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
Entity
UAM. Departamento de Anatomía, Histología y Neurociencia; UAM. Departamento de FarmacologíaPublisher
Mary Ann Liebert, Inc.Date
2013Citation
10.1089/ars.2012.4671
Antioxidants & Redox Signaling 19.11 ( 2013): 1135-1148
ISSN
1523-0864 (print); 1557-7716 (online)DOI
10.1089/ars.2012.4671Funded by
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 MPSProject
info:eu-repo/grantAgreement/EC/FP7/294709Editor's Version
http://dx.doi.org/10.1089/ars.2012.4671Subjects
Receptor nicotinic; Neuroprotection; Factor Erythroid; MedicinaNote
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.comRights
© Mary Ann Liebert, Inc.Abstract
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
Files in this item
Google Scholar:Parada, Esther
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Egea, Javier
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Buendía, Izaskun
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Negredo Madrigal, Pilar
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Cunha, Ana C.
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Cardoso, Silvia
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Soares, Miguel P.
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López, Manuela G.
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