Comparison of donepezil and memantine for protective effect against amyloid-beta(1-42) toxicity in rat septal neurons.
Donepezil, a potent acetylcholinesterase (AChE) inhibitor and memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, have been used for the treatment of Alzheimer's disease (AD), and both of them have been shown to have neuroprotective action against glutamate excitotoxicity. However, it is not known whether donepezil and memantine similarly exert neuroprotective effects against amyloid-beta peptide(1-42) [Abeta(1-42)] toxicity in cholinergic neurons. Therefore, in the present study we compared the neuroprotective effects of donepezil and memantine against Abeta(1-42) toxicity in rat cultured septal cholinergic neurons, because deficit in cholinergic neurotransmission is a major feature in AD, and medial septal cholinergic neurons are known to degenerate in AD patients. Septal neuronal cells were cultured for 7 days and then 5 micromol/L of Abeta(1-42) was added to the medium for 48 h. Measurement of the efflux of lactate dehydrogenase (LDH) indicated that septal neuronal cells were highly susceptible to Abeta toxicity and relatively resistant to NMDA toxicity. Donepezil concentration-dependently reduced the LDH efflux induced by Abeta(1-42), and the effect was significant at 1 micromol/L and above. NMDA receptor antagonists, memantine and MK-801, did not show a significant neuroprotective effect against Abeta(1-42) toxicity. It is concluded that the neuroprotective effect of donepezil against Abeta(1-42) toxicity is not mediated by interference with the NMDA-mediated excitotoxic process, and that donepezil may be more effective than memantine against cholinergic neuronal damage induced by Abeta(1-42) exposure.
Kimura
Manami
M
Department of Drug Discovery, Eisai Tsukuba Research Laboratories, 5-1-3 Tokodai, Tsukuba, Ibaraki 300-2635, Japan. m4-kimura@hhc.eisai.co.jp
Komatsu
Hiroko
H
Ogura
Hiroo
H
Sawada
Kohei
K
D000110:Acetylcholinesterase / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D007189:Indans / Q000008:administration & dosage*; D008559:Memantine / Q000008:administration & dosage*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000633:toxicity*; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D012686:Septal Nuclei / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D004338:Drug Combinations; D007189:Indans; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010880:Piperidines; C075222:amyloid beta-protein (1-42); D000077265:Donepezil; D000110:Acetylcholinesterase; D008559:Memantine