We examined the neuroprotective actions of SY-21, a potent ingredient of a traditional Chinese herb, histologically. Transient brain ischemia (15 min) was induced by four-vessel occlusion in Sprague-Dawley rats. Administration of SY-21 20 min before or 6 h after brain ischemia significantly increased the number of surviving hippocampal CA1 pyramidal cells in rats subjected to transient brain ischemia followed by 5 days of reperfusion. Neuronal cell death resulting from ischemic events is associated with abnormal activation of the NMDA receptors. Tyrosine phosphorylation of the NMDA receptor subunit NR2A by Src or Fyn has been implicated in the up-regulation of NMDA receptor activity. In order to investigate the possible mechanism of the neuroprotective action of SY-21, we examined the effects of SY-21 on the ischemia/reperfusion-induced increases in tyrosine phosphorylation of the NMDA receptor subunit 2A (NR2A) and on the interactions involving NR2A, PSD-95 and Src/Fyn. We found that the increase in the tyrosine phosphorylation of NR2A induced by brain ischemia/reperfusion is suppressed by SY-21 administered 15 min before, or instantly after, brain ischemia. Also, SY-21 attenuated the increased interactions involving NR2A, PSD-95, Fyn and Src. These results demonstrate that SY-21 has a prominent neuroprotective action against brain ischemic insult, and the mechanism may involve the regulation of the tyrosine phosphorylation of NR2A by changing the above interactions.