title: The proinflammatory RAGE/NF-κB pathway is involved in neuronal damage and reactive gliosis in a model of sleep apnea by intermittent hypoxia.
abstract: Sleep apnea (SA) causes long-lasting changes in neuronal circuitry, which persist even in patients successfully treated for the acute effects of the disease. Evidence obtained from the intermittent hypoxia (IH) experimental model of SA has shown neuronal death, impairment in learning and memory and reactive gliosis that may account for cognitive and structural alterations observed in human patients. However, little is known about the mechanism controlling these deleterious effects that may be useful as therapeutic targets in SA. The Receptor for Advanced Glycation End products (RAGE) and its downstream effector Nuclear Factor Kappa B (NF-κB) have been related to neuronal death and astroglial conversion to the pro-inflammatory neurodegenerative phenotype. RAGE expression and its ligand S100B were shown to be increased in experimental models of SA. We here used dissociated mixed hippocampal cell cultures and male Wistar rats exposed to IH cycles and observed that NF-κB is activated in glial cells and neurons after IH. To disclose the relative contribution of the S100B/RAGE/NF-κB pathway to neuronal damage and reactive gliosis after IH we performed sequential loss of function studies using RAGE or S100B neutralizing antibodies, a herpes simplex virus (HSV)-derived amplicon vector that induces the expression of RAGEΔcyto (dominant negative RAGE) and a chemical blocker of NF-κB. Our results show that NF-κB activation peaks 3 days after IH exposure, and that RAGE or NF-κB blockage during this critical period significantly improves neuronal survival and reduces reactive gliosis. Both in vitro and in vivo, S100B blockage altered reactive gliosis but did not have significant effects on neuronal survival. We conclude that both RAGE and downstream NF-κB signaling are centrally involved in the neuronal alterations found in SA models, and that blockage of these pathways is a tempting strategy for preventing neuronal degeneration and reactive gliosis in SA.
authors.affiliation: Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis", Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Maria Florencia
authors.initials: MF
authors.lastname: Angelo
authors.affiliation: Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis", Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Aguirre
authors.affiliation: Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis", Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Rolando X
authors.initials: RX
authors.lastname: Avilés Reyes
authors.affiliation: Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis", Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Villarreal
authors.affiliation: Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis", Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Lukin
authors.affiliation: Centre Internationale de Recherche en Infectiologie, INSERM U1111, CNRS UMR5038, Ecole Normale Supérieure, Université Lyon 1, Lyon, France.
authors.forename: Matías
authors.initials: M
authors.lastname: Melendez
authors.affiliation: Instituto de Bioquímica y Medicina Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Virginia
authors.initials: V
authors.lastname: Vanasco
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Phil
authors.initials: P
authors.lastname: Barker
authors.affiliation: Instituto de Bioquímica y Medicina Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Silvia
authors.initials: S
authors.lastname: Alvarez
authors.affiliation: Centre Internationale de Recherche en Infectiologie, INSERM U1111, CNRS UMR5038, Ecole Normale Supérieure, Université Lyon 1, Lyon, France.
authors.forename: Alberto
authors.initials: A
authors.lastname: Epstein
authors.affiliation: Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis", Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Diana
authors.initials: D
authors.lastname: Jerusalinsky
authors.affiliation: Instituto de Biología Celular y Neurociencia "Prof. E. De Robertis", Facultad de Medicina, Universidad de Buenos Aires, Ciudad de Buenos Aires, Argentina.
authors.forename: Alberto Javier
authors.initials: AJ
authors.lastname: Ramos
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005911:Gliosis / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D012891:Sleep Apnea Syndromes / Q000378:metabolism* / Q000473:pathology
chemical_list: D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic