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NEUROPHARMACOLOGY

Unequal Neuroprotection Afforded by the Acetylcholinesterase Inhibitors Galantamine, Donepezil, and Rivastigmine in SH-SY5Y Neuroblastoma Cells: Role of Nicotinic Receptors

Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (E.A., S.G.-S., M.V., A.G.G., M.G.L.); Servicio de Farmacología Clínica, Hospital de la Princesa, Madrid, Spain (S.G.-S., A.G.G.); and Instituto Universitario de Investigación Gerontológica y Metabólica, Hospital de la Princesa, Madrid, Spain (A.G.G., M.G.L.)

Donepezil, rivastigmine, and galantamine are three drugs with acetylcholinesterase (AChE)-inhibiting activity that are currently being used to treat patients suffering from Alzheimer's disease. We have studied the neuroprotective effects of these drugs, in comparison with nicotine, on cell death caused by -amyloid (A) and okadaic acid, two models that are relevant to Alzheimer's pathology, in the human neuroblastoma cell line SH-SY5Y. Galantamine and donepezil showed a U-shaped neuroprotective curve against okadaic acid toxicity; maximum protection was achieved at 0.3 µM galantamine and at 1 µM donepezil; at higher concentrations, protection was diminished. Rivastigmine showed a concentration-dependent effect; maximum protection was achieved at 3 µM. When apoptosis was induced by A_25-35, galantamine, donepezil, and rivastigmine showed maximum protection at the same concentrations: 0.3, 1, and 3 µM, respectively. Nicotine also afforded protection against A- and okadaic acid-induced toxicity. The neuroprotective effects of galantamine, donepezil, and nicotine were reversed by the 7 nicotinic antagonist methyllycaconitine but not by the 42 nicotinic antagonist dihydro--erythroidine. The phosphoinositide 3-kinase (PI3K)-Akt blocker 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) reversed the protective effects of galantamine, donepezil, and nicotine but not that of rivastigmine. In contrast, the bcl-2 antagonist ethyl[2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)]-4H-chromene-3-carboxylate (HA 14-1) reversed the protective effects of the three AChE inhibitors and that of nicotine. Our results show that galantamine, donepezil, and rivastigmine afford neuroprotection through a mechanism that is likely unrelated to AChE inhibition. Such neuroprotection seemed to be linked to 7 nicotinic receptors and the PI3K-Akt pathway in the case of galantamine and donepezil but not for rivastigmine.

Address correspondence to: Dr. Manuela G. López, Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, c/o Arzobispo Morcillo 4, E-28029 Madrid, Spain. E-mail: manuela.garcia{at}uam.es

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