The mitochondrial K-ATP channel opener, diazoxide, prevents ischemia-reperfusion injury in the rabbit spinal cord.
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.
Roseborough
Glen
G
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Gao
Daqing
D
Chen
Lei
L
Trush
Michael A
MA
Zhou
Shaoyu
S
Williams
G Melville
GM
Wei
Chiming
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D003981:Diazoxide / Q000627:therapeutic use*; D008928:Mitochondria / Q000502:physiology*; D008929:Mitochondria, Heart; D015221:Potassium Channels; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000139:chemically induced / Q000517:prevention & control*; D013116:Spinal Cord / Q000473:pathology*; D014665:Vasodilator Agents
D015221:Potassium Channels; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; D045647:DNA Glycosylases; D003981:Diazoxide