Mitochondrial Permeability Transition Inhibitor Shows Promise in Treating Cholestatic Liver Injury

Researchers from the Medical University of South Carolina have made a significant discovery in the treatment of cholestatic liver injury, a condition that can lead to liver failure. The study, published in the Journal of Pharmacology and Experimental Therapeutics, found that a mitochondrial permeability transition inhibitor, NIM811, can effectively reduce cholestatic necrosis and apoptosis, but not fibrosis, in mice.

Key Takeaways:

• Cholestasis causes hepatocyte death due to mitochondrial injury, which can lead to liver failure.
• NIM811, a mitochondrial permeability transition inhibitor, was found to attenuate cholestatic liver injury in mice by reducing mitochondrial depolarization, cell death, and apoptosis.
• The study showed that NIM811 decreased serum alanine aminotransferase (ALT), hepatic necrosis, and apoptosis by 60-86% in mice with bile duct ligation (BDL).
• Intravital confocal/multiphoton microscopy revealed that depolarization preceded necrosis in vehicle-treated mice, and NIM811 prevented mitochondrial depolarization and calcein entry into mitochondria.
• The researchers concluded that the mitochondrial permeability transition plays an important role in cholestatic cell death in vivo, and NIM811 shows promise as a potential treatment for cholestatic liver injury.

Statistics:

• 18 viable hepatocytes with depolarized mitochondria were found per high-power field (hpf) in vehicle-treated mice 6 hours after BDL.
• Nonviable cells were approximately 1/hpf in vehicle-treated mice 6 hours after BDL.
• NIM811 decreased depolarization by 72% and prevented calcein entry into mitochondria.
• The study found that NIM811 did not block fibrosis in mice with cholestatic liver injury.

Sources:

• Rehman, H. et al. (2008). NIM811 (N-Methyl-4-isoleucine Cyclosporine), a Mitochondrial Permeability Transition Inhibitor, Attenuates Cholestatic Liver Injury but Not Fibrosis in Mice. Journal of Pharmacology and Experimental Therapeutics, 327(3), 699-706.
• Biotech Week editors (2009). Mitochondrial Permeability Transition Inhibitor Shows Promise in Treating Cholestatic Liver Injury. Biotech Week.