Hyperglycemic Transient Ischemia Induces Massive Neutrophil Deposition in Brain.

P80 Acute hyperglycemia worsens neurological signs and accentuates neuropathology after ischemia, but the mechanisms are poorly understood. In this study, we tested whether polymorphonuclear leukocytes (neutrophils) might be contributory. Anesthetized, physiologically monitored Wistar rats underwent global forebrain ischemia for 12.5 min by bilateral carotid artery occlusions plus hypotension (45 mm Hg). To induce hyperglycemia, rats received 2.5 ml of 25% dextrose i.p. 30 min prior to ischemia. Normoglycemic rats received saline. Plasma glucose levels were 340±66 and 133 ±21 mg/dl, respectively (mean±SD). Animals were sacrificed at either 24 h or 3 days by perfusion-fixation with FAM. Brain sections were reacted for the immunohistochemical visualization of myeloperoxidase (MPO), a specific and quantitative marker of neutrophil activity in the brain. In sham rats and in normoglycemic-ischemic animals, almost no MPO-positive cells were identified. In marked contrast, brains of hyperglycemic-ischemic rats studied at 24 h contained dramatic accumulations of MPO-positive cells within pial and parenchymal blood vessels as well as within cortical and subcortical parenchyma. MPO-positivity was most robust in areas of severe injury (on H&E sections), but MPO cells were also observed in areas without overt injury. Intravascular MPO-positive cells commonly obstructed the vascular lumen. Following 3-d survival, MPO-positivity of hyperglycemic-ischemic brains had significantly decreased. In hyperglycemic brains studied at 24 h, median numbers of MPO-positive cells were increased by 130-fold in cortex and 110-fold in striatum above values in normoglycemic-ischemic rats. In summary, this study shows that preischemic hyperglycemia triggers the early and dramatic deposition of polymorphonuclear leukocytes in the postischemic brain, with neutrophil adherence to cerebral blood vessels and their migration into brain parenchyma following brief forebrain ischemia. These events may contribute to the enhanced tissue destruction, extension of infarction, and BBB disruption observed in hyperglycemic ischemia. Supported by NIH Grant NS05820.