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(American Journal of Pathology. 2006;168:1443-1451.)
© 2006 American Society for Investigative Pathology

The Mitochondrial K-ATP Channel Opener, Diazoxide, Prevents Ischemia-Reperfusion Injury in the Rabbit Spinal Cord

Glen Roseborough, Daqing Gao, Lei Chen, Michael A. Trush, Shaoyu Zhou, G. Melville Williams and Chiming Wei

From the Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland

Paraplegia resulting from ischemia is a catastrophic complication of thoracoabdominal aortic surgery. The current study was designed to investigate the effects of diazoxide (DZ) on mitochondrial structure, neurological function, DNA damage-repair, and apoptosis in spinal cord ischemia-reperfusion injury. Rabbits were subjected to 30 minutes of spinal cord ischemia and reperfusion (1 hour) with or without diazoxide (n = 6 in each group) by clamping and releasing the infrarenal aorta. The neurological functional score was significantly improved in the DZ-treated ischemia-reperfusion injury group. Electron microscopic studies demonstrated that mitochondrial damage in the spinal cord after injury was significantly reduced by DZ. Mitochondrial superoxide and hydrogen peroxide levels were also markedly decreased in the DZ-treated injury group compared with the untreated group. DZ decreased levels of the oxidative DNA damage product 8-oxoG and increased levels of the DNA repair enzyme OGG-1. Furthermore, DZ inhibited apoptosis via caspase-dependent and -independent pathways. These studies indicate for the first time that the mitochondrial K-ATP channel opener diazoxide improves neurological function after spinal cord ischemia and reperfusion by diminishing levels of reactive oxygen species, decreasing DNA oxidative damage, and inhibiting caspase-dependent and -independent apoptotic pathways while preserving mitochondrial structure.




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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]


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