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: Bo Kyung Lee, Dong Ha Lee, Sok Park, Sung Lyea Park, Jae-Seok Yoon, Min Goo Lee, Sunkyung Lee, Kyu Yang Yi, Sung Eun Yoo, Kyung Hee Lee, You-Sun Kim, Soo Hwan Lee, Eun Joo Baik, Chang-Hyun Moon, Yi-Sook Jung
• Journal: Brain research (Brain Res) Vol. 1248 Pg. 22-30 (Jan 12 2009) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 19022230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Guanidines
• N-(4-cyano-benzo(b)thiophene-2-carbonyl)guanidine
• Neuroprotective Agents
• Pyrazoles
• Sodium-Hydrogen Exchangers
• Thiophenes
• growth factor-activatable Na-H exchanger NHE-1
• Glutamic Acid
• zoniporide
• Caspase 3

Topics

• Animals
• Apoptosis (drug effects)
• Brain Ischemia
• Caspase 3 (metabolism)
• Cells, Cultured
• Cerebral Cortex (cytology, drug effects, metabolism)
• Cerebral Infarction (drug therapy, pathology, physiopathology)
• Enzyme Activation (drug effects)
• Glutamic Acid (pharmacology)
• Guanidines (pharmacology)
• In Situ Nick-End Labeling
• Mice
• Microscopy, Confocal
• Microscopy, Fluorescence
• Necrosis
• Neurons (chemistry, drug effects, physiology)
• Neuroprotective Agents (pharmacology)
• Pyrazoles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Sodium-Hydrogen Exchangers (antagonists & inhibitors)
• Thiophenes (pharmacology)