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KMID : 0606920110190040445
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Biomolecules & Therapeutics
2011 Volume.19 No. 4 p.445 ~ p.450
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KR-33028, a Novel Na+/H+ Exchanger-1 Inhibitor, Attenuates Glutamate-Induced Apoptotic Cell Death through Maintaining Mitochondrial Function
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Lee Bo-Kyung
Lee Sun-Kyung
Yi Kyu-Yang
Yoo Sung-Eun
Jung Yi-Sook
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Abstract
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Preciously, we demonstrated that a novel NHE-1 inhibitor, KR-33028 attenuated cortical neuronal apoptosis induced by glutamate. In the present study, we investigated the signaling mechanism of neuroprotective effect of KR-33028 against glutamate-induced neuronal apoptosis, especially focusing on mitochondrial death pathway. Our data showed that glutamate induces a biphasic rise in mitochondrial Ca2+ and that KR-33028 signifi cantly prevents the second phase increase, but not the fi rst phase increase in mitochondrial Ca2+. Furthermore, KR-33028 restored the ?ψm dissipation and cytochrome c release into cytoplasm induced by glutamate in a concentration-dependent manner. The inhibition of mitochondrial Ca2+ overload by ruthenium red also inhibited glutamate-induced apoptotic cell death, mitochondrial membrane potential, ?ψm dissipation and cytochrome c release. These data suggest that inhibition of mitochondrial Ca2+ overload is likely to be attributable to anti-apoptotic effect of KR-33028. Taken together, our results suggest that anti-apoptotic effects of NHE-1 inhibitor, KR-33028 may be mediated through maintenance of mitochondrial function.
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KEYWORD
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KR-33028, Glutamate excitotoxicity, Na+/H+ exchanger-1 (NHE-1), Mitochondria, Apoptosis
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