title: Postischemic treatment with ethyl pyruvate prevents adenosine triphosphate depletion, ameliorates inflammation, and decreases thrombosis in a murine model of hind-limb ischemia and reperfusion.
abstract: BACKGROUND
  Experiments were designed to investigate the effects of ethyl pyruvate (EP) in a murine model of hind-limb ischemia-reperfusion (IR) injury.
  
  
  METHODS
  C57BL6 mice underwent 90 minutes of unilateral ischemia followed by 24 hours of reperfusion using two treatment protocols. For the preischemic treatment (pre-I) protocol, mice (n=6) were given 300 mg/kg EP before ischemia, followed by 150 mg/kg of EP just before reperfusion and at 6 hours and 12 hours after reperfusion. In a postischemic treatment (post-I) protocol, mice (n=7) were treated with 300 mg/kg EP at the end of the ischemic period, then 15 minutes later, and 2 hours after reperfusion and 150 mg/kg of EP at 4 hours, 6 hours, 10 hours, 16 hours, and 22 hours after reperfusion. Controls mice for both protocols were treated with lactated Ringers alone at time intervals identical to EP. Skeletal muscle levels of adenosine triphosphate (ATP), interleukin-1β, keratinocyte chemoattractant protein, and thrombin antithrombin-3 complex were measured. Skeletal muscle architectural integrity was assessed microscopically.
  
  
  RESULTS
  ATP levels were higher in mice treated with EP compared with controls under the both treatment protocols (p=0.02). Interleukin-1β, keratinocyte chemoattractant protein, thrombin antithrombin-3 complex (p<0.05), and the percentage of injured fibers (p<0.0001) were significantly decreased in treated versus control mice under the both protocols.
  
  
  CONCLUSIONS
  Muscle fiber injury and markers of tissue thrombosis and inflammation were reduced, and ATP was preserved with EP in pre-I and post-I protocols. Further investigation of the efficacy of EP to modulate IR injury in a larger animal model of IR injury is warranted.
authors.affiliation: Division of Vascular and Endovascular Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Crawford
authors.forename: Hassan
authors.initials: H
authors.lastname: Albadawi
authors.forename: Marvin D
authors.initials: MD
authors.lastname: Atkins
authors.forename: John J
authors.initials: JJ
authors.lastname: Jones
authors.forename: Mark F
authors.initials: MF
authors.lastname: Conrad
authors.forename: William G
authors.initials: WG
authors.lastname: Austen
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Fink
authors.forename: Michael T
authors.initials: MT
authors.lastname: Watkins
mesh_terms: D000255:Adenosine Triphosphate / Q000032:analysis* / Q000378:metabolism; D000818:Animals; D000990:Antithrombin III / Q000032:analysis; D004195:Disease Models, Animal; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D007375:Interleukin-1 / Q000032:analysis; D007773:Lactates / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D010447:Peptide Hydrolases / Q000032:analysis; D009195:Peroxidase / Q000032:analysis; D011773:Pyruvates / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*
chemical_list: D007375:Interleukin-1; D007773:Lactates; D011773:Pyruvates; C046193:antithrombin III-protease complex; C046522:ethyl pyruvate; D000255:Adenosine Triphosphate; D000990:Antithrombin III; D009195:Peroxidase; D010447:Peptide Hydrolases