Inhibition of glycogen synthase kinase (GSK)-3-β improves liver microcirculation and hepatocellular function after hemorrhagic shock.

Abstract

Ischemia and reperfusion may cause liver injury and are characterized by hepatic microperfusion failure and a decreased hepatocellular function. Inhibition of glycogen synthase kinase (GSK)-3β, a serine-threonine kinase that has recently emerged as a key regulator in the modulation of the inflammatory response after stress events, may be protective in conditions like sepsis, inflammation and shock. Therefore, aim of the study was to assess the role of GSK-3β in liver microcirculation and hepatocellular function after hemorrhagic shock and resuscitation (H/R). Anesthetized male Sprague-Dawley rats underwent pretreatment with Ringer´s solution, vehicle (DMSO) or TDZD-8 (1 mg/kg), a selective GSK-3β inhibitor, 30 min before induction of hemorrhagic shock (mean arterial pressure 35±5 mmHg for 90 min) and were resuscitated with shed blood and Ringer´s solution (2h). 5h after resuscitation hepatic microcirculation was assessed by intravital microscopy. Propidium iodide (PI) positive cells, liver enzymes and alpha-GST were measured as indicators of hepatic injury. Liver function was estimated by assessment of indocyanine green plasma disappearance rate. H/R led to a significant decrease in sinusoidal diameters and impairment of liver function compared to sham operation. Furthermore, the number of PI positive cells in the liver as well as serum activities of liver enzymes and alpha-GST increased significantly after H/R. Pretreatment with TDZD-8 prevented the changes in liver microcirculation, hepatocellular injury and liver function after H/R. A significant rise in the plasma level of IL-10 was observed. Thus, inhibition of GSK-3β before hemorrhagic shock modulates the inflammatory response and improves hepatic microcirculation and hepatocellular function.

• Authors: Lena Jellestad, Tobias Fink, Sascha Pradarutti, Darius Kubulus, Beate Wolf, Inge Bauer, Chris Thiemermann, Hauke Rensing
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 724 Pg. 175-84 (Feb 05 2014) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 24389157 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
• Thiadiazoles
• Tumor Necrosis Factor-alpha
• Interleukin-10
• Glutamate Dehydrogenase
• Glutathione Transferase
• Aspartate Aminotransferases
• Alanine Transaminase
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Glycogen Synthase Kinase 3

Topics

• Alanine Transaminase (blood)
• Animals
• Aspartate Aminotransferases (blood)
• Glutamate Dehydrogenase (blood)
• Glutathione Transferase (blood)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Glycogen Synthase Kinase 3 beta
• Hepatocytes (drug effects, pathology)
• Interleukin-10 (blood)
• Liver (blood supply, drug effects)
• Male
• Microcirculation (drug effects)
• Rats
• Rats, Sprague-Dawley
• Regional Blood Flow (drug effects)
• Shock, Hemorrhagic (blood, physiopathology)
• Thiadiazoles (pharmacology)
• Tumor Necrosis Factor-alpha (blood)