Aims: Hyperglycaemia (HG), in stroke patients, is associated with worse neurological outcome by compromising endothelial cell function and the blood–brain barrier (BBB) integrity. We have studied the contribution of HG-mediated\ud generation of oxidative stress to these pathologies and examined whether antioxidants as well as normalization of\ud glucose levels following hyperglycaemic insult reverse these phenomena.\ud \ud Methods: Human brain microvascular endothelial cell (HBMEC) and human astrocyte co-cultures were used to simulate\ud the human BBB. The integrity of the BBB was measured by transendothelial electrical resistance using STX\ud electrodes and an EVOM resistance meter, while enzyme activities were measured by specific spectrophotometric\ud assays.\ud \ud Results: After 5 days of hyperglycaemic insult, there was a significant increase in BBB permeability that was reversed\ud by glucose normalization. Co-treatment of cells with HG and a number of antioxidants including vitamin C, free radical\ud scavengers and antioxidant enzymes including catalase and superoxide dismutase mimetics attenuated the detrimental\ud effects of HG. Inhibition of p38 mitogen-activated protein kinase (p38MAPK) and protein kinase C but not\ud phosphoinositide 3 kinase (PI3 kinase) also reversed HG-induced BBB hyperpermeability. In HBMEC, HG enhanced\ud pro-oxidant (NAD(P)H oxidase) enzyme activity and expression that were normalized by reverting to normoglycaemia.\ud \ud Conclusions: HG impairs brain microvascular endothelial function through involvements of oxidative stress and\ud several signal transduction pathways
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