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 |
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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 |
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