Activation of NF-?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

Publisher Website
Google Scholar
Abstract
The transcription factor NF-κB 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-α (TNFα), and excitotoxic and oxidative insults. NF-κB may play a role in the anti-death actions of TNFα in cultured hippocampal neurons exposed to metabolic and oxidative insults. We now report that pretreatment of hippocampal cell cultures with agents that activate NF-κB (TNFα and C2-ceramide) confers resistance of neurons to apoptosis induced by the oxidative insults FeSO4 and amyloid β-peptide (Aβ25–35). The neuroprotective actions of TNFα and ceramide were abolished in cultures cotreated with κB decoy DNA demonstrating a requirement for NF-κB activation for prevention of cell death. Levels of manganese superoxide dismutase (Mn-SOD) in neurons were increased following exposure of cultures to TNFα and ceramide in control cultures, but not in cultures cotreated with κB decoy DNA. FeSO4and Aβ25–35 induced accumulation of mitochondrial peroxynitrite, and membrane lipid peroxidation, in neurons. Peroxynitrite accumulation and lipid peroxidation were largely prevented in neurons pretreated with TNFα and ceramide prior to exposure to FeSO4 and Aβ25–35, an effect blocked by κB decoy DNA. Immunoreactivity of neurons with an anti-nitrotyrosine antibody was increased following exposure to FeSO4 and Aβ25–35; TNFα and C2-ceramide suppressed protein tyrosine nitration, and κB decoy DNA blocked the effects of TNFα and C2-ceramide. Finally, the peroxynitrite scavenger uric acid protected neurons against apoptosis induced by FeSO4 and Aβ, and suppressed peroxynitrite accumulation. We conclude that, by inducing production of Mn-SOD and suppressing peroxynitrite formation and membrane lipid peroxidation, NF-κB plays an anti-apoptotic role in neurodegenerative conditions that involve oxidative stress. The data further suggest important roles for peroxynitrite and NF-κB in the pathogenesis of neuronal degeneration in Alzheimer's disease. J. Neurosci. Res. 49:681–697, 1997.