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We observed the effect of 2-deoxy-D-glucose (2-DG) on the brain tissue in rat cerebral ischemia-reperfusion (I/R) and explored its mechanism. After observing the effect of 2-DG on endoplasmic reticulum stress (ERS), rats were randomly divided into sham-operation group, I/R group and I/R+2-DG group (each group with 60 rats). I/R models were prepared by middle cerebral artery occlusion. In I/R+2-DG group, each rat was given intraperitoneal 2-DG of 100 mg/kg once a day for 7 days before brain ischemia. According to different time points (3h, 6h, 12h, 24h and 48h) after I/R, each group was divided into 5 subgroups (each subgroup with 12 rats). Nerve cell apoptosis, and the expressions of mRNA and protein of glucose regulated protein 78 (GRP78), cleaved-caspase-9 and cleaved-caspase-3 were determined with TUNEL, Western blotting and RT-PCR, respectively, in rat cerebral hippocampal CA1 area at each time point. TUNEL-positive cells were significantly less in I/R+2-DG group than in I/R group at each time point (all P<0.01). In I/R and I/R+2-DG groups, the expressions of mRNA and protein of GRP78 reached the maximum 12 h after I/R, and cleaved-caspase-9 and cleaved-caspase-3 reached the maximum 24 h after I/R. Compared with sham-operation group, the expressions of mRNA and protein of GRP78, cleaved-caspase-9 and cleaved-caspase-3 were all significantly increased (all P<0.01) in I/R and I/R+2-DG groups. However, the expressions of mRNA and protein of GRP78 were significantly higher in I/R+2-DG group than in I/R group (all P<0.05), but the expressions of mRNA and protein of cleaved-caspase-9 and cleaved-caspase-3 were all significantly lower in I/R+2-DG group than in I/R group (all P<0.05). We conclude that 2-DG has a neuroprotective effect on the brain tissue in rat cerebral ischemia-reperfusion models. The mechanism may be that 2-DG starts ERS followed by up-regulation of mRNA and protein of GRP78 and down-regulation of mRNA and protein of cleaved-caspase-9 and cleaved-caspase-3, which blocks the apoptotic pathway.