Skip to main content

Advertisement

SpringerLink
Log in

RETRACTED ARTICLE: Glycogen synthase kinase-3β inhibition attenuates the development of ischaemia/reperfusion injury of the gut

  • Experimental
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

This article was retracted on 18 January 2024

This article has been updated

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Change history

References

  1. Di Paola R, Muia C, Mazzon E, Genovese T, Crisafulli C, Menegazzi M, Caputi AP, Suzuki H, Cuzzocrea S (2005) Effects of hypericum perforatum extract in a rat model of ischemia and reperfusion injury. Shock 24:255–263

    Article  PubMed  Google Scholar 

  2. Lefer AM, Lefer DJ (1993) Pharmacology of the endothelium in ischaemia-reperfusion and circulatory shock. Annu Rev Pharmacol Toxicol 33:71–90

    Article  CAS  PubMed  Google Scholar 

  3. Butcher EC (1992) Leukocyte-endothelial cell adhesion as an active, multi-step process: a combinatorial mechanism for specificity and diversity in leukocyte targeting. Adv Exp Med Biol 323:181–194

    Article  CAS  PubMed  Google Scholar 

  4. Hubbard AK, Rothlein R (2000) Intercellular adhesion molecule-1 (ICAM-1) expression and cell signaling cascades. Free Radic Biol Med 28:1379–1386

    Article  CAS  PubMed  Google Scholar 

  5. Van Wauwe J, Haefner B (2003) Glycogen synthase kinase-3 as drug target: from wallflower to center of attention. Drug News Perspect 16:557–565

    Article  PubMed  Google Scholar 

  6. Woodgett JR (2001) Judging a protein by more than its name: GSK-3. Sci STKE 100:RE12

    Google Scholar 

  7. Coghlan MP, Culbert AA, Cross DA, Corcoran SL, Yates JW, Pearce NJ, Rausch OL, Murphy GJ, Carter PS, Roxbee Cox L, Mills D, Brown MJ, Haigh D, Ward RW, Smith DG, Murray KJ, Reith AD, Holder JC (2000) Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription. Chem Biol 7:793–803

    Article  CAS  PubMed  Google Scholar 

  8. Ali A, Hoeflich KP, Woodgett JR (2001) Glycogen synthase kinase-3: properties, functions and regulation. Chem Rev 101:2527–2540

    Article  CAS  PubMed  Google Scholar 

  9. Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR (2000) Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406:86–90

    Article  CAS  PubMed  Google Scholar 

  10. Takada Y, Fang X, Jamaluddin MS, Boyd DD, Aggarwal BB (2004) Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. J Biol Chem 279:39541–39554

    Article  CAS  PubMed  Google Scholar 

  11. Dugo L, Collin M, Allen DA, Patel NS, Bauer I, Mervaala EM, Louhelainen M, Foster SJ, Yaqoob MM, Thiemermann C (2005) GSK-3 beta inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat. Crit Care Med 33:1903–1912

    Article  CAS  PubMed  Google Scholar 

  12. Martin M, Rehani K, Jope RS, Michalek SM (2005) Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 6:777–784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Whittle BJR, Varga C, Pòsa A, Molnar A, Collin M, Thiemermann C (2006) Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3β. Br J Pharmacol 147:575–582

    Article  CAS  PubMed  Google Scholar 

  14. Cuzzocrea S, Genovese T, Mazzon E, Crisafulli C, Di Paola R, Muia C, Collin M, Esposito E, Bramanti P, Thiemermann C (2006) Glycogen synthase kinase-3{beta} inhibition reduces secondary damage in experimental spinal cord trauma. J Pharmacol Exp Ther 318:79–89

    Article  CAS  PubMed  Google Scholar 

  15. Caputi AP, Rossi F, Carney K, Brezenoff HE (1980) Modulatory effect of brain acetylcholine on reflex-induced bradycardia and tachycardia in conscious rats. J Pharmacol Exp Ther 215:309–316

    CAS  PubMed  Google Scholar 

  16. Hayward R, Lefer AM (1998) Time course of endothelial-neutrophil interaction in splanchnic artery ischaemia-reperfusion Am J Physiol 275:2080–2086

    Google Scholar 

  17. Dugo L, Collin M, Allen DA, Patel NS, Bauer I, Mervaala EM, Louhelainen M, Foster SJ, Yaqoob MM, Thiemermann C (2005) GSK-3 beta inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat. Crit Care Med 33:1903–1912

    Article  CAS  PubMed  Google Scholar 

  18. Cuzzocrea S, Mazzon E, Di Paola R, Muià C, Crisafulli C, Dugo L, Collin M, Britti D, Caputi AP, Thiemermann C (2006) Glycogen synthase kinase-3β inhibition attenuate the degree of arthritis caused by type II collagen in the mouse. Clinical Immunology 120:57–67

    Article  CAS  PubMed  Google Scholar 

  19. Cuzzocrea S, Crisafulli C, Mazzon E, Esposito E, Muia C, Abdelrahman M, Di Paola R, Thiemermann C (2006) Inhibition of glycogen synthase kinase-3beta attenuates the development of carrageenan-induced lung injury in mice. Br J Pharmacol 149:687–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cuzzocrea S, Di Paola R, Mazzon E, Genovese T, Muia C, Centorrino T, Caputi AP (2004) Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors alpha (PPAR-alpha) in the development of inflammatory bowel disease in mice. Lab Invest 84:1643–1654

