Resveratrol protects against cold ischemia-warm reoxygenation-induced damages to mitochondria and cells in rat liver.
Ischemia-reperfusion is a critical event in the development of primary graft dysfunctions after liver transplantations. Ischemia-reperfusion causes cell injuries which are related to the successive cold preservation-warm reperfusion (CPWR) periods required by the graft. Recent evidences suggest that oxidative stress plays an important role in the development of these injuries and that mitochondrial dysfunctions are involved. The purpose of this study was to investigate the effect of the natural phytoalexin resveratrol on the prevention of liver injuries induced by 40-h cold preservation followed by a warm reperfusion. CPWR induced liver mitochondrial and cellular damages as attested by the increase in lipid peroxidation of liver membranes, the alteration of oxidative phosphorylation parameters, mitochondrial swelling and the activation of the cellular markers of necrosis and apoptosis, i.e., lactate dehydrogenase (LDH) leakage, mitochondrial cytochrome c release and caspase activation. Resveratrol inhibits lipid peroxidation and protects mitochondrial functions. It improves respiratory chain activity and prevents opening of the permeability transition pore, allowing better recovery of ATP energetic charge. Resveratrol also limits the activation of the cellular markers of necrosis and apoptosis. These protective effects could be related to the antioxidant properties of the drug but also to its membrane-stabilizing activity. Indeed, further experiments demonstrate that resveratrol is able to prevent the release of cytochrome c caused by oxygen deprivation in isolated liver mitochondria. These data demonstrate that resveratrol ameliorates the liver injury induced by CPWR and appears as a promising drug to improve the primary function of the grafted liver after transplantation.
Plin
Catherine
C
INSERM, U660, Créteil, F-94010 France.
Tillement
Jean-Paul
JP
Berdeaux
Alain
A
Morin
Didier
D
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D003080:Cold Temperature; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000201:enzymology; D008933:Mitochondrial Swelling / Q000187:drug effects; D009336:Necrosis; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015424:Reperfusion; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors
D000975:Antioxidants; D013267:Stilbenes; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; D020169:Caspases; D000077185:Resveratrol