Galantamine inhibits calpain-calcineurin signaling activated by beta-amyloid in human neuroblastoma SH-SY5Y cells.
Galantamine, which is currently used in the treatment of patients with Alzheimer's disease (AD), has been shown to have a neuroprotective effect against beta-amyloid (Abeta) peptide-induced toxicity, which is involved in the pathogenesis of AD. In this study, we investigated the mechanism underlying the protective effect of galantamine on Abeta-induced toxicity in human neuroblastoma cells (SH-SY5Y). Using MTT and LDH leakage assays, we observed that galantamine pretreatment significantly prevented Abeta1-40-induced cell death. Abeta1-40-induced overexpression and increased cleavage of both calpain and calcineurin were observed by Western blotting and double immunofluorescent staining. Increased calcineurin phosphatase activity and decreased level of pSer112 BAD were also observed in Abeta1-40-damaged cells. However, all these alterations were found to be reversed by galantamine pretreatment. We also found that the neuroprotection of galantamine can be blocked by an alpha7 nAChR antagonist. Overall, our results suggest that galantamine may prevent the neuronal damage induced by Abeta1-40 through a mechanism related to the regulation of calpain-calcineurin activation and BAD phosphorylation, which may involve the participation of alpha7 nAChR.
Li
Qianqian
Q
Department of Neurology, the First Affiliated Hospital of Harbin Medical University, Harbin, PR China.
Fang
Jing
J
Yang
Meimei
M
Wu
Donglai
D
Zhang
Liming
L
Zhang
Yan
Y
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D019703:Calcineurin / Q000502:physiology; D065095:Calcineurin Inhibitors; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000502:physiology; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005702:Galantamine / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D016229:Amyloid beta-Peptides; D065095:Calcineurin Inhibitors; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D005702:Galantamine; D019703:Calcineurin; D002154:Calpain