This Article Full Text Full Text (PDF) All Versions of this Article: 34/7/1796    most recent 01.STR.0000077017.60947.AEv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Teshima, Y. Articles by Marbán, E. Search for Related Content PubMed PubMed Citation Articles by Teshima, Y. Articles by Marbán, E. Related Collections Apoptosis Neuroprotectors Oxidant stress

(Stroke. 2003;34:1796.)
© 2003 American Heart Association, Inc.

Original Contributions

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 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.

Correspondence to Eduardo Marbán, MD, PhD, Institute of Molecular Cardiobiology, The Johns Hopkins University, 720 Rutland Ave, 844 Ross Bldg, Baltimore, MD 21205. 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

This article has been cited by other articles:

				Z. Sun, X. Zhang, K. Ito, Y. Li, R. A. Montgomery, S. Tachibana, and G. M. Williams Amelioration of oxidative mitochondrial DNA damage and deletion after renal ischemic injury by the KATP channel opener diazoxide Am J Physiol Renal Physiol, March 1, 2008; 294(3): F491 - F498. [Abstract] [Full Text] [PDF]

				T. P. Obrenovitch Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia Physiol Rev, January 1, 2008; 88(1): 211 - 247. [Abstract] [Full Text] [PDF]

				P. Matarrese, L. Falzano, A. Fabbri, L. Gambardella, C. Frank, B. Geny, M. R. Popoff, W. Malorni, and C. Fiorentini Clostridium difficile Toxin B Causes Apoptosis in Epithelial Cells by Thrilling Mitochondria: INVOLVEMENT OF ATP-SENSITIVE MITOCHONDRIAL POTASSIUM CHANNELS J. Biol. Chem., March 23, 2007; 282(12): 9029 - 9041. [Abstract] [Full Text] [PDF]

				T. Takeda, M. Akao, M. Matsumoto-Ida, M. Kato, H. Takenaka, Y. Kihara, T. Kume, A. Akaike, and T. Kita Serofendic Acid, a Novel Substance Extracted From Fetal Calf Serum, Protects Against Oxidative Stress in Neonatal Rat Cardiac Myocytes J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1882 - 1890. [Abstract] [Full Text] [PDF]

				S. Roth, J. C. Dreixler, A. R. Shaikh, K. H. Lee, and V. Bindokas Mitochondrial Potassium ATP Channels and Retinal Ischemic Preconditioning Invest. Ophthalmol. Vis. Sci., May 1, 2006; 47(5): 2114 - 2124. [Abstract] [Full Text] [PDF]

				C. J. Barreiro, J. A. Williams, T. P. Fitton, M. S. Lange, M. E. Blue, L. Kratz, P. B. Barker, M. Degaonkar, V. L. Gott, J. C. Troncoso, et al. Noninvasive Assessment of Brain Injury in a Canine Model of Hypothermic Circulatory Arrest Using Magnetic Resonance Spectroscopy. Ann. Thorac. Surg., May 1, 2006; 81(5): 1593 - 1598. [Abstract] [Full Text] [PDF]

				G. Roseborough, D. Gao, L. Chen, M. A. Trush, S. Zhou, G. M. Williams, and C. Wei The Mitochondrial K-ATP Channel Opener, Diazoxide, Prevents Ischemia-Reperfusion Injury in the Rabbit Spinal Cord Am. J. Pathol., May 1, 2006; 168(5): 1443 - 1451. [Abstract] [Full Text] [PDF]

				R. Bright and D. Mochly-Rosen The Role of Protein Kinase C in Cerebral Ischemic and Reperfusion Injury Stroke, December 1, 2005; 36(12): 2781 - 2790. [Abstract] [Full Text] [PDF]

				T. Kaneko, K. Yokoyama, and K. Makita Late preconditioning with isoflurane in cultured rat cortical neurones Br. J. Anaesth., November 1, 2005; 95(5): 662 - 668. [Abstract] [Full Text] [PDF]

				F. Domoki, B. Kis, K. Nagy, E. Farkas, D. W. Busija, and F. Bari Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H368 - H373. [Abstract] [Full Text] [PDF]