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| Activation of NF-kappa B protects hippocampal neurons against oxidative stress-induced apoptosis: Evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration |
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| Author(s): Mattson MP, Goodman Y, Luo H, Fu WM, Furukawa K |
| Source: JOURNAL OF NEUROSCIENCE RESEARCH Volume: 49 Issue: 6 Pages: 681-697 Published: SEP 15 1997 |
| Times Cited: 390 References: 93 |
| Abstract: The transcription factor NF-kappa B is expressed in neurons wherein it is activated in response to a variety of stress-and injury-related stimuli including exposure to cytokines such as tumor necrosis factor-alpha (TNF alpha), and excitotoxic and oxidative insults. NF-kappa B may play a role in the anti-death actions of TNF alpha in cultured hippocampal neurons exposed to metabolic and oxidative insults. We now report that pretreatment of hippocampal cell cultures with agents that activate NF-kappa B (TNF alpha and C2-ceramide) confers resistance of neurons to apoptosis induced by the oxidative insults FeSO4 and amyloid beta-peptide (A beta 25-35). The neuroprotective actions of TNF alpha and ceramide were abolished in cultures cotreated with kappa B decoy DNA demonstrating a requirement for NF-kappa B activation for prevention of cell death. Levels of manganese superoxide dismutase (Mn-SOD) in neurons were increased following exposure of cultures to TNF alpha and ceramide in control cultures, but not in cultures cotreated with kappa B decoy DNA. FeSO4 and A beta 25-35 induced accumulation of mitochondrial peroxynitrite, and membrane lipid peroxidation, in neurons. Peroxynitrite accumulation and lipid peroxidation were largely prevented in neurons pretreated with TNF alpha and ceramide prior to exposure to FeSO4 and A beta 25-35, an effect blocked by kappa B decoy DNA. Immunoreactivity of neurons with an anti-nitrotyrosine antibody was increased following exposure to FeSO4 and A beta 25-35; TNF alpha and C2-ceramide suppressed protein tyrosine nitration, and kappa B decoy DNA blocked the effects of TNF alpha and C2-ceramide. Finally, the peroxynitrite scavenger uric acid protected neurons against apoptosis induced by FeSO4 and A beta, and suppressed peroxynitrite accumulation. We conclude that, by inducing production of Mn-SOD and suppressing peroxynitrite formation and membrane lipid peroxidation, NF-kappa B plays an anti-apoptotic role in neurodegenerative conditions that involve oxidative stress. The data further suggest important roles for peroxynitrite and NF-kappa B in the pathogenesis of neuronal degeneration in Alzheimer's disease. (C) 1997 Wiley-Liss, Inc. |
| Document Type: Article |
| Language: English |
| Reprint Address: Mattson, MP (reprint author), UNIV KENTUCKY, SANDERS BROWN CTR AGING, 211 SANDERS BROWN BLDG, LEXINGTON, KY 40536 USA |
Addresses:
1. UNIV KENTUCKY, DEPT ANAT & NEUROBIOL, LEXINGTON, KY 40536 USA |
| Publisher: WILEY-LISS, DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 |
| Subject Category: Neurosciences |
| IDS Number: XY944 |
| ISSN: 0360-4012 |
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