Abstract WP235: Hyperglycemia In The Days After Stroke Exacerbates Brain Injury By Increasing Microglial Superoxide Production

It has been recognized for decades that elevated blood glucose (hyperglycemia) during ischemia/reperfusion greatly exacerbates injury; however, little is known about the effect of hyperglycemia that begins later, over the hours to days after ischemia. This often occurs after stroke as part of a systemic stress response, even in non-diabetic patients, but neither clinical evidence nor prior basic science studies provide guidance on how post-stroke hyperglycemia should be managed. Here we investigated this issue using a mouse photothrombotic model of permanent ischemia. Normoglycemia or hyperglycemia (blood glucose of 300-400 mg/dL; 15-20 mM) was maintained between 17 - 48 hours after ischemia onset. Post-stroke hyperglycemia was found to increase the final infarct volume, increase hemorrhage formation, and exacerbate motor dysfunction. Hyperglycemia also increased superoxide formation in peri-lesional microglia/macrophages. Importantly, hyperglycemia did not have these deleterious effects in p47 phox-/- mice, which cannot form an active superoxide-producing NADPH oxidase-2 complex, or in wild-type mice treated with a peptide inhibitor of NADPH oxidase-2 (gp91-TAT peptide). These results suggest that hyperglycemia occurring many hours after ischemia can increase oxidative stress in peri-infarct tissues by fueling NADPH oxidase activity in reactive microglia/macrophages, and by this mechanism may contribute to worsened outcome.