Aim:To investigate the protective role of iptakalim,a novel ATP sensitive potas-sium channel opener,on global cerebral ischemia-evoked insult in gerbils andglutamate-induced PC 12 cell injury.Methods:Global cerebral ischemia was in-duced by occluding the bilateral common carotid arteries in gerbils for 5 min.Theopen field maze and T-maze were employed to investigate the experimental thera-peutic value of iptakalim on ischemic brain insult(n=8).The pyramidal cells in thehippocampal CA1 regions were counted to assess the protective effects ofiptakalim.Glutamate released from the gerbil hippocampus and PC12 cells weredetermined by HPLC.Intracellular calcium was measured by Fluo-3 AM with ABio-Rad Radiance 2100TM confocal system in conjunction with a Nikon TE300microscope.Astrocyte glutamate uptake measurements were determined by liq-uid scintillation counting.Results:Iptakalim(0.5-4.0 mg/kg per day,ip)couldreduce the high locomotor activity evoked by ischemia and improve global cere-bral ischemia-induced working memory impairments.Histological studies revealedthat iptakalim could increase the survival neuron in the hippocampus CA1 zone ina dose-dependent manner.Moreover,iptakalim could reverse ischemia-evokedincreases of glutamate in the hippocampus of gerbils.In an in vitro study,iptakalimprotected PC12 cells against glutamate-induced excitotoxicity,reduced the[Ca~(2+)]_iincreases,and enhanced the glutamate uptake activity of primary culturedastrocytes.Conclusions:Iptakalim plays a key role in preventing global cerebralischemia-evoked insults in gerbils and glutamate-induced PC12 cell injury by anti-excitotoxicity.Iptakalim might be a promising novel candidate for the preventionand/or treatment of stroke. Aim: To investigate the protective role of iptakalim, a novel ATP-sensitive potas-sium channel opener, on global cerebral ischemia-evoked insult in gerbils and glutamate-induced PC 12 cell injury. Methods: Global cerebral ischemia was in-duced by occluding the bilateral common carotid arteries in gerbils for 5 min. Theopen field maze and T-maze were employed to investigate the experimental thera-peutic value of iptakalim on ischemic brain insult (n = 8). The pyramidal cells in thehippocampal CA1 regions were counted to assess the protective effects of iptakalim. Gllutamate released from the gerbil hippocampus and PC12 cells were determined by HPLC. Intracellular calcium was measured by Fluo-3 AM with ABio-Rad Radiance 2100TM confocal system in conjunction with a Nikon TE300 microscope. Astrocyte glutamate uptake measurements were determined by liq- uid scintillation counting. Results: Iptakalim (0.5-4.0 mg / kg per day, ip) couldreduce the high locomotor activity evoked by ischemia and improve global cerebral-bral ischemia-induced working memory impairments. Histological studies revealed that iptakalim could increase the survival neuron in the hippocampus CA1 zone in a dose-dependent manner. Moreover, iptakalim could reverse ischemia-evokedincreases of glutamate in the hippocampus of gerbils. an in vitro study, iptakalimprotected PC12 cells against glutamate-induced excitotoxicity, reduced the [Ca ~ (2 +)] _increases, and enhanced the glutamate uptake activity of primary culturedastrocytes. Conclusions: Iptakalim plays a key role in preventing global cerebral ischemia-evoked insults in gerbils and glutamate-induced PC12 cell injury by anti-excitotoxicity. Iptakalim might be a promising novel candidate for the prevention and / or treatment of stroke.