Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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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)
  • Received : 2011.09.09
  • Accepted : 2011.10.10
  • Published : 2011.10.30
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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.

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References

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