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Protection against TNF-induced liver parenchymal cell apoptosis during endotoxemia by a novel caspase inhibitor in
H Jaeschke1, A Farhood, S X Cai
1Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Abstract:
Excessive apoptotic cell death is implicated in a growing number of acute and chronic disease states. Caspases are critical for the intracellular signaling pathway leading to apoptosis. The aim of this investigation was to evaluate the efficacy and the mechanism of action of the novel caspase inhibitor CV1013 in a well-characterized model of TNF-induced apoptosis. Administration of 700 mg/kg galactosamine/100 microg/kg endotoxin (Gal/ET) induced hepatocellular apoptosis in C3Heb/FeJ mice as indicated by increased caspase-3 activity (706% above controls) and enhanced DNA fragmentation (3400% above controls) at 6 h. In addition, apoptosis was aggravated by the neutrophil-induced injury at 7 h (ALT activities: 4220 +/- 960 U/L and 48 +/- 4% necrosis). All animals died 8-12 h after Gal/ET treatment from shock and liver failure. A dose of 10 or 1 mg/kg of CV1013 administered three times (3, 4.5, and 5.5 h after Gal/ET) effectively prevented caspase-3 activation and parenchymal cell apoptosis at 6 h as well as the subsequent neutrophil-induced aggravation of the injury at 7 h after Gal/ET treatment. Animals treated with 10 mg/kg CV1013 survived for 24 h without liver injury. CV1013 reduced the processing of caspase-3 and caspase-8. This suggests that CV1013 may have inhibited the small amount of active caspase-8 generated at the receptor level. Because of the multiple amplification loops used to activate the entire caspase cascade, blocking the initial intracellular signal by CV1013 was highly effective in preventing apoptotic cell death. CV1013 has therapeutic potential for disease states with excessive apoptosis.
Insights
The novel caspase inhibitor CV1013 effectively prevented excessive apoptosis and liver injury in a mouse model. This compound shows therapeutic potential for diseases involving excessive cell death.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Excessive apoptotic cell death is linked to numerous acute and chronic diseases.
- Caspases play a crucial role in the intracellular signaling pathways that mediate apoptosis.
Purpose of the Study:
- To evaluate the efficacy and mechanism of action of the novel caspase inhibitor CV1013.
- To assess CV1013's effectiveness in a tumor necrosis factor (TNF)-induced apoptosis model.
Main Methods:
- Hepatocellular apoptosis was induced in C3Heb/FeJ mice using galactosamine/endotoxin (Gal/ET).
- The caspase inhibitor CV1013 was administered at different doses and time points post-Gal/ET induction.
- Caspase activity, DNA fragmentation, liver injury markers (ALT), and animal survival were assessed.
Main Results:
- Gal/ET treatment significantly increased caspase-3 activity and DNA fragmentation, leading to mortality from liver failure.
- CV1013 administration (10 or 1 mg/kg) prevented caspase-3 activation and apoptosis.
- The 10 mg/kg dose of CV1013 resulted in complete survival for 24 hours with no observed liver injury.
- CV1013 reduced the processing of caspase-3 and caspase-8, suggesting inhibition at the receptor level.
Conclusions:
- CV1013 effectively inhibits caspase activation and prevents apoptosis in a Gal/ET-induced liver injury model.
- Blocking early intracellular caspase signaling with CV1013 is a highly effective strategy against excessive apoptotic cell death.
- CV1013 demonstrates significant therapeutic potential for treating diseases characterized by excessive apoptosis.
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