Crossref journal-article
Wiley
European Journal of Neuroscience (311)
Abstract

AbstractWe 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 blocked in vitro protein 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 prevented in vitro protein 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.

Bibliography

Zhang, Y., & Rosenberg, P. A. (2004). Caspase‐1 and poly (ADP‐ribose) polymerase inhibitors may protect against peroxynitrite‐induced neurotoxicity independent of their enzyme inhibitor activity. European Journal of Neuroscience, 20(7), 1727–1736. Portico.

Authors 2
  1. Yumin Zhang (first)
  2. Paul A. Rosenberg (additional)
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Dates
Type When
Created 20 years, 8 months ago (Dec. 23, 2004, 1:57 a.m.)
Deposited 1 year, 10 months ago (Oct. 13, 2023, 1:57 a.m.)
Indexed 1 year, 3 months ago (May 13, 2024, 9:10 a.m.)
Issued 20 years, 11 months ago (Sept. 14, 2004)
Published 20 years, 11 months ago (Sept. 14, 2004)
Published Online 20 years, 11 months ago (Sept. 14, 2004)
Published Print 20 years, 11 months ago (Oct. 1, 2004)
Funders 0

None

@article{Zhang_2004, title={Caspase‐1 and poly (ADP‐ribose) polymerase inhibitors may protect against peroxynitrite‐induced neurotoxicity independent of their enzyme inhibitor activity}, volume={20}, ISSN={1460-9568}, url={http://dx.doi.org/10.1111/j.1460-9568.2004.03651.x}, DOI={10.1111/j.1460-9568.2004.03651.x}, number={7}, journal={European Journal of Neuroscience}, publisher={Wiley}, author={Zhang, Yumin and Rosenberg, Paul A.}, year={2004}, month=sep, pages={1727–1736} }