The protective effect of ganstigmine against amyloid beta 25-35 neurotoxicity on chicken cortical neurons is independent from the cholinesterase inhibition.
Ganstigmine (CHF2819), a novel genserine derived acetylcholinesterase inhibitor and its enantiomer CHF3360 have been investigated for neuroprotective activity in two different in vitro assay systems using isolated cortical neurons from 9 day old chicken embryos. In the first in vitro model cells were lesioned by growth factor deprivation for 8 days achieved by reduced serum supplementation (2%) to the tissue culture medium. In the second lesion model neurodegeneration due to the addition of pre-aggregated beta-amyloid(25-35) has been achieved. Neuronal viability of treated neurons evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyl tetrazolium bromid reduction assay was compared to that of untreated control cells. In a dose range between 1.0 and 10.0 microM both compounds significantly prevent progressive neuronal cell death due to growth factor deprivation. Furthermore Ganstigmine and its enantiomer in concentrations between 0.1 and 3 microM also significantly decrease neurodegeneration achieved by the addition of beta-amyloid(25-35) by approximately 50%. Dose response curves of both substances were identical concerning effect size and concentration. Because CHF3360 does not show any acetylcholine inhibitor activity in the applied dose range it is concluded that Ganstigmine provides significant neuroprotection independent from its cholinergic activity.
Windisch
Manfred
M
JSW-Research Forschungslabor GmbH., Rankengasse 28, A-8020 Graz, Austria. mwindisch@jswresearch.com
Hutter-Paier
Birgit
B
Jerkovic
Lidija
L
Imbimbo
Bruno
B
Villetti
Gino
G
D000470:Alkaloids / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D002642:Chick Embryo; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002802:Cholinesterases / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*
D000470:Alkaloids; D016229:Amyloid beta-Peptides; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D002802:Cholinesterases; C447079:ganstigmine