Galantamine prevents apoptosis induced by beta-amyloid and thapsigargin: involvement of nicotinic acetylcholine receptors.
Galantamine is currently used to treat Alzheimer's disease patients; it behaves as a mild blocker of acetylcholinesterase (AChE) and has an allosteric modulating action on nicotinic acetylcholine receptors (nAChRs). In this study, we observed that galantamine prevented cell death induced by the peptide beta-amyloid(1-40) and thapsigargin in the human neuroblastoma cell line SH-SY5Y, as well as in bovine chromaffin cells. The protective effect of galantamine was concentration-dependent in both cell types; maximum protection was produced at 300 nM. The antiapoptotic effect of galantamine at 300 nM, against beta-amyloid(1-40) or thapsigargin-induced toxicity, was reversed by alpha-bungarotoxin. At neuroprotective concentrations, galantamine caused a mild and sustained elevation of the cytosolic concentration of calcium, [Ca2+]c, measured in single cells loaded with Fura-2. Incubation of the cells for 48 h with 300 nM galantamine doubled the density of alpha7 nicotinic receptors and tripled the expression of the antiapoptotic protein Bcl-2. These results strongly suggest that galantamine can prevent apoptotic cell death by inducing neuroprotection through a mechanism related to that described for nicotine, i.e. activation of nAChRs and upregulation of Bcl-2. These findings might explain the long-term beneficial effects of galantamine in patients suffering of Alzheimer's disease.
Arias
Esperanza
E
Facultad de Medicina, Departamento de Farmacología, Instituto Teófilo Hernando, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029, Madrid, Spain.
Alés
Eva
E
Gabilan
Nelson H
NH
Cano-Abad
María F
MF
Villarroya
Mercedes
M
García
Antonio G
AG
López
Manuela G
MG
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western / Q000379:methods; D002038:Bungarotoxins / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D019439:Chromaffin Cells / Q000187:drug effects; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000633:toxicity; D005434:Flow Cytometry / Q000379:methods; D016257:Fura-2 / Q000031:analogs & derivatives* / Q000378:metabolism; D005702:Galantamine / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D009447:Neuroblastoma; D009538:Nicotine / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D019284:Thapsigargin / Q000633:toxicity*
D016229:Amyloid beta-Peptides; D002038:Bungarotoxins; D002800:Cholinesterase Inhibitors; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D011978:Receptors, Nicotinic; C078592:amyloid beta-protein (1-40); D005702:Galantamine; C049925:fura-2-am; D019284:Thapsigargin; D009538:Nicotine; D002118:Calcium; D016257:Fura-2