title: Alpha7 nicotinic receptor activation protects against oxidative stress via heme-oxygenase I induction.
abstract: Subchronic oxidative stress and inflammation are being increasingly implicated in the pathogenesis of numerous diseases, such as Alzheimer's or Parkinson's disease. This study was designed to evaluate the potential protective role of α7 nicotinic receptor activation in an in vitro model of neurodegeneration based on subchronic oxidative stress. Rat organotypic hippocampal cultures (OHCs) were exposed for 4 days to low concentration of lipopolysaccharide (LPS) and the complex III mitochondrial blocker, antimycin-A. Antimycin-A (0.1μM) and lipopolysaccharide (1ng/ml) caused low neurotoxicity on their own, measured as propidium iodide fluorescence in CA1 and CA3 regions. However, their combination (LPS/AA) caused a greater detrimental effect, in addition to mitochondrial depolarization, overproduction of reactive oxygen species (ROS) and Nox4 overexpression. Antimycin-A per se increased ROS and mitochondrial depolarization, although these effects were significantly higher when combined with LPS. More interesting was the finding that exposure of OHCs to the combination of LPS/AA triggered aberrant protein aggregation, measured as thioflavin S immunofluorescence. The α7 nicotinic receptor agonist, PNU282987, prevented the neurotoxicity and the pathological hallmarks observed in the LPS/AA subchronic toxicity model (oxidative stress and protein aggregates); these effects were blocked by α-bungarotoxin and tin protoporphyrin, indicating the participation of α7 nAChRs and heme-oxygenase I induction. In conclusion, subchronic exposure of OHCs to low concentration of antimycin-A plus LPS reproduced pathological features of neurodegenerative disorders. α7 nAChR activation ameliorated these alterations by a mechanism involving heme-oxygenase I induction.
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Navarro
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendia
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Parada
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: León
authors.affiliation: Institute for Biomedical Aging Research, Universität Innsbruck, Innsbruck, Austria.
authors.forename: Pidder
authors.initials: P
authors.lastname: Jansen-Duerr
authors.affiliation: Institute for Biomedical Aging Research, Universität Innsbruck, Innsbruck, Austria.
authors.forename: Haymo
authors.initials: H
authors.lastname: Pircher
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.affiliation: Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain; Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: manuela.garcia@uam.es.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: Lopez
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000008:administration & dosage / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects* / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology*; D008070:Lipopolysaccharides; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000378:metabolism*
chemical_list: D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D008070:Lipopolysaccharides; D018722:Nicotinic Agonists; C498513:PNU-282987; D017382:Reactive Oxygen Species; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000968:Antimycin A; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat
keywords: Heme-oxygenase I; Neuroprotection; Organotypic cultures; Oxidative stress; Protein aggregation; α7 nicotinic receptor