Neuroprotective effects of donepezil through inhibition of GSK-3 activity in amyloid-beta-induced neuronal cell death.
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.
Noh
Min-Young
MY
Department of Neurology, Hanyang University, Seoul, Korea.
Koh
Seong-Ho
SH
Kim
Youngchul
Y
Kim
Hyun Young
HY
Cho
Goang Won
GW
Kim
Seung Hyun
SH
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007189:Indans / Q000494:pharmacology*; D007211:Indoles; D008464:Mecamylamine / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D012844:Sincalide / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D002867:Chromones; D007189:Indans; D007211:Indoles; D009025:Morpholines; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42); C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012694:Serine; C007293:DAPI; D008464:Mecamylamine; D009538:Nicotine; D000077265:Donepezil; D038362:Glycogen Synthase Kinase 3; D012844:Sincalide