The neuroprotective mechanisms of cervical vagus nerve stimulation (VNS) in transient ischemia were investigated. Left VNS (0.4 mA, 40 Hz) was performed during 5 min ischemia in gerbils. About 50% of the hippocampal neurons were rescued from ischemic insult by VNS, and this effect was prevented by transection of the vagus nerve centrally to the site of cervical stimulation. VNS significantly attenuated both ischemia-induced glutamate release and transient increase of hippocampal blood flow during reperfusion. Hyperemia as well as excessive glutamate release after ischemia is regarded as an important factor in ischemic brain damage as it leads to generate considerable reactive oxygen species. Thus, VNS might protect neurons from ischemia-induced glutamate excitotoxicity and reperfusion injury via the afferent path-way of the vagus.