RT Journal Article
SR Electronic
T1 Characterization of the Caspase Inhibitor IDN-1965 in a Model of Apoptosis-Associated Liver Injury
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 811
OP 818
VO 297
IS 2
A1 Niel C. Hoglen
A1 Brad P. Hirakawa
A1 Craig D. Fisher
A1 Suzanne Weeks
A1 Anu Srinivasan
A1 Angela M. Wong
A1 Karen L. Valentino
A1 Kevin J. Tomaselli
A1 Xu Bai
A1 Don S. Karanewsky
A1 Patricia C. Contreras
YR 2001
UL http://jpet.aspetjournals.org/content/297/2/811.abstract
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