title: Boosting Endogenous Resistance of Brain to Ischemia.
abstract: Most survivors of ischemic stroke remain physically disabled and require prolonged rehabilitation. However, some stroke victims achieve a full neurological recovery suggesting that the human brain can defend itself against ischemic injury, but the protective mechanisms are unknown. This study used selective pharmacological agents and a rat model of cerebral ischemic stroke to detect endogenous brain protective mechanisms that require activation of α7 nicotinic acetylcholine receptors (nAChRs). This endogenous protection was found to be (1) limited to less severe injuries; (2) significantly augmented by intranasal administration of a positive allosteric modulator of α7 nAChRs, significantly reducing brain injury and neurological deficits after more severe ischemic injuries; and (3) reduced by inhibition of calcium/calmodulin-dependent kinase-II. The physiological role of α7 nAChRs remains largely unknown. The therapeutic activation of α7 nAChRs after cerebral ischemia may serve as an important physiological responsibility of these ubiquitous receptors and holds a significant translational potential.
authors.affiliation: Institute for Healthy Aging, Center for Neuroscience Discovery, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Sun
authors.affiliation: Carbon Dynamics Institute, LLC, Sherman, IL, 62711, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Johnson
authors.affiliation: Institute for Healthy Aging, Center for Neuroscience Discovery, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA.
authors.forename: Kunlin
authors.initials: K
authors.lastname: Jin
authors.affiliation: Institute for Healthy Aging, Center for Neuroscience Discovery, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX, 76107, USA. Victor.Uteshev@unthsc.edu.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Uteshev
mesh_terms: D061605:Administration, Intravenous; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057967:Infusions, Intraventricular; D007555:Isoxazoles / Q000008:administration & dosage*; D008297:Male; D009924:Organ Culture Techniques; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism*; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D007555:Isoxazoles; D010671:Phenylurea Compounds; D013449:Sulfonamides; D064569:alpha7 Nicotinic Acetylcholine Receptor; C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C425780:KN 92; C072105:KN 93; D000096926:Benzenesulfonamides
keywords: Allosteric modulator; Choline; Neuroprotection; Nicotinic receptors; PNU-120596; PNU120596; Stroke