Effect of Diazoxide on Neuroprotection as an Element of IV Fluid Resuscitation

摘要

Hemorrhagic shock resulting from injury is the most common cause of traumatic death in civilian and military settings. Worldwide, over 5 million people died from trauma-related injury in 2000 with up to 64% of those fatalities having suffered a coinciding brain injury. For a century, researchers have investigated resuscitative strategies to better the outcomes of traumatic casualty treatments. Initial measures in management, hemostasis and volume restoration are vital but often prove unsuccessful in improving morbidity and mortality. As a result, our team investigated the hypothesis that diazoxide (DZ), a mitochondrial K(sub ATP) channel opener, could be used during resuscitation to induce an 'ischemic postconditioning effect' in a laboratory animal model of hemorrhagic shock leading to systemic hypotension and unilateral cerebral ischemia. Male Sprague-Dawley rats underwent a 40% plasma volume hemorrhage with resuscitation one hour later. DZ was administered at one of three time points: 20 minutes before the onset of resuscitation, at the time of resuscitation, or 20 minutes after the initiation of resuscitation. Western blotting and immunohistochemistry results showed when DZ was administered intravenously 20 minutes prior to resuscitative efforts following hemorrhagic shock, that the cytoprotective heat shock proteins (HSP) 25 and HSP70 exhibited marked upregulation in ischemic areas. Further immunohistochemistry analysis demonstrated that DZ when given simultaneous with resuscitation decreased the apoptotic cleaved caspase-3 protein within the cerebral cortex and hippocampus. DZ given at the time of resuscitation in the initial resuscitation volume significantly reduced caspase-3 activity bilaterally in ischemic and hypotensive regions of the hippocampus and the perirhinal cortex following hemorrhagic shock. These results suggest DZ has a postconditioning effect that may confer brain protection and limit apoptosis following hemorrhagic shock and cerebral hypoperfusion by increasing heat shock proteins and decreasing caspase-3 activity. These effects may be independent of each other depending on the time point at which DZ is administered.