Previous studies have demonstrated that increased O-linked
N-acetylglucosamine (O-GlcNAc) level could promote cell survival following environmental stresses. This study aimed to explore the role of
O-GlcNAc transferase (OGT) during
cerebral ischemia/reperfusion (I/R) injury. The mouse model with cerebral I/R injury was induced by
middle cerebral artery occlusion/reperfusion (MCAO/R). The expression of ogt in brain tissues was detected by qRT-PCR, Western blot, and immunohistochemistry (IHC) staining assay. Neurological deficit was evaluated using a modified scoring system. The
infarct volume was assessed by TTC staining assay. Neuronal apoptosis in brain tissues was evaluated by TUNEL staining assay. The level of cleaved
caspase-3 in brain tissues was detected by Western blot and IHC staining assay. The expression of critical
proteins involved in mitochondrial fission, including OPA1, Mfn1, and Mfn2, as well as Mff and Drp1 was detected by Western blot and IHC, respectively. The expression of ogt during cerebral I/R injury was significantly upregulated. Ogt knockdown significantly increased neurological score and
infarct volume in I/R-induced mice. Meanwhile, ogt knockdown significantly enhanced neuronal apoptosis and cleaved
caspase-3 level in brain tissues of I/R-induced mice. In addition, ogt knockdown markedly decreased
serine 637 phosphorylation level of mitochondrial fission
protein dynamin-related
protein 1 (Drp1) and promoted Drp1 translocation from the cytosol to the mitochondria. Moreover, the specific Drp1 inhibitor
mdivi-1 effectively attenuated ogt knockdown-induced
brain injury of I/R-stimulated mice in vivo. Our study revealed that OGT protects against cerebral I/R injury by inhibiting the function of Drp1 in mice, suggesting that ogt may be a potential therapeutic target for cerebral I/R injury.