Published online before print April 6, 2006, doi: 10.1161/01.STR.0000217389.55009.f8
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(Stroke. 2006;37:1288.)
© 2006 American Heart Association, Inc.
Original Contributions |
Why Does Acute Hyperglycemia Worsen the Outcome of Transient Focal Cerebral Ischemia?
Role of Corticosteroids, Inflammation, and Protein O-Glycosylation
From the Department of Pharmacology and Toxicology (A.M., S.R., A.M.P.), Institut d’Investigacions Biomèdiques de Barcelona (IIBB)-Consejo Superior de Investigaciones Científicas (CSIC), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; the Stroke Unit (A.C.), Institut de Malalties del Sistema Nerviós (IMSN), Hospital Clínic, IDIBAPS, Barcelona, Spain; the IDIBAPS (C.F.); Barcelona, Spain; the Servei de Diagnòstic per la Imatge (N.B.), Hospital Clínic, Barcelona, Spain.
Correspondence to Anna M. Planas, PhD, Department of Pharmacology and Toxicology, IIBB-CSIC, IDIBAPS, Rosselló 161, E-08036-Barcelona, Spain. E-mail ampfat{at}iibb.csic.es
Background and Purpose— 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.
Key Words: brain infarction • corticosteroids • glucose • metalloproteinases • neutrophils • rats
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