Astrocyte Autophagy Flux Protects Neurons Against Oxygen-Glucose Deprivation and Ischemic/Reperfusion Injury

The role of autophagy varies with the type of acute brain injury. In general, autophagy mediates a clear neuroprotective effect in intoxication caused by various psychoactive agents, subarachnoid hemorrhage and spinal cord injury. In contrast, autophagic cell death has also been reported to actively contribute to neuronal loss in neonatal hypoxic ischemic encephalopathy. However, it still remains to be determined whether autophagy pays a cytoprotective or a cytotoxic role in stroke. Previous studies focused primarily on the role of neurons rather than the role of astrocytes in brain injury. Thus, it is unknown whether modulating the autophagy flux of astrocytes contributes to improving neuronal survival after stroke. In the current study, we investigated the time course of autophagy flux in vitro using cocultured astrocytes and neurons exposed to oxygen-glucose deprivation/reoxygenation, which mimicked the process of ischemia/reperfusion. Autophagy flux of astrocytes was regulated by treatment with the autophagy inducer rapamycin, autophagy inhibitor 3-methyladenine, and the transduction of small interfering RNA against autophagy-related gene 5. In addition, AAV-GFAP-ATG7 was used to induce astrocyte autophagy flux in mice subjected to focal cerebral ischemia. We found that induction of autophagy flux of astrocytes in vitro enhanced the viability of neurons and decreased neuronal apoptosis. Furthermore, induction of astrocyte autophagy flux in mice improved neurological outcomes. In contrast, inhibition of autophagy flux in astrocytes decreased the viability of neurons and increased neuronal apoptosis. These results suggest that upregulation of autophagy flux in astrocytes may contribute to endogenous neuroprotective and neurorecovery mechanisms after stroke.