title: Neurotoxicity induced by okadaic acid in the human neuroblastoma SH-SY5Y line can be differentially prevented by α7 and β2* nicotinic stimulation.
abstract: A good model of neuronal death that reproduces the characteristic tau (τ) hyperphosphorylation of Alzheimeŕs disease is the use of okadaic acid (OA). The aim of this study was to determine the contribution of α7 and β2* nicotinic acetylcholine receptor (nAChR) subtypes to neuroprotection against OA in the SH-SY5Y cell line by using the selective α7 and β2* nAChR agonists PNU 282987 and 5-Iodo-A85380, respectively. The results of this study show that both α7 and β2* nAChR can afford neuroprotection against OA-induced neurotoxicity. Protection mediated by α7 nAChRs was independent of Ca(2+) and involved the intracellular signaling pathway Janus Kinase-2/Phosphatidylinositol-3-kinase/Akt. When Ca(2+) entry was promoted through the α7 nAChR by using the α7-selective positive allosteric modulator PNU 120596, protection was lost. By contrast, protection mediated by β2* nAChRs was Ca(2+) dependent and implicated the signaling pathways PI3K/Akt and extracellular regulated kinase 1/2. Both α7 and β2* nAChR activation converged on downregulation of GSK-3β and reduction of τ phosphorylation in cells undergoing cell death induced by OA. Therefore, targeting nAChR could offer a strategy for reducing neurodegeneration secondary to hyperphosphorylation of protein τ.
authors.affiliation: Instituto Teófilo Hernando, Facultad de Medicina, Universidad Auto´noma de Madrid, 28029 Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Del Barrio
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Martín-de-Saavedra
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.forename: Esther
authors.initials: E
authors.lastname: Parada
authors.forename: Javier
authors.initials: J
authors.lastname: Egea
authors.forename: Jesús
authors.initials: J
authors.lastname: Avila
authors.forename: John Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Susan
authors.initials: S
authors.lastname: Wonnacott
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
mesh_terms: D001384:Azetidines / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D007476:Ionophores / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007555:Isoxazoles / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018722:Nicotinic Agonists / Q000494:pharmacology*; D019319:Okadaic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001384:Azetidines; D001549:Benzamides; D001643:Bridged Bicyclo Compounds; D002118:Calcium; D007476:Ionophores; D007555:Isoxazoles; D053614:Janus Kinase 2; D018722:Nicotinic Agonists; D019319:Okadaic Acid; D010671:Phenylurea Compounds; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C426745:5-iodo-3-(2-azetidinylmethoxy)pyridine; C579167:Chrna7 protein, human; C498513:PNU-282987; C507924:JAK2 protein, human