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

Salvatore Cuzzocrea, Emanuela Mazzon, Emanuela Esposito, Carmelo Muià, Maha Abdelrahman, Rosanna Di Paola, Concetta Crisafulli, Placido Bramanti, Christoph Thiemermann

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Objective: This study investigated the effects of TDZD-8, a potent and selective GSK-3β 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-α and IL-1β 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.

Original languageEnglish
Pages (from-to)880-893
Number of pages14
JournalIntensive Care Medicine
Volume33
Issue number5
DOIs
Publication statusPublished - May 2007

Fingerprint

Glycogen Synthase Kinase 3
Reperfusion Injury
Reperfusion
Viscera
Arteries
Intestines
Arterial Pressure
P-Selectin
Superior Mesenteric Artery
Clinical Pharmacology
Clinical Medicine
Intercellular Adhesion Molecule-1
Interleukin-1
Constriction
Abdomen
Italy
Biomedical Research
Shock
Neutrophils
Ischemia

Keywords

  • 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
  • Adhesion molecules
  • Cytokines
  • Ischaemia/reperfusion
  • Myeloperoxidase
  • Nitrotyrosine

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Glycogen synthase kinase-3β inhibition attenuates the development of ischaemia/reperfusion injury of the gut. / Cuzzocrea, Salvatore; Mazzon, Emanuela; Esposito, Emanuela; Muià, Carmelo; Abdelrahman, Maha; Di Paola, Rosanna; Crisafulli, Concetta; Bramanti, Placido; Thiemermann, Christoph.

In: Intensive Care Medicine, Vol. 33, No. 5, 05.2007, p. 880-893.

Research output: Contribution to journalArticle

Cuzzocrea, S, Mazzon, E, Esposito, E, Muià, C, Abdelrahman, M, Di Paola, R, Crisafulli, C, Bramanti, P & Thiemermann, C 2007, 'Glycogen synthase kinase-3β inhibition attenuates the development of ischaemia/reperfusion injury of the gut', Intensive Care Medicine, vol. 33, no. 5, pp. 880-893. https://doi.org/10.1007/s00134-007-0595-1
Cuzzocrea, Salvatore ; Mazzon, Emanuela ; Esposito, Emanuela ; Muià, Carmelo ; Abdelrahman, Maha ; Di Paola, Rosanna ; Crisafulli, Concetta ; Bramanti, Placido ; Thiemermann, Christoph. / Glycogen synthase kinase-3β inhibition attenuates the development of ischaemia/reperfusion injury of the gut. In: Intensive Care Medicine. 2007 ; Vol. 33, No. 5. pp. 880-893.
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AU - Muià, Carmelo

AU - Abdelrahman, Maha

AU - Di Paola, Rosanna

AU - Crisafulli, Concetta

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AU - Thiemermann, Christoph

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N2 - Objective: This study investigated the effects of TDZD-8, a potent and selective GSK-3β 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-α and IL-1β 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.

AB - Objective: This study investigated the effects of TDZD-8, a potent and selective GSK-3β 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-α and IL-1β 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.

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