PT  - JOURNAL ARTICLE
AU  - Niel C. Hoglen
AU  - Brad P. Hirakawa
AU  - Craig D. Fisher
AU  - Suzanne Weeks
AU  - Anu Srinivasan
AU  - Angela M. Wong
AU  - Karen L. Valentino
AU  - Kevin J. Tomaselli
AU  - Xu Bai
AU  - Don S. Karanewsky
AU  - Patricia C. Contreras
TI  - Characterization of the Caspase Inhibitor IDN-1965 in a Model of Apoptosis-Associated Liver Injury
DP  - 2001 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 811--818
VI  - 297
IP  - 2
4099  - http://jpet.aspetjournals.org/content/297/2/811.short
4100  - http://jpet.aspetjournals.org/content/297/2/811.full
SO  - J Pharmacol Exp Ther2001 May 01; 297
AB  - Previous studies have shown that caspase inhibitors are effective at protecting against anti-Fas antibody (α-Fas)-mediated liver injury/lethality. The purpose of these experiments was to characterize more fully the efficacy of a broad-spectrum, irreversible caspase inhibitor, IDN-1965 (N-[(1,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-fluoropentanoic acid), in this model and the role of caspase inhibition in long-term protection. The ED50 for IDN-1965 by i.p. administration, based on alanine aminotransferase activities, was 0.14 mg/kg. The caspase inhibitor was also efficacious when administered intravenously and orally (ED50 values of 0.04 and 1.2 mg/kg, respectively). Histologically, marked reduction in Fas-induced apoptosis with IDN-1965 (1 mg/kg, i.p.) was apparent at 6 h. Also, caspase 3-like activities were decreased in a dose-dependent manner, but the inhibition of caspase activity was transient. Immunohistochemical studies demonstrated that IDN-1965 greatly reduced the activation of caspase 3. In survival studies, a single i.p. treatment of 1 mg/kg IDN-1965 or continuous i.p. infusion via osmotic pumps completely blocked lethality measured up to 7 days after α-Fas administration. IDN-1965 was also effective in inhibiting liver injury when administered as long as 3 h after or 1 h before α-Fas administration. Lastly, Western blot analysis demonstrated that processing of caspases 3, 6, and 8, as well as Bid (a protein responsible for the release of mitochondrial cytochrome C and amplification of the apoptotic cascade) was inhibited by IDN-1965. In conclusion, the broad-spectrum caspase inhibitor IDN-1965 is markedly effective at inhibiting Fas-mediated apoptosis by multiple routes of administration. The therapeutic potential of caspase inhibitors appears promising for the treatment of apoptosis-mediated liver injury based on potency and postinsult efficacy. The American Society for Pharmacology and Experimental Therapeutics