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

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 deat...

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Published in:The Journal of pharmacology and experimental therapeutics 2005-12, Vol.315 (3), p.1346-1353
Main Authors: Arias, Esperanza, Gallego-Sandín, Sonia, Villarroya, Mercedes, García, Antonio G, López, Manuela G
Format: Article
Language:English
Subjects:
Aconitine - analogs & derivatives
Aconitine - pharmacology
Amyloid beta-Peptides - toxicity
Apoptosis
Benzopyrans - antagonists & inhibitors
Benzopyrans - pharmacology
Cell Culture Techniques
Cell Line, Tumor
Cholinesterase Inhibitors - pharmacology
Chromones - pharmacology
Dose-Response Relationship, Drug
Enzyme Inhibitors - pharmacology
Galantamine - antagonists & inhibitors
Galantamine - pharmacology
Humans
Indans - antagonists & inhibitors
Indans - pharmacology
L-Lactate Dehydrogenase - analysis
Morpholines - pharmacology
Neuroblastoma - metabolism
Neuroblastoma - pathology
Neuroprotective Agents - pharmacology
Nicotine - antagonists & inhibitors
Nicotine - pharmacology
Nitriles - antagonists & inhibitors
Nitriles - pharmacology
Okadaic Acid - toxicity
Phenylcarbamates - pharmacology
Phosphatidylinositol 3-Kinases - metabolism
Piperidines - antagonists & inhibitors
Piperidines - pharmacology
Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
Receptors, Nicotinic - metabolism
Rivastigmine
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Summary: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 β-amyloid (Aβ) 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 Aβ 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 Aβ- and okadaic acid-induced toxicity. The neuroprotective effects of galantamine, donepezil, and nicotine were reversed by the α7 nicotinic antagonist methyllycaconitine but not by the α4β2 nicotinic antagonist dihydro-β-erythroidine. The phosphoinositide 3-kinase (PI3K)-Akt blocker 2-(4-morpholinyl)-8-phenyl-1(4 H )-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)]-4 H -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 α7 nicotinic receptors and the PI3K-Akt pathway in the case of galantamine and donepezil but not for rivastigmine.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.105.090365