Weakness and/or paralysis of lower limbs following thoracoabdominal aortic aneurysm surgery result mainly from loss of blood flow (ischemia) to the spinal cord, a consequence of clamping the aorta to prevent bleeding. While severe deficits can be controlled through reduced ischemia time, the mere act of reintroducing blood and oxygen (reperfusion) also causes cellular damage. Ischemia-reperfusion injury exerts its effects on the spinal cord via release of reactive oxygen species, damage to cellular components such as mitochondria, and initiation of cell death.
Dr. Chiming Wei and colleagues from the Department of Surgery at The Johns Hopkins University School of Medicine have specifically targeted ischemia-reperfusion-mediated mitochondrial damage, which directly contributes to cell death. They hypothesized that they could prevent spinal cord injury if they blocked mitochondrial damage with the drug diazoxide, which prevents mitochondrial failure and subsequent cell death.
Using a rabbit model of ischemia-reperfusion injury, Dr. Wei's team demonstrated that administration of diazoxide prevented hind limb paralysis. All animals treated with diazoxide prior to clamping of the aorta retained mobility in their hind limbs, though hopping was impaired, in sharp contrast to complete hind limb paralysis in all untreated animals. Further, mitochondria from spinal cords of diazoxide-treated rabbits displayed considerably less structural damage compared to those of untreated animals. Overall, diazoxide prevented or lessened release of reactive oxygen species, oxidative DNA damage, and cell death while having no effect on expression of DNA repair enzymes.
These studies demonstrate the importance of mitochondria in release of reactive oxygen species and in initiation of cell death pathways during ischemia-reperfusion injury. In particular, the establishment of a correlation between the structural integrity and the function of mitochondria in ischemia-reperfusion injury is shown for the first time in an animal model of spinal cord injury.
Dr. Wei and colleagues are optimistic of the impact that their results hold for improving the outcome of aortic surgery. Combined with future research on ischemia-reperfusion spinal injury, diazoxide may further decrease the likelihood of neurological deficits following aortic aneurysm surgery.
This work was supported by the National Institutes of Health, the Maryland Department of Health and Mental Hygiene, the Johns Hopkins Fund for Medical Discovery, and a Johns Hopkins Institutional Research grant.
Roseborough G*, Gao D*, Chen L, Trush MA, Zhou S, Williams GM, Wei C: The mitochondrial K-ATP channel opener, diazoxide, prevents ischemia-reperfusion injury in the rabbit spinal cord. Am J Pathol 2006 168:1443-1451
* These authors contributed equally to this work.
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The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.
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