BRAIN CAPILLARY TISSUE-PLASMINOGEN ACTIVATOR IN A DIABETES STROKE MODEL

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 isc hemic brain injury. Methods Diabetes type 1 was induced by streptozoto cin for 7 days. Acute hyperglycemia was induced by 50% dextrose. Expre ssion of TPA in brain capillaries was determined by Western blot and r everse 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 neuropat hologic examinations were performed after 24 hours of reperfusion. Res ults All rats developed comparable hyperglycemia (approximate to 15 mm ol/L). A complete depletion of TPA protein and 6,5-fold decrease in TP A mRNA were found in brain capillaries of diabetic rats, in contrast t o normal TPA capillary levels in hyperglycemic rats. The blood flaw in the periphery of the ischemic core was significantly reduced during r eperfusion 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. Signif icant 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 ra ts relative to control and hyperglycemic rats, respectively. Conclusio ns Diabetes type 1, but net acute hyperglycemia, produces downregulati on of TPA in rat brain capillaries. This TPA reduction is associated w ith impaired restoration of blood flow after an ischemic insult, poor neurological outcome, and enhanced ischemic brain injury.