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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

NIM811 (N-Methyl-4-isoleucine Cyclosporine), a Mitochondrial Permeability Transition Inhibitor, Attenuates Cholestatic Liver Injury but Not Fibrosis in Mice

Departments of Pharmaceutical and Biomedical Sciences (H.R., V.K.R., T.P.T., I.K., J.J.L., Z.Z.) and Biochemistry and Molecular Biology (J.J.L.) and Children's Research Institute (S.G.), Medical University of South Carolina, Charleston, South Carolina; and Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina (R.T.C.)

Cholestasis causes hepatocyte death, possibly because of mitochondrial injury. This study investigated whether NIM811 (N-methyl-4-isoleucine cyclosporine), an inhibitor of the mitochondrial permeability transition (MPT), attenuates cholestatic liver injury in vivo. Cholestasis was induced in mice by bile duct ligation (BDL). NIM811 was gavaged (20 mg/kg) before BDL and daily (10 mg/kg) afterward. Mitochondrial depolarization, cell death, and MPT onset were assessed by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. After BDL, serum alanine aminotransferase (ALT), hepatic necrosis, and apoptosis all increased. NIM811 decreased ALT, necrosis, and apoptosis by 60 to 86%. In vehicle-treated mice at 6 h after BDL, viable hepatocytes with depolarized mitochondria were 18/high-power field (hpf), and nonviable cells were 1/hpf, showing that depolarization preceded necrosis. Calcein entered mitochondria after BDL, indicating MPT onset in vivo. NIM811 decreased depolarization by 72%, prevented calcein entry into mitochondria, and blocked release of cytochrome c. Hepatic tumor necrosis factor , transforming growth factor-β1, procollagen 1(I) mRNA, -smooth muscle actin, and Sirius red staining for collagen increased after BDL but were not different in vehicle- and NIM811-treated mice. Taken together, NIM811 decreased cholestatic necrosis and apoptosis but did not block fibrosis, indicating that the MPT plays an important role in cholestatic cell death in vivo.

Address correspondence to: Dr. Zhi Zhong, Department of Pharmaceutical and Biomedical, Sciences, Medical University of South Carolina, 280 Calhoun Street, P.O. Box 250140, Charleston, SC 29425. E-mail: zhong{at}musc.edu