Protective effects of iptakalim,a novel ATP-sensitive potassium channel opener,on global cerebral ischemia-evoked insult in gerbils  

作　　者：Hua CHEN Yong YANG Hong-hong YAO Xing-chun TANG Jian-hua DING Hai WANG Gang HU 

机构地区：[1]Laboratory of Neuropharmacology, Department of Anatomy, Histology and Pharmacology, Nanjing Medical University, Nanjing 210029, China [2]Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China

出　　处：《Acta Pharmacologica Sinica》2006年第6期665-672,共8页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China （No 30572172）; the Key Project of Jiangsu Health Department （No K200501）; the Key Project of Natural Science Foundation of Jiangsu Education Department （No 05KJA31014）; the Specialized Research Fund for the Doctoral Program of Higher Education of China （No 20040312004）.

摘　　要：Aim： To investigate the protective role of iptakalim, a novel ATP sensitive potassium channel opener, on global cerebral ischemia-evoked insult in gerbils and glutamate-induced PC12 cell injury. Methods： Global cerebral ischemia was induced by occluding the bilateral common carotid arteries in gerbils for 5 rain. The open field maze and T-maze were employed to investigate the experimental therapeutic value of iptakalim on ischemic brain instilt （n=8）. The pyramidal cells in the hippocampal CA1 regions were counted to assess the protective effects of iptakalim. Glutamate released from the gerbil hippocampus and PC 12 cells were determined by HPLC. Intracellular calcium was measured by Fluo-3 AM with A Bio-Rad Radiance 2100TM confocal system in conjunction with a Nikon TE300 microscope. Astrocyte glutamate uptake measurements were determined by liquid scintillation counting. Results： Iptakalim （0.5-4.0 mg/kg per day, ip） could reduce the high locomotor activity evoked by ischemia and improve global cerebral 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-evoked increases of glutamate in the hippocampus of gerbils. In an in vitro study, iptakalim protected PC 12 cells against glutamate-induced excitotoxicity, reduced the [Ca^2＋]i increases, and enhanced the glutamate uptake activity of primary cultured astrocytes. Conclusions： Iptakalim plays a key role in preventing global cerebral ischemia-evoked insults in gerbils and glutamate-induced PC12 cell injury by antiexcitotoxicity. Iptakalim might be a promising novel candidate for the prevention and/or treatment of stroke.Aim： To investigate the protective role of iptakalim, a novel ATP sensitive potassium channel opener, on global cerebral ischemia-evoked insult in gerbils and glutamate-induced PC12 cell injury. Methods： Global cerebral ischemia was induced by occluding the bilateral common carotid arteries in gerbils for 5 rain. The open field maze and T-maze were employed to investigate the experimental therapeutic value of iptakalim on ischemic brain instilt （n=8）. The pyramidal cells in the hippocampal CA1 regions were counted to assess the protective effects of iptakalim. Glutamate released from the gerbil hippocampus and PC 12 cells were determined by HPLC. Intracellular calcium was measured by Fluo-3 AM with A Bio-Rad Radiance 2100TM confocal system in conjunction with a Nikon TE300 microscope. Astrocyte glutamate uptake measurements were determined by liquid scintillation counting. Results： Iptakalim （0.5-4.0 mg/kg per day, ip） could reduce the high locomotor activity evoked by ischemia and improve global cerebral 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-evoked increases of glutamate in the hippocampus of gerbils. In an in vitro study, iptakalim protected PC 12 cells against glutamate-induced excitotoxicity, reduced the [Ca^2＋]i increases, and enhanced the glutamate uptake activity of primary cultured astrocytes. Conclusions： Iptakalim plays a key role in preventing global cerebral ischemia-evoked insults in gerbils and glutamate-induced PC12 cell injury by antiexcitotoxicity. Iptakalim might be a promising novel candidate for the prevention and/or treatment of stroke.

关 键 词：ATP-sensitive potassium channel opener IPTAKALIM global cerebral ischemia neuroprotection EXCITOTOXICITY 

分 类 号：R74[医药卫生—神经病学与精神病学]