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Indirubin-3'-oxime Prevents Hepatic I/R Damage by Inhibiting GSK-3beta and Mitochondrial Permeability Transition

Indirubin-3'-oxime Prevents Hepatic I/R Damage by Inhibiting GSK-3beta and Mitochondrial Permeability Transition

Ana T Varela, Anabela M Simões, João S Teodoro, Filipe V Duarte, Ana P Gomes, Carlos M Palmeira, Anabela P Rolo

Mitochondrion. 2010 Aug;10(5):456-63.

PMID: 20433952

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP160807498-A	Indirubin-3′-oxime		160807-49-8	Price

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