Neuroprotective effects of donepezil through inhibition of GSK-3 activity in amyloid-beta-induced neuronal cell death.
J Neurochem
; 108(5): 1116-25, 2009 Mar.
Article
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| MEDLINE
| ID: mdl-19077054
ABSTRACT
Acetylcholinesterase inhibitors (AChE-inhibitors) are used for the treatment of Alzheimer's disease. Recently, the AChE-inhibitor donepezil was found to have neuroprotective effects. However, the protective mechanisms of donepezil have not yet been clearly identified. We investigated the neuroprotective effects of donepezil and other AChE-inhibitors against amyloid-beta1-42 (Abeta42)-induced neurotoxicity in rat cortical neurons. To evaluate the neuroprotective effects of AChE-inhibitors, primary cultured cortical neurons were pre-treated with several concentrations of AChE-inhibitors for 24 h and then treated with 20 microM Abeta42 for 6 h. In addition to donepezil, other AChE-inhibitors (galantamine and huperizine A) also showed increased neuronal cell viability against Abeta42 toxicity in a concentration-dependent manner. However, we demonstrated that donepezil has a more potent effect in inhibiting glycogen synthase kinase-3 (GSK-3) activity compared with other AChE-inhibitors. The neuroprotective effects of donepezil were blocked by LY294002 (10 microM), a phosphoinositide 3 kinase inhibitor, but only partially by mecamylamine (10 microM), a blocker of nicotinic acetylcholine receptors. Additionally, donepezil's neuroprotective mechanism was related to the enhanced phosphorylation of Akt and GSK-3beta and reduced phosphorylation of tau and glycogen synthase. These results suggest that donepezil prevents Abeta42-induced neurotoxicity through the activation of phosphoinositide 3 kinase/Akt and inhibition of GSK-3, as well as through the activation of nicotinic acetylcholine receptors.
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1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
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Piperidinas
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Péptidos beta-Amiloides
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Apoptosis
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Fármacos Neuroprotectores
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Glucógeno Sintasa Quinasa 3
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Indanos
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Neuronas
Límite:
Animals
Idioma:
En
Revista:
J Neurochem
Año:
2009
Tipo del documento:
Article