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

Abstract

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.

Roles for NF-κB in nerve cell survival, plasticity, and disease

“…When pretreated with TNF, the neurons were more resistant to death when exposed to metabolic and excitotoxic insults. [57][58][59] Inhibiting NF-kB using a decoy DNA approach provided evidence that activation of NF-kB was necessary for the neuron survival-promoting action of TNF. 57 TNF pretreatment was associated with increased production of the antiapoptotic proteins Bcl-2 and Bcl-xL, and expression of a dominant negative form of IkB inhibited the ability of TNF to protect hippocampal neurons.…”

“…[57][58][59] Inhibiting NF-kB using a decoy DNA approach provided evidence that activation of NF-kB was necessary for the neuron survival-promoting action of TNF. 57 TNF pretreatment was associated with increased production of the antiapoptotic proteins Bcl-2 and Bcl-xL, and expression of a dominant negative form of IkB inhibited the ability of TNF to protect hippocampal neurons. 59 Stimulation of neuronal cultures through either TNFR1 or TNFR2 has been reported to lead, respectively, to either transient or lasting (4 h) activation of NF-kB.…”

“…29 Moreover, inhibition of NF-kB transcriptional activity with decoy DNA results in increased vulnerability of neurons to death induced by amyloid b-peptide. 57 Oxidative stress may impair NF-kB functions as it has been shown that membrane lipid peroxidation inhibits NF-kB activity, possibly by a direct interaction of 4-hydroxynonenal with NF-kB subunits. The proapoptotic protein prostate-apoptosis response-4 (Par-4), which is implicated in Alzheimer's disease, 77 kills neurons in part, by inhibiting NF-kB activity.…”

The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival

“…For example, NF-κB is an inducible transcription factor that initiates the subsequent expression of several inflammatory molecules [12,13]. Several studies now indicate that neuronal expression of NF-κB is induced by a variety of insults, including TNF and mechanical injury and that this neuronal induction is associated with subsequent neuronal expression of inducible nitric oxide synthase (INOS) and superoxide dismutase (SOD) [14][15][16][17].…”

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

“…Activation of ERK1/2, CREB, and NF-κB can enhance anti-apoptic actions by inducing expression of anti-apoptotic Bcl-2 proteins and antioxidant enzymes such as manganese superoxide dismutase (SOD2) that protect against superoxide radicals (Hetman and Gozdz, 2004;Hinerfeld et al, 2004;Martinou et al, 1994;Mattson et al, 1997;Mattson and Meffert, 2006). The increased levels of ERK1/2, CREB, and NF-κB coupled with the increased levels of the neuronal protein enolase and glial protein GFAP suggested that these downstream neuroprotective proteins could also be altered by chronic CXCL10.…”