title: Selective activation of α7 nicotinic acetylcholine receptor by PHA-543613 improves Aβ25-35-mediated cognitive deficits in mice.
abstract: Agonists of α7 nicotinic acetylcholine receptors (nAChRs) are currently being considered as therapeutic approaches for managing cognitive deficits in Alzheimer's disease (AD). Present study was designed to evaluate the effect of α7 nAChR selective activation by PHA-543613 (PHA) on beta-amyloid (Aβ)25-35-mediated cognitive deficits in mice. For this purpose, PHA (1mg/kg, i.p.), a selective α7 nAChR agonist, and galantamine (Gal) (3mg/kg, s.c.), an acetylcholine-esterase inhibitor (AChEI) effects on α7 nAChR were tested in Aβ25-35-received (intracerebroventricular, 10 nmol) mice model of AD. Methyllycaconitine (MLA) (1mg/kg, i.p.), a α7 nAChR antagonist, was used for receptor blockage effects evaluation. Working and reference memory in animals was assessed by the Morris water maze (MWM) task. The mRNA and protein levels of α7 subunit were analyzed by real-time PCR and Western blotting, respectively. PHA and Gal, ameliorate Aβ-impaired working and reference memory. However, Gal had less effect than PHA in this regard. Pretreatment with MLA reverses both Gal and PHA effects in MWM. PHA and Gal treatment prevent Aβ-induced α7 subunit protein reduction, but Gal has lesser effect than PHA. This effect blocked by pretreatment with MLA. In neither the pretreatment nor treatment group, the mRNA levels of nAChR α7 subunit were significantly changed. Therefore, α7 nAChR activation, reduces Aβ-induced cognitive deficits and increases the α7 protein level and subsequent neuron survival. However, blockage of receptor, increases Aβ toxicity and cognitive impairment and reduces the α7 nAChR protein level and flowing neuroprotection.
authors.affiliation: Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: S
authors.initials: S
authors.lastname: Sadigh-Eteghad
authors.affiliation: Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address: Mahnaz.Talebi511@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Talebi
authors.affiliation: Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: J
authors.initials: J
authors.lastname: Mahmoudi
authors.affiliation: Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: S
authors.initials: S
authors.lastname: Babri
authors.affiliation: Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: D
authors.initials: D
authors.lastname: Shanehbandi
mesh_terms: D000157:Aconitine / Q000031:analogs & derivatives / Q000627:therapeutic use; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D005702:Galantamine / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D018733:Nicotinic Antagonists / Q000627:therapeutic use; D010446:Peptide Fragments / Q000633:toxicity*; D011597:Psychomotor Performance / Q000187:drug effects; D011812:Quinuclidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002800:Cholinesterase Inhibitors; C513163:N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011812:Quinuclidines; D012333:RNA, Messenger; D064569:alpha7 Nicotinic Acetylcholine Receptor; C074636:amyloid beta-protein (25-35); D005702:Galantamine; C054634:methyllycaconitine; D000157:Aconitine
keywords: Aβ(25–35); PHA-543613; cognition; galantamine; α(7) nAChR