Calpain inhibitor I reduces intestinal ischemia-reperfusion injury in the rat.
In this study we evaluated the effect of calpain inhibitor I on splanchnic artery occlusion (SAO) shock-mediated injury. SAO shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min. After 1 h of reperfusion, SAO-shocked rats developed a significant fall in mean arterial blood pressure. Western blot analysis of ileum revealed a marked decrease in of IkappaB-alpha expression, and immunohistochemical examination of necrotic ileum demonstrated a marked increase in the immunoreactivity to P-selectin, intracellular adhesion molecule (ICAM-1), nitrotyrosine formation, and nuclear enzyme poly[adenosine diphosphate (ADP)-ribose] synthase (PARS) activation. An increase in myeloperoxidase activity (143 +/- 22 4.5 U/100 mg wet tissue vs. 4.5 +/- 2.5 U/100 mg wet tissue of sham-operated rats) and in malondialdehyde levels (13.12 +/- 1.2 micromol/100 mg wet tissue vs. 3.9 +/- 1.1 micromol/100 mg wet tissue of sham-operated rats) was also observed in rats subjected to ischemia-reperfusion injury. Calpain inhibitor I, given intraperitoneally 30 min before ischemia at a dose of 15 mg/kg, significantly improved mean arterial blood pressure, markedly reduced IkappaB-alpha degradation and the intensity of P-selectin and ICAM-1 in the reperfused ileum. Calpain inhibitor I also significantly prevented neutrophil infiltration (32.95 +/- 9.82 U/100 mg wet tissue), reduced malondialdehyde levels (6.76 +/- 0.98 micromol/100 mg wet tissue) and markedly improved the histological status of the reperfused tissue. In conclusion, this study demonstrates that calpain inhibitor I exerts multiple protective effects in splanchnic artery occlusion-reperfusion shock and suggests that calpain inhibitor I may be a candidate for consideration as a therapeutic intervention for ischemia-reperfusion injury.
Marzocco
Stefania
S
Department of Pharmaceutical Sciences, University of Salerno, Fisciano-Salerno, Italy.
Di Paola
Rosanna
R
Autore
Giuseppina
G
Mazzon
Emanuela
E
Pinto
Aldo
A
Caputi
Achille P
AP
Thiemermann
Cristoph
C
Cuzzocrea
Salvatore
S
D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism; D007082:Ileum / Q000378:metabolism; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009504:Neutrophils / Q000473:pathology; D019007:P-Selectin / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D012769:Shock; D013152:Splanchnic Circulation; D013997:Time Factors; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D020672:I-kappa B Proteins; C000606206:Nfkbia protein, rat; D019007:P-Selectin; C039304:calpain inhibitors; D018799:Intercellular Adhesion Molecule-1; D000072000:NF-KappaB Inhibitor alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D008315:Malondialdehyde; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases