Skip to main content
Article thumbnail
Location of Repository

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

By C.L. Allen and Ulvi Bayraktutan


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

Publisher: Wiley InterScience
Year: 2009
OAI identifier:
Provided by: Nottingham ePrints

Suggested articles


  1. (1994). A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. doi
  2. (2002). Acetoacetate increases expression of intercellular adhesion molecule-1 (ICAM-1) in human brain microvascular endothelial cells. Neurosci Lett doi
  3. (2000). Activation of mitogen-activated protein kinases in gerbil hippocampus with ischemic tolerance induced by 3-nitropropionic acid. Neurosci Lett doi
  4. (1995). Activation of protein kinase C does not participate in disruption of the blood-brain barrier to albumin during acute hypertension. Brain Res doi
  5. (2002). Astrocyte-endothelial interactions and blood-brain barrier permeability.
  6. (2005). Augmented BH4 by gene transfer restores nitric oxide synthase function in hyperglycemic human endothelial cells. Cardiovasc Res
  7. (2003). Avci A et al. Pentose phosphate pathway, glutathione-dependent enzymes and antioxidant defense during oxidative stress in diabetic rodent brain and peripheral organs: effects of stobadine and vitamin E. Neurochem Res
  8. (2001). Biochemistry and molecular cell biology of diabetic complications.
  9. (1998). Constitutive nitric oxide synthase expression in retinal vascular endothelial cells is suppressed by high glucose and advanced glycation end products. Diabetes doi
  10. (2006). Decreased mortality by normalizing blood glucose after acute ischemic stroke. Acad Emerg Med doi
  11. (1995). Distribution and translocation of isoforms of protein kinase C in rat submandibular acinar cells. Life Sci doi
  12. (2002). Expression and adhesive properties of basement membrane proteins in cerebral capillary endothelial cell cultures. Cell Tissue Res doi
  13. (2002). Free radicals, diabetes and endothelial dysfunction. Diabetes Obes Metab
  14. (1997). High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation doi
  15. (2007). Hyperglycemia increases the levels of vascular cellular adhesion molecule-1 and monocyte-chemoattractant-protein-1 in the diabetic endothelial cell. Biochem Biophys Res Commun doi
  16. (2003). Increased brain injury and vascular leakage after pretreatment with p38-inhibitor SB203580 in transient ischemia. Acta Neurol Scand doi
  17. (2002). Increased superoxide and vascular dysfunction in CuZnSOD-deficient mice. Circ Res doi
  18. (2007). Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: relation to blood-brain barrier dysfunction. Stroke doi
  19. (2001). Inhibition of p38 mitogen-activated protein kinase provides neuroprotection in cerebral focal ischemia. Med Res Rev doi
  20. (2001). Intensive insulin therapy in the critically ill patients. doi
  21. (2000). Kinase pathways in chemoattractant-induced degranulation of neutrophils: the role of p38 mitogen-activated protein kinase activated by Src family kinases.
  22. (1996). Malignant' middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol
  23. (2002). Molecular mechanisms of cerebral ischemia-induced neuronal death. Int Rev Cytol
  24. (2005). NAD(P)H oxidases in rat basilar arterial endothelial cells. Stroke
  25. (2006). Neuroprotective effect of etomidate in the central nervous system of streptozotocin-induced diabetic rats. Neurochem Res doi
  26. (1989). Observations on the activity and immunologic properties of CuZnSOD of whole blood in cancer patients. Zhonghua Yi Xue Za Zhi
  27. (1992). Oxygen radicals in cerebral ischemia.
  28. (1992). Polyethylene glycol superoxide dismutase and catalase attenuate increased blood-brain barrier permeability after ischemia in piglets. Stroke doi
  29. (2002). Prereperfusion saline infusion into ischemic territory reduces inflammatory injury after transient middle cerebral artery occlusion in rats. Stroke doi
  30. (2005). Reactive oxygen species and the modulation of stroke. Free Radic Biol Med
  31. (1985). Regional cerebral blood flow decreases during hyperglycemia. Ann Neurol doi
  32. (2001). Risk factors, outcome, and treatment in subtypes of ischemic stroke: the German stroke data bank. Stroke doi
  33. (2004). Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury. doi
  34. (1998). Selective dysregulation of nitric oxide synthase type 3 in cardiac myocytes but not coronary microvascular endothelial cells of spontaneously hypertensive rat. Cardiovasc Res
  35. (2001). Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke
  36. (1994). Stroke in the diabetic patient. Diabetes Care doi
  37. (1992). Stroke topography and outcome in relation to hyperglycaemia and diabetes.
  38. (2002). The influence of diabetes mellitus and hyperglycaemia on stroke incidence and outcome.
  39. (2003). The influence of the extracellular matrix on the morphology and intracellular pH of cultured astrocytes exposed to media lacking bicarbonate. Neuroscience doi
  40. (2000). Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors. Circ Res doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.