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Treatment with a novel hemigramicidin-TEMPO conjugate prolongs survival in a rat model of lethal hemorrhagic shock

Macias, CA and Chiao, JW and Xiao, J and Arora, DS and Tyurina, YY and Delude, RL and Wipf, P and Kagan, VE and Fink, MP (2007) Treatment with a novel hemigramicidin-TEMPO conjugate prolongs survival in a rat model of lethal hemorrhagic shock. Annals of Surgery, 245 (2). 305 - 314. ISSN 0003-4932

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Abstract

OBJECTIVE: 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. METHODS AND RESULTS: 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 μmol/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. CONCLUSION: 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. Copyright © 2007 Lippincott Williams & Wilkins.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Macias, CA
Chiao, JW
Xiao, J
Arora, DS
Tyurina, YYyyt1@pitt.eduYYT1
Delude, RL
Wipf, Ppwipf@pitt.eduPWIPF
Kagan, VEkagan@pitt.eduKAGAN
Fink, MP
Date: 1 February 2007
Date Type: Publication
Journal or Publication Title: Annals of Surgery
Volume: 245
Number: 2
Page Range: 305 - 314
DOI or Unique Handle: 10.1097/01.sla.0000236626.57752.8e
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0003-4932
MeSH Headings: Animals; Anti-Bacterial Agents--therapeutic use; Cells, Cultured; Cyclic N-Oxides--therapeutic use; Disease Models, Animal; Drug Therapy, Combination; Follow-Up Studies; Gramicidin--therapeutic use; Intestinal Mucosa--metabolism; Intestinal Mucosa--pathology; Lipid Peroxidation--drug effects; Male; Mitochondria--drug effects; Mitochondria--metabolism; Permeability--drug effects; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic--drug therapy; Shock, Hemorrhagic--metabolism; Shock, Hemorrhagic--mortality; Spin Labels; Superoxide Dismutase--metabolism; Survival Rate; Treatment Outcome
Other ID: NLM PMC1876982
PubMed Central ID: PMC1876982
PubMed ID: 17245186
Date Deposited: 09 Oct 2013 16:24
Last Modified: 02 Feb 2019 14:56
URI: http://d-scholarship.pitt.edu/id/eprint/19855

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