| Autor: |
N C, Hoglen, B P, Hirakawa, C D, Fisher, S, Weeks, A, Srinivasan, A M, Wong, K L, Valentino, K J, Tomaselli, X, Bai, D S, Karanewsky, P C, Contreras |
| Rok vydání: |
2001 |
| Předmět: |
|
| Zdroj: |
The Journal of pharmacology and experimental therapeutics. 297(2) |
| ISSN: |
0022-3565 |
| Popis: |
Previous studies have shown that caspase inhibitors are effective at protecting against anti-Fas antibody (alpha-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 ED(50) 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 (ED(50) 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 alpha-Fas administration. IDN-1965 was also effective in inhibiting liver injury when administered as long as 3 h after or 1 h before alpha-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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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