Glycogen synthase kinase-3β inhibitors protect against the organ injury and dysfunction caused by hemorrhage and resuscitation

Laura Dugo, Maha Abdelrahman, Oliver Murch, Emanuela Mazzon, Salvatore Cuzzocrea, Christoph Thiemermann

Research output: Contribution to journalArticle

Abstract

Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. Dysregulation of GSK-3β has been implicated in the pathogenesis of several diseases including sepsis. Here we investigate the effects of 2 chemically distinct inhibitors of GSK-3β, TDZD-8 and SB216763, on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock. Male Wistar rats were subjected to hemorrhage (sufficient to lower mean arterial blood pressure to 35 mmHg for 90 min) and subsequently resuscitated with shed blood for 4 h. Hemorrhage and resuscitation resulted in an increase in serum levels of (a) creatinine and, hence, renal dysfunction, and (b) alanine aminotransferase and aspartate aminotransferase and, hence, hepatic injury. Treatment of rats with either TDZD-8 (1 mg/kg, i.v.) or SB216763 (0.6 mg/ kg, i.v.) 5 min before resuscitation abolished the renal dysfunction and liver injury caused by hemorrhagic shock. In addition, TDZD-8, but not SB216763, attenuated the increase caused by hemorrhage and resuscitation in plasma levels of the proinflammatory cytokine interleukin 6 and also of the anti-inflammatory cytokine interleukin 10. Neither of the GSK-3β inhibitors however affected the delayed fall in blood pressure caused by hemorrhagic shock. Thus, we propose that inhibition of GSK-3β may represent a novel therapeutic approach in the therapy of hemorrhagic shock.

Original languageEnglish
Pages (from-to)485-491
Number of pages7
JournalShock
Volume25
Issue number5
DOIs
Publication statusPublished - May 2006

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Keywords

  • Multiple organ failure
  • Rat
  • SB216763
  • Shock
  • TDZD-8

ASJC Scopus subject areas

  • Physiology
  • Critical Care and Intensive Care Medicine

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