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- Title
Neuroprotective effects of donepezil through inhibition of GSK-3 activity in amyloid-β-induced neuronal cell death.
- Authors
Min-Young Noh; Seong-Ho Koh; Youngchul Kim; Hyun Young Kim; Goang Won Cho; Seung Hyun Kim
- 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-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.
- Subjects
NEUROPROTECTIVE agents; CELL death; ALZHEIMER'S disease; AMYLOID; NEURAL physiology; PHOSPHORYLATION; NEUROTRANSMITTER receptors
- Publication
Journal of Neurochemistry, 2009, Vol 108, Issue 5, p1116
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2008.05837.x