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Minocycline and N ‐methyl‐4‐isoleucine cyclosporin (NIM811) mitigate storage/reperfusion injury after rat liver transplantation through suppression of the mitochondrial permeability transition
Author(s) -
Theruvath Tom P.,
Zhong Zhi,
Pediaditakis Peter,
Ramshesh Venkat K.,
Currin Robert T.,
Tikunov Andrey,
Holmuhamedov Ekhson,
Lemasters John J.
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21912
Subject(s) - minocycline , mitochondrial permeability transition pore , transplantation , pharmacology , mptp , chemistry , apoptosis , programmed cell death , biology , medicine , pathology , biochemistry , surgery , parkinson's disease , disease , antibiotics
Graft failure after liver transplantation may involve mitochondrial dysfunction. We examined whether prevention of mitochondrial injury would improve graft function. Orthotopic rat liver transplantation was performed after 18 hours' cold storage in University of Wisconsin solution and treatment with vehicle, minocycline, tetracycline, or N ‐methyl‐4‐isoleucine cyclosporin (NIM811) of explants and recipients. Serum alanine aminotransferase (ALT), necrosis, and apoptosis were 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 liver mitochondria. After transplantation with vehicle or tetracycline, ALT increased to 5242 U/L and 4373 U/L, respectively. Minocycline and NIM811 treatment decreased ALT to 2374 U/L and 2159 U/L, respectively ( P < 0.01). Necrosis and terminal deoxynucleotidyl transferase‐mediated nick‐end labeling (TUNEL) also decreased from 21.4% and 21 cells/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 survival was 27% and 33%, respectively, after vehicle and tetracycline treatment, which increased to 60% and 70% after minocycline and NIM811 ( P < 0.05). In isolated mitochondria, minocycline and NIM811 but not tetracycline blocked the MPT. Minocycline blocked the MPT by decreasing mitochondrial Ca 2+ 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 improved graft survival. Minocycline and/or NIM811 might be useful clinically in hepatic surgery and transplantation. (H EPATOLOGY 2007.)