Acute hyperglycemia induces NETosis and futile recanalization after ischemic stroke via RAGE/DIAPH1 pathway

Acute hyperglycemia significantly exacerbates cerebral ischemia‒reperfusion injury and worsens clinical outcomes. Notably, insulin-based hypoglycemic therapy during the perioperative period of recanalization does not have a clear protective effect, suggesting that the underlying mechanisms are complex and require further investigation. In this study, we established a middle cerebral artery occlusion/reperfusion (MCAO/r) mouse model and induced acute hyperglycemia via intraperitoneal injection of 50% glucose solution before surgery. Blood glucose levels in acute hyperglycemic MCAO/r mice spontaneously returned to normal within 3 h. Nevertheless, 24 h after reperfusion, acute hyperglycemia significantly promoted the formation of neutrophil extracellular traps (NETs) via the receptor for advanced glycation end products (RAGE)/diaphanous-1 (DIAPH1) signaling axis, thereby exacerbating microvascular obstruction and brain injury following ischemic stroke. Intervention with FPS-ZM1 (N-benzyl-4-chloro-N-cyclohexylbenzamide) or deoxyribonuclease I (DNase I) significantly alleviated these pathological features. These data provide novel mechanistic insights into this pathological process and suggest a potential therapeutic strategy for improving outcomes in stroke patients at risk of futile recanalization.