Antioxidants attenuate hyperglycaemia-mediated brain endothelial cell dysfunction and blood–brain barrier hyperpermeability

Article English OPEN
Allen, C.L. ; Bayraktutan, Ulvi (2009)

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.
  • References (12)
    12 references, page 1 of 2

    11. Ceriello A, dello Russo P, Amstad P, Cerutti P. High glucose induces antioxidant enzymes in human endothelial cells in culture. Evidence linking hyperglycemia and oxidative stress. Diabetes 1996; 45: 471-477.

    12. Traystman RJ, Moore LE, Helfaer MA et al. Nitro-L-arginine analogues. Dose- and time-related nitric oxide synthase inhibition in brain. Stroke 1995; 26: 864-869.

    13. Morikawa E, Moskowitz MA, Huang Z et al. L-arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat. Stroke 1994; 25: 429-435.

    14. Grau AJ, Weimar C, Buggle F et al. Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke 2001; 32: 2559-2566.

    15. Duckrow RB, Beard DC, Brennan RW. Regional cerebral blood flow decreases during hyperglycemia. Ann Neurol 1985; 17: 267-272.

    16. Bell DS. Stroke in the diabetic patient. Diabetes Care 1994; 17: 213-219.

    17. Hou ST, MacManus JP. Molecular mechanisms of cerebral ischemia-induced neuronal death. Int Rev Cytol 2002; 221: 93-148.

    18. Crack PJ, Taylor JM. Reactive oxygen species and the modulation of stroke. Free Radic Biol Med 2005; 38: 1433-1444.

    19. Guzik TJ, West NE, Black E et al. Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res 2000; 86: E85-90.

    20. Kusaka I, Kusaka G, Zhou C et al. Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. Am J Physiol Heart Circ Physiol 2004; 286: H2442-2451.

  • Metrics
    No metrics available
Share - Bookmark