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 death caused by beta-amyloid (Abeta) 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 microM galantamine and at 1 microM donepezil; at higher concentrations, protection was diminished. Rivastigmine showed a concentration-dependent effect; maximum protection was achieved at 3 microM. When apoptosis was induced by Abeta25-35, galantamine, donepezil, and rivastigmine showed maximum protection at the same concentrations: 0.3, 1, and 3 microM, respectively. Nicotine also afforded protection against Abeta- and okadaic acid-induced toxicity. The neuroprotective effects of galantamine, donepezil, and nicotine were reversed by the alpha7 nicotinic antagonist methyllycaconitine but not by the alpha4beta2 nicotinic antagonist dihydro-beta-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 alpha7 nicotinic receptors and the PI3K-Akt pathway in the case of galantamine and donepezil but not for rivastigmine.
Arias
Esperanza
E
Instituto Teófilo Hernando, Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, c/o Arzobispo Morcillo 4, E-28029 Madrid, Spain.
Gallego-Sandín
Sonia
S
Villarroya
Mercedes
M
García
Antonio G
AG
López
Manuela G
MG
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D017209:Apoptosis; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005702:Galantamine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007189:Indans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D009025:Morpholines / Q000494:pharmacology; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009570:Nitriles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019319:Okadaic Acid / Q000633:toxicity; D048448:Phenylcarbamates / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010880:Piperidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D011978:Receptors, Nicotinic / Q000378:metabolism*; D000068836:Rivastigmine
D016229:Amyloid beta-Peptides; D001578:Benzopyrans; D002800:Cholinesterase Inhibitors; D002867:Chromones; D004791:Enzyme Inhibitors; D007189:Indans; D009025:Morpholines; D018696:Neuroprotective Agents; D009570:Nitriles; D048448:Phenylcarbamates; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D011978:Receptors, Nicotinic; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D005702:Galantamine; D019319:Okadaic Acid; C054634:methyllycaconitine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D009538:Nicotine; D000077265:Donepezil; D007770:L-Lactate Dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; D000068836:Rivastigmine; D000157:Aconitine