Due to the nature of neuron which is irreversible to damage, ischemic preconditioning is unlikely to give any benefit to ischemic stroke patients. However, preconditioning is an appealing avenue for surgical procedures which predisposed the patients with higher risk of ischemic brain injury such as endarterectomy and cerebral aneurysm surgery. We demonstrated that preconditioning with lower doses of (S)-3,5-DHPG showed to be protective against subsequent ischemic insult in the acute ischemic stroke rats. Therefore, understanding of mechanisms underlying the preconditioning effect of (S)-3,5-DHPG is a critical point of salvation in this area.