RRC ID 19665
Author Parada E, Egea J, Buendia I, Negredo P, Cunha AC, Cardoso S, Soares MP, López MG.
Title 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.
Journal Antioxid. Redox Signal.
Abstract 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 (α7 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 α7 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 α-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 1 h 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(Δ/Δ) in which HO-1 expression is inhibited in myeloid cells, including the microglia.
INNOVATION:This study suggests the participation of the microglial α7 nAChR in the brain cholinergic anti-inflammatory pathway.
CONCLUSION:Activation of the α7 nAChR/Nrf2/HO-1 axis in microglia regulates neuroinflammation and oxidative stress, affording neuroprotection under brain ischemic conditions.
Volume 19(11)
Pages 1135-48
Published 2013-10-10
DOI 10.1089/ars.2012.4671
PMID 23311871
PMC PMC3785807
MeSH Animals Anti-Inflammatory Agents / pharmacology Antioxidants / pharmacology Cell Death / drug effects Cell Survival / drug effects Cerebral Infarction / drug therapy Cerebral Infarction / metabolism Cerebral Infarction / pathology Cultural Deprivation Heme Oxygenase-1 / metabolism* Hippocampus / cytology Hippocampus / drug effects Hippocampus / metabolism Mice Mice, Transgenic Microglia / metabolism* NF-E2-Related Factor 2 / metabolism* Neuroprotective Agents / pharmacology Nicotinic Agonists / pharmacology Organ Culture Techniques Oxidative Stress Rats Reactive Oxygen Species / metabolism Signal Transduction / drug effects Tumor Necrosis Factor-alpha / biosynthesis alpha7 Nicotinic Acetylcholine Receptor / metabolism*
IF 5.828
Times Cited 45
Mice Nrf2 knockout mouse/C57BL6J (RBRC01390) B6J.129P2-Hmox1<tm1Mym> (RBRC03163)