- S100B effects on neurons are determined by RAGE expression and the basal NFKB activity: Implications for neuro-glial cross-talk after ischemia.

ALBERTO JAVIER RAMOS. ALEJANDRO VILLARREAL, ROLANDO X. AVILES REYES, MARIA FLORENCIA ANGELO, AGUSTINA GONZALE1, ANALIA G. REINES

Chicago, EE. UU:

Congreso; Congreso de la Society for Neuroscience (SFN); 2009

Society for Neuroscience (SFN)

Ischemic brain injury increases S100B secretion from astrocytes. Extracellular form of glial S100B demonstrated to have autocrine effects on glial cells inducing reactive gliosis, secretion of proinflammatory cytokines and paracrine effects on neurons where induces neuronal survival or death at nanomolar (nM) or micromolar (uM) range of concentration 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 it has been proposed that brain injury induces RAGE re-expression.Male Wistar rats were subjected to an experimental model of focal ischemia produced by cortical devascularization (CD). Three days after the CD 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 paradigms that also produced changes in Sp1 transcription factor abundance. While, in absence of any stressor, primary cortical neurons are sensitive to the described dose-dependent S100B effects (pro-survival or pro-death), the previous exposure to excitotoxic glutamate pulse sensitized neurons to both S100B pro-survival or pro-death effects. The treatment with nM S100B concentration increased the NFKB nuclear traslocation and augmented the expression of NFKB-responsive antiapoptotic genes Bcl-2 and Bcl-XL in glutamate-exposed neurons. In addition, neurons pretreated with nM S100B also improved their survival to an acute oxidative stress induced by a subsequent H2O2 exposure. Loss of function studies blocking NFKB activity with sulfazalazine (SFZ) dramatically reduced neuronal survival in absence of S100B. Surprisingly, both pro-survival (nM) and pro-death (uM) S100B concentrations rescued neurons from death produced by SFZ-induced NFKB blockage. The present results demonstrated that i) penumbra neurons express RAGE probably by an excitotoxicity-mediated mechanism that increases Sp1 abundance (a transcription factor reported to be required for RAGE expression), ii) RAGE expression potentiates S100B effects, iii) NFKB-responsive genes are likely to be involved in S100B pro-survival activity in primary neurons and iii) the basal level of NFKB activity in the target neuron determines the prevalence of pro-death or pro-survival S100B effects. We propose that S100B-RAGE-NFKB may represent a mechanism of neuro-glial crosstalk involved in the determination of neuronal survival after brain ischemia.