The microglial α7-acetylcholine nicotinic receptor is a key element in promoting neuroprotection by inducing heme oxygenase-1 via nuclear factor erythroid-2-related factor 2

Autor: Pilar Negredo, Miguel P. Soares, Esther Parada, Ana C. Cunha, Javier Egea, Manuela G. López, Silvia Cardoso, Izaskun Buendia
Přispěvatelé: UAM. Departamento de Anatomía, Histología y Neurociencia, UAM. Departamento de Farmacología
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Receptor nicotinic
alpha7 Nicotinic Acetylcholine Receptor
Physiology
Clinical Biochemistry
Anti-Inflammatory Agents
Factor Erythroid
Pharmacology
Biochemistry
Hippocampus
Antioxidants
chemistry.chemical_compound
Mice
0302 clinical medicine
Nicotinic Agonists
General Environmental Science
0303 health sciences
Cell Death
Cerebral Infarction
Neuroprotection
3. Good health
Nicotinic acetylcholine receptor
Original Research Communications
Nicotinic agonist
Neuroprotective Agents
Microglia
Signal transduction
Signal Transduction
Programmed cell death
Cell Survival
NF-E2-Related Factor 2
Medicina
Mice
Transgenic

Biology
03 medical and health sciences
Organ Culture Techniques
Animals
Propidium iodide
Molecular Biology
030304 developmental biology
Tumor Necrosis Factor-alpha
Cell Biology
Rats
Heme oxygenase
Oxidative Stress
chemistry
Cultural Deprivation
General Earth and Planetary Sciences
Cholinergic
Reactive Oxygen Species
030217 neurology & neurosurgery
Heme Oxygenase-1
Zdroj: Repositório Científico de Acesso Aberto de Portugal
Repositório Científico de Acesso Aberto de Portugal (RCAAP)
instacron:RCAAP
Biblos-e Archivo. Repositorio Institucional de la UAM
instname
Popis: This is copy of an article published in the Antioxidants & Redox Signaling © 2013 Mary Ann Liebert, Inc. Antioxidants& Redox Signalingi available online at: http://online.liebertpub.com
We asked whether the neuroprotective effect of cholinergic microglial stimulation during an ischemic event acts via a mechanism involving the activation of nuclear factor erythroid-2-related factor 2 (Nrf2) and/or the expression of its target cytoprotective gene, heme oxygenase-1 (HO-1). Specifically, the protective effect of the pharmacologic alpha-7 nicotinic acetylcholine receptor (a7 nAChR) agonist PNU282987 was analyzed in organotypic hippocampal cultures (OHCs) subjected to oxygen and glucose deprivation (OGD) in vitro as well as in photothrombotic stroke in vivo. Results: OHCs exposed to OGD followed by reoxygenation elicited cell death, measured by propidium iodide and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide staining. Activation of a7 nAChR by PNU282987, after OGD, reduced cell death, reactive oxygen species production, and tumor necrosis factor release. This was associated with induction of HO-1 expression, an effect reversed by abungarotoxin and by tin–protoporphyrin IX. The protective effect of PNU282987 was lost in microglial-depleted OHCs as well as in OHCs from Nrf2-deficient-versus-wild-type mice, an effect associated with suppression of HO- 1 expression in microglia. Administration of PNU282987 1 h after induction of photothrombotic stroke in vivo reduced the infarct size and improved motor skills in Hmox1lox/lox mice that express normal levels of HO-1, but not in LysMCreHmox1D/D in which HO-1 expression is inhibited in myeloid cells, including the microglia. Innovation: This study suggests the participation of the microglial a7 nAChR in the brain cholinergic anti-inflammatory pathway. Conclusion: Activation of the a7 nAChR/Nrf2/HO-1 axis in microglia regulates neuroinflammation and oxidative stress, affording neuroprotection under brain ischemic conditions. Antioxid. Redox Signal. 19, 1135–1148
This work was supported in part by grants from Spanish Ministry of Science and Innovation Ref. SAF2009-12150 and SAF2012-32223 and the Spanish Ministry of Health (Instituto de Salud Carlos III) RETICS-RD06/0026 to MGL. E.P. and I.B. have a predoctoral fellowship from the Spanish Ministry of Economy. We would also like to thank the Fundacion Teofilo Hernando for its continued support. Funding: Fundac¸ao para a Ciencia e Tecnologia (Portugal) grants to MPS: PTDC/BIABCM/ 101311/2008, PTDC/SAU-FCF/100762/2008, and PTDC/SAU-TOX/116627/2010) and European Community 6th Framework Grant LSH-2005-1.2.5-1 and 7th Framework Grant ERC-2011-AdG. 294709–DAMAGECONTROL. Ana Cunha was supported by a fellowship within the project PTDC/SAU-FCF/100762/2008 awarded to MPS
Databáze: OpenAIRE