Premium
Neuroprotective effects of donepezil through inhibition of GSK‐3 activity in amyloid‐β‐induced neuronal cell death
Author(s) -
Noh MinYoung,
Koh SeongHo,
Kim Youngchul,
Kim Hyun Young,
Cho Goang Won,
Kim Seung Hyun
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05837.x
Subject(s) - donepezil , neuroprotection , acetylcholinesterase , pharmacology , gsk 3 , neurotoxicity , acetylcholinesterase inhibitor , chemistry , biochemistry , phosphorylation , biology , medicine , toxicity , enzyme , dementia , disease , organic chemistry
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.