Treatment With a Novel Hemigramicidin-TEMPO Conjugate Prolongs Survival in a Rat Model of Lethal Hemorrhagic Shock

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Abstract
We sought to develop a therapeutic agent that would permit prolongation of survival in rats subjected to lethal hemorrhagic shock (HS), even in the absence of resuscitation with asanguinous fluids or blood. We synthesized a series of compounds that consist of the electron scavenger and superoxide dismutase mimic, 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl (4-NH2-TEMPO), conjugated to fragments and analogs of the membrane-active cyclopeptide antibiotic, gramicidin S. Using an in vivo assay, wherein isolated intestinal segments were loaded inside the lumen with various test compounds, we studied these compounds for their ability to prevent ileal mucosal barrier dysfunction induced by subjecting rats to profound HS for 2 hours. The most active compound in this assay, XJB-5-131, ameliorated peroxidation of the mitochondrial phospholipid, cardiolipin, in ileal mucosal samples from rats subjected to HS. XJB-5-131 also ameliorated HS-induced activation of the pro-apoptotic enzymes, caspases 3 and 7, in ileal mucosa. Intravenous treatment with XJB-5-131 (2 micromol/kg) significantly prolonged the survival of rats subjected to profound blood loss (33.5 mL/kg) despite administration of only a minimal volume of crystalloid solution (2.8 mL/kg) and the absence of blood transfusion. These data support the view that mitochondrially targeted electron acceptors and SOD mimics are potentially valuable therapeutics for the treatment of serious acute conditions, such as HS, which are associated with marked tissue ischemia.