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Received for publication June 16, 2005.
Revised August 5, 2005.
Accepted for publication August 5, 2005.
Donepezil, rivastigmine and galantamine are three drugs with acetylcholinesterase (AChE) inhibiting activity that are currently being used to treat patients suffering of Alzheimer's disease. We have studied the neuroprotective effects of these drugs, in comparison to 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 miroM 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 Abeta, galantamine, donepezil, and rivastigmine showed maximum protection at the same concentrations: 0.3 microM, 1 microM 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-betha-erithroidine. The PI3K/AKt blocker LY294002 reversed the protective effects of galantamine, donepezil and nicotine but not that of rivastigmine. On the other hand, the bcl-2 antagonist 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 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.
Key words:
Acetylcholinesterase Inhibitors, Beta amyloid, Neuroblastoma, Neuroprotection, Nicotinic receptors, Okadaic acid
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