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http://dx.doi.org/10.4062/biomolther.2011.19.4.445

KR-33028, a Novel Na+/H+ Exchanger-1 Inhibitor, Attenuates Glutamate-Induced Apoptotic Cell Death through Maintaining Mitochondrial Function  

Lee, Bo-Kyung (College of Pharmacy, Ajou University)
Lee, Sun-Kyung (Medical Science Division, Korea Research Institute of Technology)
Yi, Kyu-Yang (Medical Science Division, Korea Research Institute of Technology)
Yoo, Sung-Eun (Medical Science Division, Korea Research Institute of Technology)
Jung, Yi-Sook (College of Pharmacy, Ajou University)
Publication Information
Biomolecules & Therapeutics / v.19, no.4, 2011 , pp. 445-450 More about this Journal
Abstract
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 $Ca^{2+}$ and that KR-33028 significantly prevents the second phase increase, but not the first phase increase in mitochondrial $Ca^{2+}$. Furthermore, KR-33028 restored the ${\Delta}{\Psi}_m$ dissipation and cytochrome c release into cytoplasm induced by glutamate in a concentration-dependent manner. The inhibition of mitochondrial $Ca^{2+}$ overload by ruthenium red also inhibited glutamate-induced apoptotic cell death, mitochondrial membrane potential, ${\Delta}{\Psi}_m$ dissipation and cytochrome c release. These data suggest that inhibition of mitochondrial $Ca^{2+}$ 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.
Keywords
KR-33028; Glutamate excitotoxicity; $Na^+/H^+$ exchanger-1 (NHE-1); Mitochondria; Apoptosis;
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