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Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration



Activation of NF-kappaB protects hippocampal neurons against oxidative stress-induced apoptosis: evidence for induction of manganese superoxide dismutase and suppression of peroxynitrite production and protein tyrosine nitration



Journal of Neuroscience Research 49(6): 681-697



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 FeSO-4 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. FeSO-4 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 FeSO-4 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 FeSO-4 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 FeSO-4 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.

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Accession: 008100241

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PMID: 9335256

DOI: 10.1002/(sici)1097-4547(19970915)49:6<681::aid-jnr3>3.0.co;2-3


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