Activation of NF-κB protects hippocampal neurons against oxidative stress-induced apoptosis: Evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration
✍ Scribed by Mark P. Mattson; Yadong Goodman; Hong Luo; Weiming Fu; Katsutoshi Furukawa
- Publisher
- John Wiley and Sons
- Year
- 1997
- Tongue
- English
- Weight
- 651 KB
- Volume
- 49
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
The transcription factor NF-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-␣ (TNF␣), and excitotoxic and oxidative insults. NF-B may play a role in the anti-death actions of TNF␣ in cultured hippocampal neurons exposed to metabolic and oxidative insults. We now report that pretreatment of hippocampal cell cultures with agents that activate NF-B (TNF␣ and C2-ceramide) confers resistance of neurons to apoptosis induced by the oxidative insults FeSO 4 and amyloid -peptide (A25-35). The neuroprotective actions of TNF␣ and ceramide were abolished in cultures cotreated with B decoy DNA demonstrating a requirement for NF-B activation for prevention of cell death. Levels of manganese superoxide dismutase (Mn-SOD) in neurons were increased following exposure of cultures to TNF␣ and ceramide in control cultures, but not in cultures cotreated with B decoy DNA. FeSO 4 and A25-35 induced accumulation of mitochondrial peroxynitrite, and membrane lipid peroxidation, in neurons. Peroxynitrite accumulation and lipid peroxidation were largely prevented in neurons pretreated with TNF␣ and ceramide prior to exposure to FeSO 4 and A25-35, an effect blocked by B decoy DNA. Immunoreactivity of neurons with an anti-nitrotyrosine antibody was increased following exposure to FeSO 4 and A25-35; TNF␣ and C2-ceramide suppressed protein tyrosine nitration, and B decoy DNA blocked the effects of TNF␣ and C2-ceramide. Finally, the peroxynitrite scavenger uric acid protected neurons against apoptosis induced by FeSO 4 and A, and suppressed peroxynitrite accumulation. We conclude that, by inducing production of Mn-SOD and suppressing peroxynitrite formation and membrane lipid peroxidation, NF-B plays an anti-apoptotic role in neurodegenerative conditions that involve oxidative stress. The data further suggest important roles for peroxynitrite and NF-B in the pathogenesis of neuronal degeneration in Alzheimer's disease.