Luteolin (3’,4’,5,7-tetrahydroxyflavone) has powerful anti-apoptotic and antioxidant properties. This study aimed to investigate the effects of luteolin on hyperglycemia-mediated apoptosis in the hippocampi of rats with streptozotocin-induced diabetic encephalopathy after injection into the tail veins, and the molecular mechanisms involved. Biochemistry and terminal deoxynucleotidyl transferase mediated dUTP nick end labelling detection results showed that luteolin treatment (given twice daily for 15 days) significantly inhibited hyperglycemia-mediated apoptosis, decreased malondialdehyde levels and increased glutathione levels in the hippocampi of streptozotocin-induced diabetic rats. Western blot analysis revealed that luteolin also inhibited the expression of apoptosis-related factors and cytochrome c release from mitochondria. Luteolin also improved the learning and memory abilities of rats with diabetic encephalopathy in a water maze test. Further western blot analysis revealed that luteolin treatment facilitated neuronal cell survival through activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, an extracellular signal pathway involved in the suppression of cell apoptosis and promotion of cell survival. These experimental findings indicate that luteolin can inhibit apoptosis of hippocampal nerve cells in rats with diabetic encephalopathy, and that this effect is mediated by an indirect antioxidative effect, the inhibition of activation of apoptosis-related factors and the activation of phosphatidylinositol 3-kinase/Akt signal pathway. This study aimed to investigate the effects of luteolin on hyperglycemia-mediated apoptosis in the hippocampi of rats with streptozotocin-induced diabetic encephalopathy after injection into the tail veins, and the molecular mechanisms involved. Biochemistry and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling results showed that luteolin treatment (given twice daily for 15 days) was inhibited hyperglycemia-mediated apoptosis, decreased malondialdehyde levels and increased glutathione levels in the hippocampi of streptozotocin-induced diabetic rats. Western blot analysis revealed that luteolin also inhibited the expression of apoptosis-related factors and cytochrome c release from mitochondria. Luteolin also improved the learning and memory abilities of rats with diabetic encephalopathy in a water maze test. Further western blot analysis revealed th at luteolin treatment facilitated neuronal cell survival through activation of the phosphatidylinositol 3-kinase / Akt signaling pathway, an extracellular signal pathway involved in the suppression of cell apoptosis and promotion of cell survival. These experimental findings indicate that luteolin can inhibit apoptosis of hippocampal nerve cells in rats with diabetic encephalopathy, and that this effect is mediated by an indirect antioxidative effect, the inhibition of activation of apoptosis-related factors and the activation of phosphatidylinositol 3-kinase / Akt signal pathway.