title: Activation of Alpha-7 Nicotinic Acetylcholine Receptor Reduces Brain Edema in Mice with Ischemic Stroke and Bone Fracture.
abstract: Stroke is an important risk factor for bone fracture. We showed previously that bone fracture at the acute stage of ischemic stroke worsens, and activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) improves, stroke recovery by attenuating inflammation. We hypothesized that activation of α-7 nAchR also improves the blood-brain barrier (BBB) integrity. Permanent distal middle cerebral artery occlusion (pMCAO) was performed on C57BL/6J mice followed by tibia fracture 1 day later. Mice were treated with 0.8 mg/kg PHA 568487 (PHA, α-7 nAchR-specific agonist), 6 mg/kg methyllycaconitine (MLA, α-7 nAchR antagonist), or saline 1 and 2 days after pMCAO. Brain water content, the expression of monoamine oxidase B (MAO-B), and tight junction protein (claudin-5) were assessed. We found that tibia fracture increased water content in the ischemic stroke brain (p = 0.006) and MAO-B-positive astrocytes (p < 0.001). PHA treatment reduced water content and MAO-B-positive astrocytes and increased claudin-5 expression in stroke and stroke + tibia fracture mice (p < 0.05), while MLA had the opposite effect. Our findings suggest that in addition to inhibiting inflammation, activation of α-7 nAchR also reduces brain edema, possibly through diminished astrocyte oxidative stress and improved BBB integrity. Thus, the α-7 nAchR-specific agonist could be developed into a new therapy for improving recovery of patients with stroke or stroke + bone fracture.
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.|Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Dingquan
authors.initials: D
authors.lastname: Zou
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.|Department of Neurology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Man
authors.initials: M
authors.lastname: Luo
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Zhenying
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhan
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Wan
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Kang
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Bao
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Nelson
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, San Francisco, CA, 94143, USA. hua.su@ucsf.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Su
mesh_terms: D000818:Animals; D001929:Brain Edema / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D050723:Fractures, Bone / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D020521:Stroke / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D013977:Tibia / Q000293:injuries / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000378:metabolism*
chemical_list: D064569:alpha7 Nicotinic Acetylcholine Receptor
keywords: Blood-brain barrier integrity; Claudin-5; Ischemic stroke; Oxidative stress; PHA