Objective：To observe the neuroprotective mechanism of astrocytes after oxidative stress injury by up-regulating endogenous gap junction protein alpha 1 truncated monomer- 20k（GJA1-20k）of neurons. Methods：Neurons and astrocytes were obtained from C57BL/6 fetal mice by primary culture method，and co-culture model was established. Neurons were injured by hydrogen peroxide（H2O2），insulin-like growth factor-1（IGF-1）receptor blocker AG1024 was given to astrocytes，respectively. Thus，Neuron+Astrocyte+Stress group and Neuron+Astrocyte+Stress+AG1024 group were established. Meanwhile，Neuron（Neuron alone without treatment）group and Neuron+Stress group（separately cultured Neuron given with H2O2）were also set up as control groups. The changes of GJA1-20k，non-phosphorylated（NP）-Cx43，glutamate transporter-1（GLT-1），mitochondrial function-related proteins（PGC-1α，mtTFA，Tom20，CoxⅣ），apoptosis-related proteins（Bcl-2，Bax，Caspases-9）were measured by Western blot. The oxidative stress factor NAPDH oxidase activity，inflammatory factors interleukin（IL）-1β，IL-6 and tumor necrosis factor-α（TNF-α）were detected by ELFA and ELISA，apoptosis of neurons was measured by Annexin V-FITC/PI assay，respectively. Results：Astrocytes co-culture significantly up-regulated the expression of endogenous GJA1-20k and NP-Cx43，reversed the down-regulation of PGC-1α，mtTFA，Tom20 and CoxⅣ，up-regulated apoptotic inhibitor Bcl-2，down-regulated apoptotic promoter Bax，Caspase-9，and reduced the expression of NAPDH oxidase activity and inflammatory products IL-1β，IL-6 and TNF-α（P < 0.05）. The protective effect of astrocytes on neurons was significantly inhibited by AG1024（P < 0.05）. Conclusion：The protective mechanism of astrocyte on neuron associated with IGF-1 may be related to the increase of endogenous GJA1-20k and protection of mitochondria function in neurons.