Neuronal Activation of NF-κB Contributes to Cell Death in Cerebral Ischemia

Abstract

The transcription factor NF-kappaB is a key regulator of inflammation and cell survival. NF-kappaB is activated by cerebral ischemia in neurons and glia, but its function is controversial. To inhibit NF-kappaB selectively in neurons and glial cells, we have generated transgenic mice that express the IkappaBalpha superrepressor (IkappaBalpha mutated at serine-32 and serine-36, IkappaBalpha-SR) under transcriptional control of the neuron-specific enolase (NSE) and the glial fibrillary acidic protein (GFAP) promoter, respectively. In primary cortical neurons of NSE-IkappaBalpha-SR mice, NF-kappaB activity was partially inhibited. To assess NF-kappaB activity in vivo after permanent middle cerebral artery occlusion (MCAO), we measured the expression of NF-kappaB target genes by real-time polymerase chain reaction (PCR). The induction of c-myc and transforming growth factor-beta2 by cerebral ischemia was inhibited by neuronal expression of IkappaBalpha-SR, whereas induction of GFAP by MCAO was reduced by astrocytic expression of IkappaBalpha-SR. Neuronal, but not astrocytic, expression of the NF-kappaB inhibitor reduced both infarct size and cell death 48 hours after permanent MCAO. In summary, the data show that NF-kappaB is activated in neurons and astrocytes during cerebral ischemia and that NF-kappaB activation in neurons contributes to the ischemic damage.

Dysfunctional NF-κB and brain myelin formation

“…Likewise, functional parameters of visual acuity and contrast sensitivity were indistinguishable between WT and RelA CNSKO mice (published elsewhere). These findings are in line with previous reports showing that mice with inactivated upstream regulators of NF-kB (IkBa, IKK) in the neuro-glial compartment are indiscernible regarding overall neuro-anatomical and behavioral features 3,4 and, in particular, display normal myelination. 5 Among the NF-kB family members (RelA, RelB, c-Rel, p105/50, p100/52), only deletion of the subunit p50, which lacks a transcriptional activator domain, results in a destructive neuronal phenotype as characterized by precocious aging, neuronal apoptosis and spontaneous demyelination in young adult mice.…”

Neuronal Estrogen Receptor-α Mediates Neuroprotection by 17β-Estradiol

“…In addition, ERs are known to inhibit the transcription factor nuclear factor-kB (Biswas et al, 2005), an effect that has also been reported in a model of cerebral ischemia in vivo (Wen et al, 2004). Inhibition of nuclear factor-kB in neurons is protective in stroke models Zhang et al, 2005), suggesting that pathwayselective ER ligands that inhibit nuclear factor-kB (Chadwick et al, 2005) might be an option for stroke treatment. Another way to refine estrogen treatment for stroke therapy would be the development of neuron-specific selective ER modulators (neuroSERMs) (Zhao et al, 2005), a strategy that would exploit the important role of neuronal ERa shown in this study.…”

Biphasic Role of Nuclear Factor-k B on Cell Survival and COX-2 Expression in SOD1 Tg Astrocytes after Oxygen Glucose Deprivation

“…Evidence for NF-kB activation has also been reported in important examples of neurodegeneration, such as Alzheimer's disease (Kaltschmidt et al, 1997;Akama et al, 1998) and Parkinson's disease (Hunot et al, 1997). Zhang et al (2005) recently observed that neuronal activation of NF-kB in cerebral ischemia contributed to ischemic brain damage in vivo. A dual action for NF-kB has been proposed in hippocampal neurons in a global ischemia model, whereby it might be either protective or detrimental depending on the onset and duration of its activation (Clemens et al, 1998).…”