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It is well known that brain is sensitive to ischemia/reperfusion (I/R) induced injury.α-lipoic acid (LA), a free radical scavenger and antioxidant, has protective effects against I/R induced injury.Therefore, this study was undertaken to evaluate whether LA could protect against cerebral I/R induced injury in vivo and in vitro, and explore the potential mechanisms.We studied the neuroprotection by LA using a rat model of transient focal ischemia induced by middle cerebral artery occlusion (MCAO) followed by reperfusion in vivo combined with using simulated cerebral I/R induced by C6 cells exposed to oxygen-glucose deprivation (OGD) followed by reperfusion in vitro.We found that pretreatment with LA significantly decreased the infarction size and brain water content, and improved Neurological deficit score (NDS).It markedly reversed the levels of oxidative parameters [malondialdehyde (MDA), nitric oxide (NO), total antioxidant capacity (T-AOC), and superoxide dismutase (SOD)] to their normal state in brains after cerebral I/R.Also, the expression of brain-derived neurotrophic factor (BDNF), PI3K, p-Akt and p-Erk1/2 significantly increased, and cleaved caspase-3 markedly decreased detected by western blotting.In vitro, pretreatment of LA significantly enhanced cell viability, decreased the concentration of intracellular reactive oxygen species (ROS), apoptotic rate and the level of cleaved caspase-3.These findings demonstrate that LA exhibits neuroprotective effects in vivo and in vitro through its anti-oxidative stress and anti-apoptosis.Moreover, we prove LA exerts its neuroprotection partly by activation of the BDNF-PI3K/Akt-ERK1/2 pathway.