title: Genetic deficiency of β2-containing nicotinic receptors attenuates brain injury in ischemic stroke.
abstract: One of the major consequences of stroke is brain injury caused by glutamate-mediated excitotoxicity. Glutamate-mediated excitatory activities are partially driven by β2-containing nicotinic acetylcholine receptors (β2-nAChRs). In examining the role of β2-nAChRs in cerebral ischemic injury, excitotoxicity and stroke outcome, we found that deficiency of β2-nAChRs attenuated brain infarction and neurological deficit at 24 and 72 h after transient middle cerebral artery occlusion (MCAO). Genetic deletion of β2-nAChRs associated with reduced terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL(+)) and cleaved caspase-3(+) cells after MCAO, together with a reduction of extracellular glutamate and oxygen-glucose deprivation-induced increase of excitatory inputs in cortical neurons. Pharmacologic pretreatment with a selective β2-nAChRs antagonist reduced brain infarction, neurological deficit, and MCAO-induced glutamate release. These findings suggest that deficiency of β2-nAChRs, also achievable by pharmacological blockade, can decrease brain infarction and improve the neurological status in ischemic stroke. The improved outcome is associated with reduced extracellular glutamate level and lower excitatory inputs into ischemic neurons, suggesting a reduction of glutamate-mediated excitotoxicity in the mechanisms of neuroprotection.
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA; Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China. Electronic address: Qiang.Liu@dignityhealth.org.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Gan
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: W
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kousari
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: A
authors.initials: A
authors.lastname: La Cava
authors.affiliation: Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA; Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: F-D
authors.initials: FD
authors.lastname: Shi
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency; D000860:Hypoxia / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000235:genetics*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
chemical_list: D004079:Dihydro-beta-Erythroidine; D005947:Glucose; D007770:L-Lactate Dehydrogenase; D018696:Neuroprotective Agents; D011978:Receptors, Nicotinic
keywords: ACSF; DHβE; EGTA; HEPES; LDH; MCAO; MRI; N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid; OGD; TTX; TUNEL; WT; artificial cerebrospinal fluid; dihydro-β-erythroidine; ethylene glycol tetraacetic acid; ischemic stroke; lactate dehydrogenase; mEPSCs; magnetic resonance imaging; middle cerebral artery occlusion; miniature excitatory postsynaptic currents; neuroprotection; nicotinic receptor; oxygen–glucose deprivation; terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling; tetrodotoxin; wild-type; β2-containing nicotinic acetylcholine receptors; β2-nAChRs