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Background Activation of N-methyl-D-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors play an important role in the neurons death induced by ischemia.The mitigating effect of intravenous anesthetics on ischemic neuron injury is related to their influence on NMDA receptors. This study was performed to investigate the effect of ketamine-midazolam anesthesia on the NMDA and AMPA receptor subunits expression in the peri-infarction of ischemic rat brain and explore its potential mechanism of neuroprotection.This study was supported by National Natural Science Foundation of China (NSFC) (No.30200291).Methods Thirty Sprague Dawley (SD) rats were subjected to permanent middle cerebral artery occlusion under ketamine/atropine (100/0.05 mg/kg) or ketamine-midazolam/atropine (60/50/0.05 mg/kg) intraperitoneal anesthesia (n=15 each). Twenty-four hours after ischemia, five rats in each group were killed by injecting the above dosage of ketamine or ketamine-midazolam intraperitoneally and infarct size was measured. Twenty-four and 72 hours after ischemia, four rats in each group were killed by injecting the above dosage of ketamine or ketamine-midazolam intraperitoneally. After staining the brain tissue slices with toluidine blue, the survived neurons in the peri-infarction were observed. Also, the expression level of NMDA receptors 1 (NR1), NMDA receptors 2A (NR2A), NMDA receptors 2B (NR2B) and AMPA (GluR1 subunit) were determined by grayscale analysis in immunohistochemical stained slices.Results Compared with ketamine anesthesia, ketamine-midazolam anesthesia produced not only smaller infarct size [(24.1±4.6)% vs (38.4±4.2)%, P＜0.05], but also higher neuron density (24 hours: 846± 16 vs 756±24,P＜0.05; 72 hours: 882±22 vs 785± 18, P＜0.05) and lower NR2A (24 hours: 123.0±4.9 vs 95.0±2.5, P＜0.05; 72 hours: 77.8±4.1 vs 54.2±3.9, P＜0.05) and NR2B (24 hours: 98.5±2.7 vs 76.3±2.4, P＜0.05; 72hours: 67.2 ± 7.5 vs 22.2 ± 2.6, P＜0.05) expression level in the peri-infarction following ischemia.Conclusion The protective effects of ketamine-midazolam anesthesia on ischemic brain injury may relate to decreasing NR2A and NR2B expression.