title: Activation of α-7 nicotinic acetylcholine receptor reduces ischemic stroke injury through reduction of pro-inflammatory macrophages and oxidative stress.
abstract: Activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) has a neuro-protective effect on ischemic and hemorrhagic stroke. However, the underlying mechanism is not completely understood. We hypothesized that α-7 nAchR agonist protects brain injury after ischemic stroke through reduction of pro-inflammatory macrophages (M1) and oxidative stress. C57BL/6 mice were treated with PHA568487 (PHA, α-7 nAchR agonist), methyllycaconitine (MLA, nAchR antagonist), or saline immediately and 24 hours after permanent occlusion of the distal middle cerebral artery (pMCAO). Behavior test, lesion volume, CD68(+), M1 (CD11b(+)/Iba1(+)) and M2 (CD206/Iba1+) microglia/macrophages, and phosphorylated p65 component of NF-kB in microglia/macrophages were quantified using histological stained sections. The expression of M1 and M2 marker genes, anti-oxidant genes and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were quantified using real-time RT-PCR. Compared to the saline-treated mice, PHA mice had fewer behavior deficits 3 and 7 days after pMCAO, and smaller lesion volume, fewer CD68(+) and M1 macrophages, and more M2 macrophages 3 and 14 days after pMCAO, whereas MLA's effects were mostly the opposite in several analyses. PHA increased anti-oxidant genes and NADPH oxidase expression associated with decreased phosphorylation of NF-kB p65 in microglia/macrophages. Thus, reduction of inflammatory response and oxidative stress play roles in α-7 nAchR neuro-protective effect.
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America; Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Zhenying
authors.initials: Z
authors.lastname: Han
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Fanxia
authors.initials: F
authors.lastname: Shen
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Yue
authors.initials: Y
authors.lastname: He
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America; Hôpital Pitié Salpetrière, Assistance Publique-Hopitaux de Paris (APHP), Université Pierre et Marie Curie-Paris VI and UMR INSERM 1141, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Degos
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Marine
authors.initials: M
authors.lastname: Camus
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Mervyn
authors.initials: M
authors.lastname: Maze
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America; Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America; Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: William L
authors.initials: WL
authors.lastname: Young
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Su
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D004147:Dioxins / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018384:Oxidative Stress; D020521:Stroke / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D001372:Aza Compounds; D004147:Dioxins; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; C514026:PHA-568487E; D064569:alpha7 Nicotinic Acetylcholine Receptor