Glycogen synthase kinase-3beta inhibition attenuates the development of ischaemia/reperfusion injury of the gut

Intensive Care Med. 2007 May;33(5):880-893. doi: 10.1007/s00134-007-0595-1. Epub 2007 Mar 24.

Abstract

Objective: This study investigated the effects of TDZD-8, a potent and selective GSK-3beta inhibitor, on tissue injury caused by ischaemia/reperfusion (I/R) of the gut.

Design and setting: Animal study in the Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.

Subjects: Splanchnic artery occlusion (SAO) shocked rats.

Interventions: I/R injury of the intestine was caused by clamping both the superior mesenteric artery and the coeliac trunk for 45 min followed by release of the clamp allowing reperfusion for 1 or 6 h. This procedure results in SAO shock.

Measurements and results: Only 10% of the SAO animals survived the entire 6 h reperfusion period. In a separate set of experiments after 60 min of reperfusion animals were killed for histological examination and biochemical studies. Administration of TDZD-8 (1 mg/kg i.v.) 5 min prior to the reperfusion significantly reduced the (a) fall in mean arterial blood pressure, (b) mortality rate, (c) infiltration of the reperfused intestine with polymorphonuclear neutrophils (MPO activity), (d) production of pro-inflammatory cytokines (TNF-alpha and IL-1 beta and (e) histological evidence of gut injury. Administration of TDZD-8 also markedly reduced the immunoreactivity of nitrotyrosine formation and the expression of ICAM-1 and P-selectin during reperfusion.

Conclusions: Based on these findings we propose that TDZD-8 would be useful in the treatment of various ischaemia and reperfusion diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / blood
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta
  • Ileum / injuries
  • Ileum / pathology
  • In Situ Nick-End Labeling
  • Male
  • Malondialdehyde / blood
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / prevention & control*
  • Splanchnic Circulation*
  • Thiadiazoles / pharmacology*
  • Thiadiazoles / therapeutic use

Substances

  • 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
  • Cytokines
  • Thiadiazoles
  • Malondialdehyde
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3