    Article  CAS  PubMed  Google Scholar 

  21. Mullane KM, Kraemer R, Smith B (1985) Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium. J Pharmacol Methods 14:157–167

    Article  CAS  PubMed  Google Scholar 

  22. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 92:351–358

    Article  Google Scholar 

  23. Cuzzocrea S, Sautebin L, De Sarro G, Costantino G, Rombola L, Mazzon E, Ialenti A, De Sarro A, Ciliberto G, Di Rosa M, Caputi AP, Thiemermann C (1999) Role of IL-6 in the pleurisy and lung injury caused by carrageenan. J Immunol 163:5094–5104

    Article  CAS  PubMed  Google Scholar 

  24. Albert CJ, Ford DA (1998) Identification of specific nuclear protein kinase C isozymes and accelerated protein kinase C-dependent nuclear protein phosphorylation during myopcardial ischemia. FEBS Lett 438:32–36

    Article  CAS  PubMed  Google Scholar 

  25. Cuzzocrea S, Riley DP, Caputi AP, Salvemini D (2001) Antioxidant therapy: a new pharmacological approach in shock, inflammation, and ischemia/reperfusion injury. Pharmacol Rev 53:135–159

    CAS  PubMed  Google Scholar 

  26. Verma IM (2004) Nuclear factor (NF)-kappaB proteins: therapeutic targets. Ann Rheum Dis 2:57–61

    Google Scholar 

  27. Cuzzocrea S (2004) Peroxisome proliferator-activated receptors gamma ligands and ischemia and reperfusion injury. Vascul Pharmacol 41:187–195

    Article  CAS  PubMed  Google Scholar 

  28. Salvemini D, Muscoli C, Riley DP, Cuzzocrea S (2002) Superoxide dismutase mimetics. Pulm Pharmacol Ther 15:439–447

    Article  CAS  PubMed  Google Scholar 

  29. Cuzzocrea S, Costantino G, Mazzon E, Micali A, De Sarro A, Caputi AP (2000) Beneficial effects of melatonin in a rat model of splanchnic artery occlusion and reperfusion. J Pineal Res 28:52–63

    Article  CAS  PubMed  Google Scholar 

  30. Romeo C, Antonuccio P, Esposito M, Marini H, Impellizzeri P, Turiaco N, Altavilla D, Bitto A, Zuccarello B, Squadrito F (2004) Raxofelast, a hydrophilic vitamin e-like antioxidant, reduces testicular ischemia-reperfusion injury. Urol Res 32:367–371

    Article  CAS  PubMed  Google Scholar 

  31. Cuzzocrea S, Mazzon E, Dugo L, Caputi AP, Aston K, Riley DP, Salvemini D (2001) Protective effects of a new stable, highly active SOD mimetic, M40401 in splanchnic artery occlusion and reperfusion. Br J Pharmacol 132:19–29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Misko TP, Costantino G, Mazzon E, Micali A, Caputi AP, Macarthur H, Salvemini D (2000) Beneficial effects of peroxynitrite decomposition catalyst in a rat model of splanchnic artery occlusion and reperfusion. FASEB J 14:1061–1072

    Article  PubMed  Google Scholar 

  33. Pap M, Cooper GM (1998) Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 273:19929–19932

    Article  CAS  PubMed  Google Scholar 

  34. Bournat JC, Brown AM, Soler AP (2000) Wnt-1 dependent activation of the survival factor NF-kB in PC12 cells. J Neurosci Res 61:21–32

    Article  CAS  PubMed  Google Scholar 

  35. Ozes ON, Mayo LD, Gustin JA et al (1999) NF-kB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85

    Article  CAS  PubMed  Google Scholar 

  36. Carbott DE, Duan L, Davis MA (2002) Phosphoinositol 3 kinase inhibitor, LY294002 increases bcl-2 protein and inhibits okadaic acid-induced apoptosis in Bcl-2 expressing renal epithelial cells. Apoptosis 7:69–76

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grant from a University Minister grant. The authors thank Giovanni Pergolizzi and Carmelo La Spada for their excellent technical assistance during this study, Mrs. Caterina Cutrona for secretarial assistance and Miss Valentina Malvagni for editorial assistance with the manuscript.

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy

    Salvatore Cuzzocrea, Emanuela Mazzon, Carmelo Muià, Rosanna Di Paola & Concetta Crisafulli

  2. IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy

    Salvatore Cuzzocrea, Emanuela Mazzon, Rosanna Di Paola & Placido Bramanti

  3. Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy

    Emanuela Esposito

  4. William Harvey Research Institute, Centre for Experimental Medicine, Nephrology and Critical Care, St. Bartholomew’s, and Royal London School of Medicine and Dentistry, London, UK

    Maha Abdelrahman & Christoph Thiemermann

Authors
  1. Salvatore Cuzzocrea
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emanuela Mazzon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emanuela Esposito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carmelo Muià
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maha Abdelrahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rosanna Di Paola
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Concetta Crisafulli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Placido Bramanti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christoph Thiemermann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Salvatore Cuzzocrea.

About this article

Cite this article

Cuzzocrea, S., Mazzon, E., Esposito, E. et al. RETRACTED ARTICLE: Glycogen synthase kinase-3β inhibition attenuates the development of ischaemia/reperfusion injury of the gut. Intensive Care Med 33, 880–893 (2007). https://doi.org/10.1007/s00134-007-0595-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-007-0595-1

Keywords

Search

Navigation