Neuroprotective effects of donepezil through inhibition of GSK-3 activity in amyloid-β-induced neuronal cell death

• Published in: Journal of neurochemistry 2009-03, Vol.108 (5), p.1116-1125
• Main Authors: Noh, Min-Young, Koh, Seong-Ho, Kim, Youngchul, Kim, Hyun Young, Cho, Goang Won, Kim, Seung Hyun
• Format: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Amyloid beta-Peptides - toxicity; amyloid-β; Analysis of Variance; Animals; Apoptosis - drug effects; Biological and medical sciences; Cell Survival; Cells, Cultured; Cerebral Cortex - cytology; Cholinesterase Inhibitors - pharmacology; Chromones - pharmacology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; donepezil; Dose-Response Relationship, Drug; Embryo, Mammalian; Glycogen Synthase Kinase 3 - antagonists & inhibitors; Glycogen Synthase Kinase 3 - metabolism; glycogen synthase kinase-3; Indans - pharmacology; Indoles; Mecamylamine - pharmacology; Medical sciences; Morpholines - pharmacology; Neurology; Neurons - drug effects; Neurons - physiology; neuroprotection; Neuroprotective Agents - pharmacology; Nicotine - pharmacology; nicotinic acetylcholine receptors; Nicotinic Agonists - pharmacology; Nicotinic Antagonists - pharmacology; Organic mental disorders. Neuropsychology; Peptide Fragments - toxicity; phosphoinositide 3 kinase; Phosphorylation - drug effects; Piperidines - pharmacology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Sprague-Dawley; Serine - metabolism; Sincalide - metabolism
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05837.x

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-β1-42 (Aβ42)-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 μM Aβ42 for 6 h. In addition to donepezil, other AChE-inhibitors (galantamine and huperizine A) also showed increased neuronal cell viability against Aβ42 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 μM), a phosphoinositide 3 kinase inhibitor, but only partially by mecamylamine (10 μM), a blocker of nicotinic acetylcholine receptors. Additionally, donepezil's neuroprotective mechanism was related to the enhanced phosphorylation of Akt and GSK-3β and reduced phosphorylation of tau and glycogen synthase. These results suggest that donepezil prevents Aβ42-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.