Objective  To investigate the molecular mechanism of hyperglycemia on brain damage caused by ischemia.   Methods  Sixty-five male SD rats were divided into normoglycemia+ischemia group (n=20)

diabetes+ischemia group (n=20)

diabetes+ischemia+U0126 group (n=20) and normal control (n=5). Streptozotocin (60 mg/kg) was injected through vena caudalis to induce diabetes. The global cerebral ischemia was made by ligating bilateral common carotid arteries for 30 min and reperfusing for 1

3

or 6 h. ERK inhibitor U0126 (4 g/kg) was injected through vena caudalis 30 min before ischemia

while normal saline was as substitute in other groups. The phosphorylation of ERK1/2 expression and neuronal apoptosis were studied by TUNEL

immunohistochemistry and Western blot.   Results  Increased phospho-ERK1/2 immunoreactive neurons in the cingulate cortex and hippocampal CA3 were detected in euglycemia+ischemia group. The number of phospho-ERK1/2 positive and apoptotic neurons was much more in diabetes+ischemia group than normoglycemia+ischemia group (P0.05). Pretreatment with U0126 in diabetes+ischemia group significantly decreased ERK1/2 immunoreactive cells and apoptotic neurons. Western blot analysis confirmed that phospho-ERK1/2 increased significantly after ischemia and reperfusion as compared to normal controls. The amount of phospho-ERK1/2 was obviously increased after 3-hour or 6-hour reperfusion in diabetes+ischemia group in comparison with normoglycemia+ischemia group (P0.05). Treatment with U0126 significantly reduced phospho-ERK1/2 in the diabetic rats.   Conclusion  ERK1/2 may play a role in mediating the apoptosis of neuronal cells under hyperglycemic condition.