LIVER BIOLOGY/PATHOBIOLOGY Minocycline and N-Methyl-4-Isoleucine Cyclosporin (NIM811) Mitigate Storage/Reperfusion Injury After Rat Liver Transplantation Through Suppression of the Mitochondrial Permeability Transition

Graft failure after liver transplantation may involve mitochondrial dysfunction. We examined whetherpreventionofmitochondrial injurywould improvegraft function.Orthotopic rat liver transplantationwas performed after 18 hours’ cold storage inUniversity ofWisconsin solution and treatment with vehicle, minocycline, tetracycline, or N-methyl-4-isoleucine cyclosporin (NIM811) of explants and recipients. Serumalanine aminotransferase (ALT), necrosis, and apoptosiswere assessed 6 hours after implantation. Mitochondrial polarization and cell viability were assessed by intravital microscopy. Respiration and the mitochondrial permeability transition (MPT) were assessed in isolated rat livermitochondria. After transplantationwith vehicle or tetracycline,ALT increased to5242 U/L and 4373 U/L, respectively. Minocycline and NIM811 treatment decreased ALT to 2374 U/L and2159U/L, respectively (P<0.01).Necrosis and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL)alsodecreased from21.4%and21cells/field, respectively, after vehicle to 10.1% and 6 cells/field after minocycline and to 8.7% and 5.2 cells/field after NIM811 (P< 0.05). Additionally, minocycline decreased caspase-3 activity in graft homogenates (P< 0.05). Long-term graft survivalwas27%and33%,respectively,aftervehicleandtetracyclinetreatment,whichincreased to 60%and 70%afterminocycline andNIM811 (P< 0.05). In isolatedmitochondria,minocycline and NIM811 but not tetracycline blocked the MPT. Minocycline blocked the MPT by decreasing mitochondrial Ca2 uptake, whereas NIM811 blocks by interaction with cyclophilin D. Intravital microscopy showed that minocycline and NIM811 preserved mitochondrial polarization and cell viability after transplantation (P < 0.05). Conclusion: Minocycline and NIM811 attenuated graft injury after rat liver transplantation and improvedgraft survival.Minocycline and/orNIM811might be useful clinically in hepatic surgery and transplantation. (HEPATOLOGY 2008;47:236-246.)