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

The transcription factor NF-kappa B is expressed in neurons wherein it is activated in response to a variety of stress-and injury-related st imuli including exposure to cytokines such as tumor necrosis factor-al pha (TNF alpha), and excitotoxic and oxidative insults. NF-kappa B may play a role in the anti-death actions of TNF alpha in cultured hippoc ampal neurons exposed to metabolic and oxidative insults. We now repor t that pretreatment of hippocampal cell cultures with agents that acti vate NF-kappa B (TNF alpha and C2-ceramide) confers resistance of neur ons to apoptosis induced by the oxidative insults FeSO4 and amyloid be ta-peptide (A beta 25-35). The neuroprotective actions of TNF alpha an d 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 ne urons were increased following exposure of cultures to TNF alpha and c eramide in control cultures, but not in cultures cotreated with kappa B decoy DNA. FeSO4 and A beta 25-35 induced accumulation of mitochondr ial peroxynitrite, and membrane lipid peroxidation, in neurons. Peroxy nitrite accumulation and lipid peroxidation were largely prevented in neurons pretreated with TNF alpha and ceramide prior to exposure to Fe SO4 and A beta 25-35, an effect blocked by kappa B decoy DNA. Immunore activity of neurons with an anti-nitrotyrosine antibody was increased following exposure to FeSO4 and A beta 25-35; TNF alpha and C2-ceramid e 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 FeS O4 and A beta, and suppressed peroxynitrite accumulation. We conclude that, by inducing production of Mn-SOD and suppressing peroxynitrite f ormation and membrane lipid peroxidation, NF-kappa B plays an anti-apo ptotic role in neurodegenerative conditions that involve oxidative str ess. The data further suggest important roles for peroxynitrite and NF -kappa B in the pathogenesis of neuronal degeneration in Alzheimer's d isease. (C) 1997 Wiley-Liss, Inc.