title: Effects of KR-33028, a novel Na+/H+ exchanger-1 inhibitor, on glutamate-induced neuronal cell death and ischemia-induced cerebral infarct.
abstract: We investigated the effects of a novel Na(+)/H(+) exchanger-1 (NHE-1) inhibitor KR-33028 on glutamate excitotoxicity in cultured neuron cells in vitro and cerebral infarct in vivo by comparing its potency with that of zoniporide, a well-known, highly potent NHE-1 inhibitor. KR-33028 inhibited NHE-1 activation in a concentration-dependent manner (IC(50)=2.2 nM), with 18-fold greater potency than that of zoniporide (IC(50)=40.7 nM). KR-33028 significantly attenuated glutamate-induced LDH release with approximately 100 times lower EC(25) than that of zoniporide in cortical neurons in vitro (EC(25) of 0.007 and 0.81 microM, respectively), suggesting its 100-fold greater potency than zoniporide in producing anti-necrotic effect. In addition, the EC(50) of KR-33028 for anti-apoptotic effect was 100 times lower than that of zoniporide shown by TUNEL positivity (0.005 and 0.62 microM, respectively) and caspase-3 activity (0.01 and 2.64 microM, respectively). Furthermore, the EC(50) value of KR-33028 against glutamate-induced intracellular Ca(2+) overload was also 100 times lower than that of zoniporide (EC(50) of 0.004 and 0.65 microM, respectively). In the in vivo cerebral infarct model (60 min middle cerebral artery occlusion followed by 24 h reperfusion), KR-33028 reduced infarct size in a dose-dependent manner. Its ED(25) value, however, was quite similar to that of zoniporide (ED(25) of 0.072 and 0.097 mg/kg, respectively). Hence these results suggest that the novel NHE-1 inhibitor, KR-33028, could be an efficient therapeutic tool to protect neuronal cells against ischemic injury.
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon 442-749, Republic of Korea.
authors.forename: Bo Kyung
authors.initials: BK
authors.lastname: Lee
authors.forename: Dong Ha
authors.initials: DH
authors.lastname: Lee
authors.forename: Sok
authors.initials: S
authors.lastname: Park
authors.forename: Sung Lyea
authors.initials: SL
authors.lastname: Park
authors.forename: Jae-Seok
authors.initials: JS
authors.lastname: Yoon
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Sunkyung
authors.initials: S
authors.lastname: Lee
authors.forename: Kyu Yang
authors.initials: KY
authors.lastname: Yi
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Yoo
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Lee
authors.forename: You-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Soo Hwan
authors.initials: SH
authors.lastname: Lee
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Baik
authors.forename: Chang-Hyun
authors.initials: CH
authors.lastname: Moon
authors.forename: Yi-Sook
authors.initials: YS
authors.lastname: Jung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D009336:Necrosis; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D006146:Guanidines; C507425:N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine; D018696:Neuroprotective Agents; D011720:Pyrazoles; D017923:Sodium-Hydrogen Exchangers; D013876:Thiophenes; C069139:growth factor-activatable Na-H exchanger NHE-1; D018698:Glutamic Acid; C424422:zoniporide; D053148:Caspase 3