Indirubin-3'-oxime prevents hepatic I/R damage by inhibiting GSK-3beta and mitochondrial permeability transition

Mitochondrion. 2010 Aug;10(5):456-63. doi: 10.1016/j.mito.2010.04.006. Epub 2010 Apr 28.

Abstract

Indirubin-3'-oxime is an indirubin analogue that shows favorable inhibitory activity targeting glycogen synthase kinase 3beta (GSK-3beta). In this study, we evaluated if acute treatment with indirubin-3'-oxime (Ind) prevents hepatic ischemia/reperfusion (I/R) damage. Wistar rats were subjected to 150 min of 70% warm ischemia and 16 h of reperfusion. In the treated group 1 microM indirubin-3'-oxime was administered in the hepatic artery 30 min before ischemia. Acute treatment with Ind decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels, comparatively to I/R livers. Bax translocation to the mitochondria and cytochrome c release were higher in I/R livers. Ind treatment significantly attenuated Bax translocation and preserved mitochondrial cytochrome c content. Ind also protected mitochondria from calcium-induced mitochondrial permeability transition (MPT), as well as the decrease in state 3 mitochondrial respiration, the delay in the repolarization after a phosphorylative cycle and the decrease in ATP content caused by I/R. By addressing GSK-3beta activity and phosphorylated GSK-3beta at Ser(9) content in liver homogenates and isolated mitochondria, data suggests that inhibition of GSK-3beta by indirubin-3'-oxime prevents the increase in mitochondrial phosphorylated GSK-3beta at Ser(9) induced by I/R, thus correlating with MPT inhibition and preservation of cytochrome c content. Pre-treatment with indirubin-3'-oxime in conditions of hepatic I/R, protects the liver by maintaining mitochondrial function and hepatic energetic balance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / metabolism
  • Animals
  • Aspartate Aminotransferases / metabolism
  • Cytochromes c / metabolism
  • Enzyme Inhibitors / administration & dosage*
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 beta
  • Indoles / administration & dosage*
  • L-Lactate Dehydrogenase / metabolism
  • Liver / drug effects*
  • Liver Function Tests
  • Male
  • Mitochondria / drug effects*
  • Oximes / administration & dosage*
  • Permeability / drug effects*
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / prevention & control*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Bax protein, rat
  • Enzyme Inhibitors
  • Indoles
  • Oximes
  • bcl-2-Associated X Protein
  • indirubin-3'-monoxime
  • Cytochromes c
  • L-Lactate Dehydrogenase
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3