Modulatory role of NFκB in neuronal and glial responses to injury

identification of the exact mechanisms by which neurons live or die following injury would highlight the most direct and appropriate targets for therapeutic interventions in brain injury (e.g. ischemia). Many different signaling pathways are activated in injured cells, and considerable effort has been placed on linking such signaling pathways to the cell death process. The initial association of a particular enzyme or transcription factor with cell injury often leads to the theory that its factor must either contribute to or be a consequence of the death process. However, this "guilt by association" reasoning has given way to the understanding that many signaling pathways activated in injured cells are designed to bolster cell resistance. The transcription factor NF kappa B (nuclear factor KB) provides a classic example of such a signal. NF kappa B is widely expressed in mammalian cells and regulates the expression of a variety of genes which code for proteins involved in immunity and inflammation. As in the periphery, NF kappa B in the brain encodes for proteins with immune and inflammatory activities, but accumulating evidence indicates that NF kappa B also has a unique role in the CNS, modulating such functions as neuronal plasticity and response to brain injury. Activation of NF kappa B occurs rapidly under conditions of neuronal injury (increased levels of free radicals and/or calcium) and appears to play an important role in adaptive responses of neurons to potentially lethal excitotoxic, metabolic and oxidative insults. The NF kappa B transcriptional pathway is also activated in response to synaptic activity, and thereby provides a mechanism of synapse-to-nucleus signaling that likely plays important roles in long-term activity-dependent changes in neuronal structure and function. NF kappa B induces the expression of genes encoding cytoprotective proteins including those that suppress accumulation of free radicals (manganese superoxide dismutase) and stabilize calcium homeostasis (the calcium-binding protein calbindin). Additionally, NF kappa B regulates the function of nonneuronal cells in the CNS, and astrocytes, microglia, and endothelial cells respond vigorously to NF kappa B activation. Through the rapid and stimulus-specific modulation of neuronal and glial responses to injury, NF kappa B has a unique regulatory role in affecting the outcome of brain injury following CNS damage.