The proinflammatory RAGE/NFkB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia

ANGELO, MARÍA FLORENCIA; AGUIRRE, ALEJANDRA; AVILÉS REYES, ROLANDO; VILLAREAL, ALEJANDRO; LUKIN, JERÓNIMO; MELENDEZ, MATÍAS; VANASCO, VIRGINIA; BAKER, PHIL; ALVAREZ, SILVIA; EPSTEIN, ALBERTO; JERUSALINSKY, DIANA; RAMOS, ALBERTO JAVIER

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2014 vol. 9 p. 1 - 14

1932-6203

Sleep apnea (SA) causes long-lasting changes in neuronal circuitry, which persist evenin patients successfully treated for the acute effects of the disease. Evidence obtainedfrom the intermittent hypoxia (IH) experimental model of SA has shown neuronal death,impairment in learning and memory and reactive gliosis that may account for cognitiveand structural alterations observed in human patients. However, little is known aboutthe mechanism controlling these deleterious effects that may be useful as therapeutictargets in SA. The Receptor for Advanced Glycation End products (RAGE) and itsdownstream effector Nuclear Factor Kappa B (NF-κB) have been related to neuronaldeath and astroglial conversion to the proinflammatory neurodegenerative phenotype.RAGE expression and its ligand S100B were shown to be increased in experimentalmodels of SA. We here used dissociated mixed hippocampal cell cultures and maleWistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells andneurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κBpathway to neuronal damage and reactive gliosis after IH we performed sequential lossof function studies using RAGE or S100B neutralizing antibodies, a herpes simplexvirus (HSV)-derived amplicon vector that induces the expression of RAGEΔcyto(dominant negative RAGE) and a chemical blocker of NF-κB. Our results show thatNF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockageduring this critical period significantly improves neuronal survival and reduces reactivegliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did nothave significant effects on neuronal survival.We conclude that both RAGE and downstream NF-κB signalling are centrally involvedin the neuronal alterations found in SA models, and that blockage of these pathways isa tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.