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(Stroke. 1996;27:712-719.)
© 1996 American Heart Association, Inc.

Articles

Brain Capillary Tissue Plasminogen Activator in a Diabetes Stroke Model

Mamoru Kittaka, MD; Liang Wang, MD; Ning Sun, MS; Steven S. Schreiber, MD; Nicholas W. Seeds, PhD; Mark Fisher, MD Berislav V. Zlokovic, MD, PhD

From the Departments of Neurosurgery (M.K., L.W., B.V.Z.) and Neurology (N.S., S.S.S., M.F.) and Division of Neurosurgery, Children's Hospital (B.V.Z.), University of Southern California School of Medicine, Los Angeles, and the Neuroscience Center, University of Colorado, Health Sciences Center (N.W.S.), Denver, Colo.

Background and Purpose Tissue plasminogen activator (TPA) is normally expressed in rat brain capillaries. This study examines the expression of TPA in brain capillaries of diabetic rats in relation to focal ischemic brain injury.

Methods Diabetes type 1 was induced by streptozotocin for 7 days. Acute hyperglycemia was induced by 50% dextrose. Expression of TPA in brain capillaries was determined by Western blot and reverse transcription-polymerase chain reaction analyses. Focal stroke was produced by 1 hour of reversible middle cerebral artery occlusion. Physiological variables and cerebral blood flow were monitored during occlusion and within 1 hour of reperfusion. Neurological and neuropathologic examinations were performed after 24 hours of reperfusion.

Results All rats developed comparable hyperglycemia (15 mmol/L). A complete depletion of TPA protein and 6.5-fold decrease in TPA mRNA were found in brain capillaries of diabetic rats, in contrast to normal TPA capillary levels in hyperglycemic rats. The blood flow in the periphery of the ischemic core was significantly reduced during reperfusion by 52% to 62% (P<.001) in diabetic rats and by 23% to 25% (P<.05) in hyperglycemic rats. The neurological score was worsened by 3.2-fold (P<.0003) by diabetes and by 24% by hyperglycemia only. Significant 41% (P<.007) and 29% (P<.05) increases in infarct volume and 163% (P<.007) and 60% increases in edema volume were found in diabetic rats relative to control and hyperglycemic rats, respectively.

Conclusions Diabetes type 1, but not acute hyperglycemia, produces downregulation of TPA in rat brain capillaries. This TPA reduction is associated with impaired restoration of blood flow after an ischemic insult, poor neurological outcome, and enhanced ischemic brain injury.

Key Words: cerebral blood flow • cerebral ischemia • diabetes mellitus • hyperglycemia • tissue plasminogen • rats

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