S100b effects on neurons are determined by RAGE expression and the basal NFKB activity: Implications for neuro-glia cross talk after ischemia.

A RAMOS, A VILLARREAL, RX AVILÉS-REYES, M. ANGELO, A. GONZALEZ, A. G. REINES

Chicago, Estados Unidos

Congreso; Meeting of the Society for Neuroscience; 2009

SFN

Ischemic brain injury increases S100B secretion from astrocytes. Extracellular form of S100B demonstrated to have autocrine effects on glial cells inducing reactive gliosis and secretion of proinflammatory cytokines and paracrine effects on neurons where induces neuronal survival or death at nM or uM concentrations respectively. Evidences from several studies have shown that S100B interacts with the receptor for advanced glycation end products (RAGE). RAGE is not detectable in adult brain; however brain injury induces RAGE re-expression. Using a model of ischemia by cortical devascularization, we showed that RAGE is selectively expressed by neurons from ischemic penumbra surrounding the infarct core. In vitro in primary cortical neurons, RAGE expression was effectively induced by an excitotoxic glutamate pulse or by hypo-osmolar stress, two stressors also produced changes in Sp1 transcription factor abundance that have previously shown to modify RAGE expression. While primary cortical neurons in absence of any stressor are sensitive to the described S100B effects (pro-death or pro-survival), the previous exposure to excitotoxic glutamate pulse sensitized neurons to the S100B prosurvival effects, increased the NFKB activity and augmented the expression of Bcl-2 and Bcl-XL antiapoptotic genes. In addition, neurons exposed to nM S100B dosis also improved their survival to an oxidative stress induced by a subsequent H2O2 exposure. Loss of function studies blocking NFKB activity with sulfazalazine (SFZ) dramatically reduced neuronal survival. Surprisingly, both pro-survival nM or pro-death uM S100B rescued neurons from death induced by NFKB blockage by SFZ.   The present results demonstrated that i) penumbra neurons express RAGE probably by an excitotoxicity-mediated mechanism, ii) RAGE expression potentiates S100B pro-survival effects and expression of NFKB-responsive genes on neurons and iii) the basal level of NFKB activity in the target neuron determines the prevalence of pro-death or pro-survival S100B effects .