Journal
ANTIOXIDANTS & REDOX SIGNALING
Volume 19, Issue 11, Pages 1135-1148Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2012.4671
Keywords
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Funding
- Spanish Ministry of Science and Innovation [SAF2009-12150, SAF2012-32223]
- Spanish Ministry of Health (Instituto de Salud Carlos III) [RETICS-RD06/0026]
- Spanish Ministry of Economy
- Fundacao para a Ciencia e Tecnologia (Portugal) [PTDC/BIA-BCM/101311/2008, PTDC/SAU-FCF/100762/2008, PTDC/SAU-TOX/116627/2010]
- European Community [LSH-2005-1.2.5-1, ERC-2011-AdG. 294709-DAMAGECONTROL]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-TOX/116627/2010, PTDC/SAU-FCF/100762/2008, PTDC/BIA-BCM/101311/2008] Funding Source: FCT
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Aims: 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 (7 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 7 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 -bungarotoxin 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 1h after induction of photothrombotic stroke in vivo reduced the infarct size and improved motor skills in Hmox1(lox/lox) mice that express normal levels of HO-1, but not in LysM(Cre)Hmox1(/) in which HO-1 expression is inhibited in myeloid cells, including the microglia. Innovation: This study suggests the participation of the microglial 7 nAChR in the brain cholinergic anti-inflammatory pathway. Conclusion: Activation of the 7 nAChR/Nrf2/HO-1 axis in microglia regulates neuroinflammation and oxidative stress, affording neuroprotection under brain ischemic conditions. Antioxid. Redox Signal. 19, 1135-1148.
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