here, four characterized polyphenol-rich extracts from A. borbonica , A. triplinervis , D. viscosa , and T. bentzoe medicinal plants were assessed for their capacity to protect endothelial functions during hyperglycemic condition.…”

“…Our recent study conducted on a mouse stroke model co-exposed to hyperglycemia and A. borbonica plant polyphenols or pure caffeic acid, led to demonstrate the presence of caffeic acid and its circulating metabolite ferulic acid in the infarcted hemisphere. Moreover, we found that the capacity of polyphenols to decrease cerebral infarct volume and hemorrhagic transformation aggravated by hyperglycemia was associated with an improvement of the production of vascular endothelial-cadherin used as a BBB integrity marker, and with a reduction of neuroinflammation [ 40 ]. Further work will be needed in order to assess the gut absorption, metabolism, and ability of other medicinal plant polyphenols to target cerebrovascular cells in in vivo diabetic and ischemic conditions.…”

“…Murine bEnd3 cerebral endothelial cells were obtained from the American Type Culture Collection (ATCC ® CRL-2299™, Manassas, VA, USA) and cultured in Dulbecco’s Modified Eagle Medium (DMEM) containing 25 mM glucose, 10% heat-inactivated fetal bovine serum, 5 mM L-glutamine, 50 µU/mL penicillin, and 2 µg/mL streptomycin (Pan Biotech, Dutscher, Brumath, France). For the bEnd3-Blue cell line model, the bEnd3 cells were transfected with the plasmid pNiFty-secreted alkaline phosphatase (pNiFty2-SEAP, Invivogen, Toulouse, France) using lipofectamine 3000 (ThermoFischer Scientific, Les Ulis, France) and selection with Zeocin™ at 200 μg/mL (Invivogen, Toulouse, France) during three weeks, according to the previously published method [ 40 ]. pNiFty2-SEAP plasmid contains five specific NFκB repeated transcription factor binding sites, an endothelial cell-leukocyte adhesion molecule proximal promoter and a SEAP reporter gene.…”

“…Our previous studies demonstrated that polyphenolic extracts from medicinal plants, like Antirhea borbonica or Curcuma longa turmeric from Réunion Island, exert protective effects on adipose cells exposed to metabolic or bacterial stimuli inducing redox and inflammatory damages that are associated with insulin resistance markers [ 37 , 38 , 39 ]. Recently, we found that Antirhea borbonica polyphenols protect against hyperglycemia-mediated alterations in a mouse stroke model by reducing brain infarct volume and hemorrhagic transformation aggravated by hyperglycemia [ 40 ].…”

Caffeic Acid, One of the Major Phenolic Acids of the Medicinal Plant Antirhea borbonica, Reduces Renal Tubulointerstitial Fibrosis

“…More recent data obtained in vivo also highlight a preventive protective effect of A. borbonica aqueous extract in a zebrafish diet-induced overweight model in displaying cerebral oxidative stress and blood-brain barrier leakage [30], as well as in a mouse stroke model [31]. Registration at the French pharmacopeia supposes that the medicinal plants are devoid of toxic effects in humans.…”