title: Why does acute hyperglycemia worsen the outcome of transient focal cerebral ischemia? Role of corticosteroids, inflammation, and protein O-glycosylation.
abstract: OBJECTIVE
  Hyperglycemia adversely affects the outcome of stroke. Global ischemia data support that the harmful effect of hyperglycemia is mediated by glucose-induced elevated plasma glucocorticoids. Here we sought to evaluate the negative effects of hyperglycemia on transient focal ischemia in the rat, and to test whether these could be prevented by inhibition of either corticosteroid production or neutrophil infiltration.
  
  
  METHODS
  Sprague-Dawley rats (n=217) were used. Ischemia was induced by 1 hour middle cerebral artery occlusion (n=196). Acute hyperglycemia was induced by IP injection of dextrose 30 minutes before ischemia. Neutrophil infiltration was blocked by neutropenia with vinblastine. Corticosterone synthesis was inhibited by chemical adrenalectomy with metyrapone. We measured MRI lesion and tissue infarct volumes, evaluated the neurological function, brain myeloperoxidase and matrix metalloproteinase-9 activities, and protein O-glycosylation.
  
  
  RESULTS
  Hyperglycemia significantly enhanced MRI diffusion-weighted imaging alterations, increased cortical, but not subcortical, infarct volume, worsened neurological score, and enhanced brain myeloperoxidase and matrix metalloproteinase-9 activities. Metyrapone did not prevent hyperglycemic brain damage despite successful reduction of plasma corticosterone. Yet, metyrapone tended to reduce cortical infarction and apparent diffusion coefficient lesion volume, indicating some negative contribution of corticosterone. Blocking neutrophil infiltration was also ineffective to prevent the harmful effect of hyperglycemia. A new finding was that O-linked glycosylation of cerebral proteins was increased under hyperglycemia.
  
  
  CONCLUSIONS
  In transient middle cerebral artery occlusion, the hyperglycemia-exacerbated brain damage cannot be fully explained by the negative effects of plasma corticosteroids or neutrophil infiltration. The contribution of other intrinsic effects of high glucose, such as brain protein O-glycosylation, deserves further investigation.
authors.affiliation: Department of Pharmacology and Toxicology, Institut d'Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones Científicas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barrcelona, Spain.
authors.forename: Abraham
authors.initials: A
authors.lastname: Martín
authors.forename: Santiago
authors.initials: S
authors.lastname: Rojas
authors.forename: Angel
authors.initials: A
authors.lastname: Chamorro
authors.forename: Carles
authors.initials: C
authors.lastname: Falcón
authors.forename: Núria
authors.initials: N
authors.lastname: Bargalló
authors.forename: Anna M
authors.initials: AM
authors.lastname: Planas
mesh_terms: D000305:Adrenal Cortex Hormones / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D018450:Disease Progression; D006031:Glycosylation; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology*; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000503:physiopathology*; D007249:Inflammation; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced / Q000503:physiopathology; D009504:Neutrophils / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014747:Vinblastine / Q000633:toxicity
chemical_list: D000305:Adrenal Cortex Hormones; D000963:Antimetabolites; D009419:Nerve Tissue Proteins; D014747:Vinblastine; D008797:Metyrapone