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

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Acta Pharmacologica Sinica 2006年第6期27卷 665-672页

作者： Hua CHEN~(2,4)Yong YANG~(2,4)Hong-hong YAO~2 Xing-chun TANG~2 Jian-hua DING~2 Hai WANG~3 Gang HU~(2,5)2 Laboratory of Neuropharmacology,Department of Anatomy,Histology and Pharmacology,Nanjing Medical University,Nanjing 210029,China 3 Department of Cardiovascular Pharmacology,Beijing Institute of Pharmacology and Toxicology,Beijing 100850,China Department of Anatomy Laboratory of Neuropharmacology Histology and Pharmacology Nanjing Medical University Nanjing China Department of Cardiovascular Pharmacology Beijing Institute of Pharmacology and Toxicology Beijing China

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[Ca2+]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.

关键词： atp-sensitive potassium channel opener iptakalim global cerebral ischemia neuroprotection excitotoxicity

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