Protective effect of MDL28170 against thioacetamide-induced acute liver failure in mice.
Liver injury is known to often progress even after the hepatotoxicant is dissipated. The hydrolytic enzyme calpain, which is released from dying hepatocytes, destroys the surrounding cells and results in progression of injury. Therefore, control of calpain activation may be a suitable therapeutic intervention in cases of fulminant hepatic failure. This study evaluated the effects of a potent cell-permeable calpain inhibitor, MDL28170, and its mechanisms of action on thioacetamide (TAA)-induced hepatotoxicity in mice. We found that MDL28170 significantly decreased mortality and change in serum transaminase after TAA administration. The necroinflammatory response in the liver was also suppressed. Furthermore, a significant suppression of hepatocyte apoptosis could be found by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. The upregulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha), both of which are known to mediate the propagation of inflammation, was abolished. MDL2810 also effectively blocked hepatic stellate cell activation, which is assumed to be the early step in liver fibrosis. These results demonstrated that MDL28170 attenuated TAA-induced acute liver failure by inhibiting hepatocyte apoptosis, abrogating iNOS and TNF-alpha mRNA upregulation and blocking hepatic stellate cell activation.
Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, ROC.
Cheng-Haung
CH
Wang
Yann-Jang
YJ
Chen
Tsung-Hsing
TH
Lee
Yi-Shen
YS
Chen
Bruno
B
Jawan
Kuo-Sheng
KS
Hung
Cheng-Nan
CN
Lu
Jong-Kang
JK
Liu
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013853:Thioacetamide / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D014409:Tumor Necrosis Factor-alpha; D013853:Thioacetamide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000410:Alanine Transaminase; C058076:calpain inhibitor III