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.
The transcription factor NF-kappaB 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 (TNFalpha), and excitotoxic and oxidative insults. NF-kappaB may play a role in the anti-death actions of TNFalpha in cultured hippocampal neurons exposed to metabolic and oxidative insults. We now report that pretreatment of hippocampal cell cultures with agents that activate NF-kappaB (TNFalpha and C2-ceramide) confers resistance of neurons to apoptosis induced by the oxidative insults FeSO4 and amyloid beta-peptide (Abeta25-35). The neuroprotective actions of TNFalpha and ceramide were abolished in cultures cotreated with kappaB decoy DNA demonstrating a requirement for NF-kappaB activation for prevention of cell death. Levels of manganese superoxide dismutase (Mn-SOD) in neurons were increased following exposure of cultures to TNFalpha and ceramide in control cultures, but not in cultures cotreated with kappaB decoy DNA. FeSO4 and Abeta25-35 induced accumulation of mitochondrial peroxynitrite, and membrane lipid peroxidation, in neurons. Peroxynitrite accumulation and lipid peroxidation were largely prevented in neurons pretreated with TNFalpha and ceramide prior to exposure to FeSO4 and Abeta25-35, an effect blocked by kappaB decoy DNA. Immunoreactivity of neurons with an anti-nitrotyrosine antibody was increased following exposure to FeSO4 and Abeta25-35; TNFalpha and C2-ceramide suppressed protein tyrosine nitration, and kappaB decoy DNA blocked the effects of TNFalpha and C2-ceramide. Finally, the peroxynitrite scavenger uric acid protected neurons against apoptosis induced by FeSO4 and Abeta, and suppressed peroxynitrite accumulation. We conclude that, by inducing production of Mn-SOD and suppressing peroxynitrite formation and membrane lipid peroxidation, NF-kappaB plays an anti-apoptotic role in neurodegenerative conditions that involve oxidative stress. The data further suggest important roles for peroxynitrite and NF-kappaB in the pathogenesis of neuronal degeneration in Alzheimer's disease.
Mattson
M P
MP
Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
Goodman
Y
Y
Luo
H
H
Fu
W
W
Furukawa
K
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D015227:Lipid Peroxidation / Q000187:drug effects; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D009566:Nitrates / Q000378:metabolism*; D017672:Nitrogen Compounds / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; C064769:N-acetylsphingosine; D016328:NF-kappa B; D009566:Nitrates; D017672:Nitrogen Compounds; D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; C039642:peroxynitric acid; D014527:Uric Acid; D014443:Tyrosine; D004247:DNA; D013482:Superoxide Dismutase; D013110:Sphingosine