Background Transient sublethal ischemia is known as ischemic preconditioning,which enables cells and tissues to survive subsequent prolonged lethal ischemic injury.Ischemic preconditioning exerts neuroprotection through phosphatidylinositol 3-kinase (PI3K)/Akt pathway.Cbl-b belongs to the Casitas B-lineage lymphoma (Cbl) family,and it can regulate the cell signal transduction.The roles of ubiquitin ligase Cbl-b and PI3K/Akt pathway and the relationship between them in oxygen-glucose deprivation preconditioning (OGDPC) in PC12 cells were investigated in the present study.Methods Oxygen and glucose deprivation (OGD) model in PC12 cells was used in the present study.The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay,nuclear staining with Hoechst 33258,and West blotting were applied to explore the roles of Cbl-b and PI3K/Akt pathway and the relationship between them in OGDPC in PC12 cells.Results Cell viability was significantly changed by OGD and OGDPC.OGD significantly decreased cell viability compared with the control group (P ＜0.05),and preconditioning could rescue this damage was demonstrated by the increase of cell viability (P ＜0.05).The expression of Cbl-b was significantly increased after OGD treatment.However,the activation of Akt and GSK3β was greatly inhibited.Preconditioning could inhibit the increase of Cbl-b caused by OGD and increase the activation of Akt and GSK3β.LY294002,a specific inhibitor of PI3K,could effectively inhibit the increase of Akt and GSK3β after preconditioning treatment.It partly inhibited the decrease of Cbl-b expression after preconditioning treatment.Conclusion Ubiquitin ligase Cbl-b and PI3K/Akt pathway are differently involved in OGDPC in PC12 cells.