title: Heme-Oxygenase I and PCG-1α Regulate Mitochondrial Biogenesis via Microglial Activation of Alpha7 Nicotinic Acetylcholine Receptors Using PNU282987.
abstract: A loss in brain acetylcholine and cholinergic markers, subchronic inflammation, and impaired mitochondrial function, which lead to low-energy production and high oxidative stress, are common pathological factors in several neurodegenerative diseases (NDDs). Glial cells are important for brain homeostasis, and microglia controls the central immune response, where α7 acetylcholine nicotinic receptors (nAChR) seem to play a pivotal role; however, little is known about the effects of this receptor in metabolism. Therefore, the aim of this study was to evaluate if glial mitochondrial energetics could be regulated through α7 nAChR.
  
  
  
  Primary glial cultures treated with the α7 nicotinic agonist PNU282987 increased their mitochondrial mass and their mitochondrial oxygen consumption without increasing oxidative stress; these changes were abolished when nuclear erythroid 2-related factor 2 (Nrf2) was absent, heme oxygenase-1 (HO-1) was inhibited, or peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) was silenced. More specifically, microglia of animals treated intraperitoneally with the α7 nAChR agonist PNU282987 (10 mg/kg) showed a significant increase in mitochondrial mass. Interestingly, LysMcre-Hmox1Δ/Δand PGC-1α-/-animals showed lower microglial mitochondrial levels and treatment with PNU282987 did not produce effects on mitochondrial levels.
  
  
  
  Increases in microglial mitochondrial mass and metabolism can be achieved via α7 nAChR by a mechanism that implicates Nrf2, HO-1, and PGC-1α. This signaling pathway could open a new strategy for the treatment of NDDs, such as Alzheimer's, characterized by a reduction of cholinergic markers.
  
  
  
  α7 nAChR signaling increases glial mitochondrial mass, both in vitro and in vivo, via HO-1 and PCG-1α. These effects could be of potential benefit in the context of NDDs. Antioxid. Redox Signal. 27, 93-105.
authors.affiliation: 1 Instituto Teófilo Hernando, Departamento Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid , Madrid, Spain .|2 Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain .
authors.forename: Elisa
authors.initials: E
authors.lastname: Navarro
authors.affiliation: 1 Instituto Teófilo Hernando, Departamento Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid , Madrid, Spain .
authors.forename: Laura
authors.initials: L
authors.lastname: Gonzalez-Lafuente
authors.affiliation: 1 Instituto Teófilo Hernando, Departamento Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid , Madrid, Spain .
authors.forename: Irene
authors.initials: I
authors.lastname: Pérez-Liébana
authors.affiliation: 1 Instituto Teófilo Hernando, Departamento Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid , Madrid, Spain .|2 Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain .
authors.forename: Izaskun
authors.initials: I
authors.lastname: Buendia
authors.affiliation: 2 Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain .|3 Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Departamento de Biología Molecular, Universidad Autónoma de Madrid , Madrid, Spain .
authors.forename: Elia
authors.initials: E
authors.lastname: López-Bernardo
authors.affiliation: 4 Instituto de Investigaciones Biomédicas Alberto Sols , Madrid, Spain .
authors.forename: Cristina
authors.initials: C
authors.lastname: Sánchez-Ramos
authors.affiliation: 4 Instituto de Investigaciones Biomédicas Alberto Sols , Madrid, Spain .
authors.forename: Ignacio
authors.initials: I
authors.lastname: Prieto
authors.affiliation: 4 Instituto de Investigaciones Biomédicas Alberto Sols , Madrid, Spain .
authors.forename: Antonio
authors.initials: A
authors.lastname: Cuadrado
authors.affiliation: 3 Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Departamento de Biología Molecular, Universidad Autónoma de Madrid , Madrid, Spain .
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrustegui
authors.affiliation: 2 Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain .|3 Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Departamento de Biología Molecular, Universidad Autónoma de Madrid , Madrid, Spain .
authors.forename: Susana
authors.initials: S
authors.lastname: Cadenas
authors.affiliation: 4 Instituto de Investigaciones Biomédicas Alberto Sols , Madrid, Spain .
authors.forename: Maria
authors.initials: M
authors.lastname: Monsalve
authors.affiliation: 1 Instituto Teófilo Hernando, Departamento Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid , Madrid, Spain .|2 Instituto de Investigación Sanitaria Princesa (IIS-IP) , Madrid, Spain .
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D001678:Organelle Biogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics*; D051381:Rats; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism
chemical_list: D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D051267:NF-E2-Related Factor 2; C498513:PNU-282987; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D064569:alpha7 Nicotinic Acetylcholine Receptor; D051547:Heme Oxygenase-1
keywords: PGC-1alpha; PNU282987; alpha-7 nicotinic receptors; heme-oxygenase-1; microglia; mitochondrial biogenesis