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Caspase-1 and poly (ADP-ribose) polymerase inhibitors may protect against peroxynitrite-induced neurotoxicity independent of their enzyme inhibitor activity.
In: European Journal of Neuroscience, Jg. 20 (2004-10-01), Heft 7, S. 1727-1736
Online
academicJournal
Zugriff:
We investigated the mechanism of 3-morpholinosyndnomine (SIN-1) neurotoxicity in nearly pure neuronal cultures. In a simple saline solution, SIN-1 neurotoxicity was found to be mediated by peroxynitrite and independent of glutamate receptor activation[Y. Zhang&P.A. Rosenberg (2002)Eur. J. Neurosci,16, 1015–1024]. To further study the mechanism of peroxynitrite toxicity to neurons we investigated the role of caspases and poly (ADP-ribose) polymerase (PARP) in this model system. Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (Ac-YVAD-cmk), a specific caspase-1 inhibitor, completely blocked neurotoxicity as well as ATP depletion induced by SIN-1. However, a caspase-3 inhibitor and a pan-caspase inhibitor were both without effect. These results suggested that the protection of Ac-YVAD-cmk might not be due to its inhibition of caspase-1. Indeed, Western blot analysis and assay of caspase activity indicated that caspase activation was not involved in SIN-1 toxicity. Ac-YVAD-cmk also completely blockedin vitroprotein nitration induced by SIN-1 or peroxynitrite, suggesting that Ac-YVAD-cmk may interact with peroxynitrite directly. Similarly, although activation of PARP is thought to be a major cause of peroxynitrite-induced ATP depletion, and two PARP inhibitors, 1,5-dihydroxyisoquinoline (DHQ) and 3-aminobenzamide (3-AB), completely prevented ATP depletion and neurotoxicity induced by SIN-1, SIN-1 did not increase poly (ADP-ribosyl)ation and PARP activity. Furthermore, DHQ and 3-AB completely preventedin vitroprotein nitration induced by peroxynitrite, indicating that DHQ and 3-AB directly interact with peroxynitrite. Taken together, these results suggest that in the model system used here peroxynitrite neurotoxicity is independent of caspase and PARP activation, and therefore implicate a novel mechanism. [ABSTRACT FROM AUTHOR]
Titel: |
Caspase-1 and poly (ADP-ribose) polymerase inhibitors may protect against peroxynitrite-induced neurotoxicity independent of their enzyme inhibitor activity.
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Autor/in / Beteiligte Person: | Zhang, Yumin ; Rosenberg, Paul A. |
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Zeitschrift: | European Journal of Neuroscience, Jg. 20 (2004-10-01), Heft 7, S. 1727-1736 |
Veröffentlichung: | 2004 |
Medientyp: | academicJournal |
ISSN: | 0953-816X (print) |
DOI: | 10.1111/j.1460-9568.2004.03651.x |
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