Characterization of the effect of ganstigmine (CHF2819) on amyloid precursor protein metabolism in SH-SY5Y neuroblastoma cells.
We have investigated the effect of ganstigmine (CHF2819), a novel geneserine derived acetylcholinesterase (AChE) inhibitor, on the expression and metabolism of the amyloid precursor protein (APP) in neuroblastoma cell line SH-SY5Y. The rationale was based on the suggestion that cholinergic activity may also be involved in the regulation of APP metabolism. We studied the acute effect on APP metabolism following the secretion of sAPPalpha in the conditioned medium of cells. Following short term treatment (2h), ganstigmine promoted a slight increase in the release of sAPPalpha, the maximal effect approaching on average 1.5 fold baseline value. The data obtained in the long term experiments demonstrate that continuous inhibition of AchE obtained with 100 nM ganstigmine following an exposure of 24 hours did not influence APP isoforms expression. However, the compound appeared to increase the constitutive release of sAPPalpha, with a mechanism that is derived from an indirect cholinergic stimulation.
Mazzucchelli
M
M
Department of Experimental and Applied Pharmacology, University of Pavia, Pavia, Italy.
Porrello
E
E
Villetti
G
G
Pietra
C
C
Govoni
S
S
Racchi
M
M
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002219:Carbamates / Q000494:pharmacology*; D002460:Cell Line; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D006801:Humans; D009447:Neuroblastoma; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*
D000470:Alkaloids; D016564:Amyloid beta-Protein Precursor; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase; D000109:Acetylcholine; C447079:ganstigmine