Published Online
on June 5, 2003

A more recent version of this article appeared on July 1, 2003

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Submitted on January 16, 2003
Accepted on February 11, 2003

Mitochondrial ATP-Sensitive Potassium Channel Activation Protects Cerebellar Granule Neurons From Apoptosis Induced by Oxidative Stress

Yasushi Teshima MD, PhD; Masaharu Akao MD, PhD; Ronald A. Li PhD; Tae H. Chong BA; William A. Baumgartner MD; Michael V. Johnston MD; and Eduardo Marbán MD, PhD^*

From the Institute of Molecular Cardiobiology (Y.T., M.A., R.A.L., E.M.), Kennedy Krieger Institute (T.H.C., M.V.J.), and Department of Surgery (W.A.B.), The Johns Hopkins University, Baltimore, Md.

^* To whom correspondence should be addressed. E-mail: marban{at}jhmi.edu.

Background and Purpose--Mitochondrial ATP-sensitive potassium (mitoK_ATP) channels are present in the brain, and several reports have shown that mitoK_ATP channel openers protect the brain against ischemic injury. However, the precise mechanisms of this protection are not well established. We hypothesized that mitoK_ATP channel openers prevent apoptosis by preserving mitochondrial membrane potential.

Methods--We investigated the effect of mitoK_ATP channel openers on apoptosis induced by oxidative stress using cultured cerebellar granule neurons.

Results--The mitoK_ATP channel opener diazoxide (100 µmol/L) significantly suppressed the number of cells with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive nuclei and the increase in caspase-3 activity induced by 20 µmol/L H₂O₂. Diazoxide and another opener, pinacidil, prevented the loss of mitochondrial inner membrane potential (_m) induced by H₂O₂. These effects were abolished by 5-hydroxydecanoate (500 µmol/L), a mitoK_ATP channel blocker. Cyclosporin A and bongkrekic acid, inhibitors of the mitochondrial permeability transition pore, also prevented _m loss, confirming the involvement of the mitochondrial permeability transition in the apoptotic cascade in neurons. Furthermore, diazoxide prevented the increase in extracellular glutamate concentration induced by H₂O₂, but this effect was not attributable to activation of surface K_ATP channels.

Conclusions--MitoK_ATP channel openers inhibited apoptosis by preserving mitochondrial inner membrane potential. These beneficial effects may suggest a possible new target for neuroprotection.

Key words: apoptosis • mitochondria • neurons • oxidative stress • potassium channels

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