Neurotoxicity Induced by Okadaic Acid in the Human Neuroblastoma SH-SY5Y Line Can Be Differentially Prevented by alpha 7 and beta 2*Nicotinic Stimulation

L del Barrio, M D Martin-de-Saavedra, A Romero, E Parada, J Egea, J Avila, J M McIntosh, Susan Wonnacott, M G Lopez

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Abstract

A good model of neuronal death that reproduces the characteristic tau (tau) hyperphosphorylation of Alzheimers disease is the use of okadaic acid (OA). The aim of this study was to determine the contribution of alpha 7 and beta 2* nicotinic acetylcholine receptor (nAChR) subtypes to neuroprotection against OA in the SH-SY5Y cell line by using the selective alpha 7 and beta 2* nAChR agonists PNU 282987 and 5-Iodo-A85380, respectively. The results of this study show that both alpha 7 and beta 2* nAChR can afford neuroprotection against OA-induced neurotoxicity. Protection mediated by alpha 7 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 alpha 7 nAChR by using the alpha 7-selective positive allosteric modulator PNU 120596, protection was lost. By contrast, protection mediated by beta 2* nAChRs was Ca(2+) dependent and implicated the signaling pathways PI3K/Akt and extracellular regulated kinase 1/2. Both alpha 7 and beta 2* nAChR activation converged on downregulation of GSK-3 beta and reduction of tau phosphorylation in cells undergoing cell death induced by OA. Therefore, targeting nAChR could offer a strategy for reducing neurodegeneration secondary to hyperphosphorylation of protein tau.
Original languageEnglish
Pages (from-to)193-205
Number of pages13
JournalToxicological Sciences
Volume123
Issue number1
DOIs
Publication statusPublished - Sep 2011

Keywords

  • 5IA 85380
  • SH-SY5Y neuroblastoma
  • PNU 282987
  • nicotinic receptors
  • okadaic acid
  • hyperphosphorylation of tau

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