The present study tested the hypothesis that induction of autophagy by producing appropriate amount of ER stress and autophagy activation is associated with neuroprotection in a rat model of focal cerebral ischemic preconditioning (IPC).This study was taken to determine the role of autophagy induced by ER stress in an animal model of IPC and permanent focal ischemia (PFI).Focal cerebral IPC was produced in rats by a brief ischemic insult followed by permanent focal ischemia (PFI) 24 h later using the suture occlusion technique.The rats were pretreated with intracerebral ventricle infusion of the ER stress inhibitors salubrinal (SAL) or the ER stress inducer tunicamycin (TM) to evaluate the contribution of ER stress to IPC-induced neuroprotection.The results showed that SAL pretreatment increased infarct volume, brain edema and motor deficits, whereas SAL suppressed the neuroprotection induced by IPC.SAL pretreatment also significantly attenuated upregulation of LC3-Ⅱ , GRP78 and HSP70 and downregulation of p62 and caspase-12.To further determine if autophagy induced by ER stress is responsible for IPC-induced neuroprotection, rats were treated with TM 24 h before the onset of PFI.The results showed that TM reduced infarct volume, brain edema and motor deficits induced by PFI.TM pretreatment increased the protein levels of LC3-Ⅱ, p-eif2α, GRP78 and HSP70 and reduced the protein levels of p62 and caspase-12.These results demonstrate that ER stress inhibitors salubrinal (SAL) can inhibit autophagy and cancel out IPCs neuroprotective effects,whereas ER stress inducer tunicamycin (TM) can induce autophagy and mimick IPCs neuroprotective effects.