Protective effects of iptakalim, a novel ATP-sensitive potassium channel opener, on global cerebral ischemia-evoked insult in gerbils.
OBJECTIVE
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 min. The open field maze and T-maze were employed to investigate the experimental therapeutic value of iptakalim on ischemic brain insult (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 PC12 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 PC12 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 anti-excitotoxicity. Iptakalim might be a promising novel candidate for the prevention and/or treatment of stroke.
Chen
Hua
H
Laboratory of Neuropharmacology, Department of Anatomy, Histology and Pharmacology, Nanjing Medical University, Nanjing 210029, China.
Yang
Yong
Y
Yao
Hong-Hong
HH
Tang
Xing-Chun
XC
Ding
Jian-Hua
JH
Wang
Hai
H
Hu
Gang
G
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology*; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D005849:Gerbillinae; D005971:Glutamates / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016716:PC12 Cells / Q000166:cytology / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists*; D011437:Propylamines / Q000008:administration & dosage / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000473:pathology; D051381:Rats
D000596:Amino Acids; D005971:Glutamates; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D018696:Neuroprotective Agents; D024661:Potassium Channels, Inwardly Rectifying; D011437:Propylamines; D011188:Potassium; D002118:Calcium