title: Diazoxide, as a postconditioning and delayed preconditioning trigger, increases HSP25 and HSP70 in the central nervous system following combined cerebral stroke and hemorrhagic shock.
abstract: Combined hemorrhagic shock (Shock) and unilateral common carotid artery occlusion (Stroke) results in a decrease of oxygen availability to peripheral tissues and organs and the central nervous system (CNS). A variety of biochemical processes ensue, including organ failure, cellular apoptosis, and necrosis. The present study used male, Sprague-Dawley rats to assess the impact of cerebral insult. Using heat-shock protein 25 and 70 (HSP25, HSP70) as biomarkers, measured 24 h after injury, we tested the hypothesis that pharmacological induction of preconditioning can offer cytoprotection from combined Stroke and Shock. The compound, diazoxide (DZ), is known to induce preconditioning through its effect as a mitochondrial potassium ATP (mK(ATP)) channel opener and succinate dehydrogenase inhibitor. When administered 24 h prior to Stroke and Shock (delayed preconditioning), DZ increased cerebral cortical and hippocampal levels of HSP25 and HSP70. A more clinically relevant treatment paradigm was tested, where DZ was administered after the induction of Stroke and Shock (postconditioning). When administered 60 min (but not 10 min) after the induction of Stroke and Shock, DZ significantly increased HSP25 and HSP70 expression in the ipsilateral cerebral cortex and hippocampus. Taken together, these results suggest that DZ treatment may be efficacious for CNS injury resulting from blood loss and anoxia from combined cerebral ischemia and hemorrhagic shock. "Postconditioning" triggered by DZ, immediately before resuscitation, is a potentially effective treatment for ischemia-reperfusion injury from combined Stroke and Shock.
authors.affiliation: Graduate Program in Neuroscience, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: O'Sullivan
authors.forename: Xiang-Lan
authors.initials: XL
authors.lastname: Yao
authors.forename: Hasan
authors.initials: H
authors.lastname: Alam
authors.forename: Joseph T
authors.initials: JT
authors.lastname: McCabe
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002490:Central Nervous System / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000097:blood / Q000378:metabolism*; D003981:Diazoxide / Q000494:pharmacology*; D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D019194:Ischemic Preconditioning; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000097:blood / Q000378:metabolism*; D020521:Stroke / Q000097:blood / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D055551:HSP27 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009363:Neoplasm Proteins; D003981:Diazoxide