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.
References
89
Referenced
20
10.1073/pnas.95.13.7659
10.1038/sj.onc.1202823
10.1523/JNEUROSCI.18-16-06241.1998
10.1016/S0165-0270(99)00062-X
10.1159/000111432
10.1073/pnas.87.4.1620
10.1152/ajpcell.1996.271.5.C1424
10.1006/excr.1994.1093
10.1046/j.1471-4159.1995.64051965.x
10.1016/S0891-5849(96)00240-7
10.1073/pnas.92.16.7162
10.1074/jbc.M001077200
10.1523/JNEUROSCI.19-01-00147.1999
10.1074/jbc.M909978199
10.1007/s000180050353
10.1046/j.1471-4159.1997.69051945.x
10.1038/sj.cdd.4400641
10.1016/0006-8993(78)90476-6
10.1007/s000180050357
10.1038/nm1097-1089
{'key': 'e_1_2_25_22_1', 'first-page': '670', 'article-title': 'Mechanisms of cell injury by activated oxygen species', 'volume': '62', 'author': 'Farber J.L.', 'year': '1990', 'journal-title': 'Laboratory Invest.'}
/ Laboratory Invest. / Mechanisms of cell injury by activated oxygen species by Farber J.L. (1990)10.1097/00005344-198914110-00004
10.1038/40299
10.1038/sj.cdd.4400433
10.1073/pnas.96.24.13978
10.1016/S0005-2728(98)00168-6
10.1006/exnr.2000.7322
10.1042/bj2810419
10.4049/jimmunol.151.6.2965
/ J. Immunol. / Apoptosis in splenic B lymphocytes. Regulation by protein kinase C and IL‐4 by Illera V.A. (1993)10.1074/jbc.273.21.12716
10.1002/ijc.2910520622
10.1006/exnr.1995.1074
10.1007/978-1-4419-8632-0_25
10.1016/0076-6879(86)33055-6
10.1084/jem.185.8.1481
10.1006/excr.1999.4514
10.1111/j.1471-4159.1991.tb08220.x
10.1126/science.288.5464.335
10.1038/364626a0
10.1016/S0891-5849(97)00295-5
10.1021/bi971894b
10.1523/JNEUROSCI.20-21-08005.2000
10.1016/S0091-679X(08)61929-9
10.1523/JNEUROSCI.18-10-03659.1998
10.1016/S0968-0004(97)01085-2
10.1038/20446
10.1523/JNEUROSCI.17-09-03064.1997
10.1073/pnas.95.26.15763
10.1016/S0165-6147(99)01292-4
10.1016/0003-9861(91)90224-7
10.1002/glia.440040111
10.1016/0304-3940(89)90569-7
10.1523/JNEUROSCI.12-01-00056.1992
10.1523/JNEUROSCI.20-16-06294.2000
10.1073/pnas.95.5.2659
10.1016/S0092-8674(00)80430-4
10.1073/pnas.83.13.4908
10.1023/A:1006852306789
10.1002/1531-8249(199901)45:1<120::AID-ART18>3.3.CO;2-9
10.1523/JNEUROSCI.20-09-03139.2000
10.1021/bi00291a019
10.1046/j.1365-2222.1998.00312.x
10.1006/abbi.2000.1721
10.1152/ajpcell.1991.260.5.C910
10.1523/JNEUROSCI.19-15-06235.1999
10.1097/00024382-199608000-00001
10.1016/S0378-4274(02)00507-6
10.1016/S0165-6147(98)01193-6
10.1006/niox.1997.0143
10.1073/pnas.95.7.3867
10.1046/j.1471-4159.1998.71041588.x
10.1016/S0891-5849(03)00392-7
10.1016/S0165-0173(99)00014-4
10.1046/j.1471-4159.2001.00584.x
10.1046/j.1365-2567.1998.00534.x
10.1038/sj.bjp.0702332
10.1096/fj.00-0299com
10.1124/pr.54.3.375
10.1124/mol.53.1.88
10.1002/em.2850190303
10.1007/BF00276973
10.1074/jbc.274.29.20049
10.1097/00024382-199807000-00003
10.1016/S1383-5742(97)00011-2
10.1523/JNEUROSCI.17-19-07415.1997
10.1038/35037739
10.1126/science.8080500
10.1046/j.1460-9568.2002.02169.x
10.4049/jimmunol.165.3.1252
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) |
@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} }