Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model.
BACKGROUND
APP23 mice are a promising model of Alzheimer's disease, expressing several histopathological, cognitive and behavioural hallmarks of the human condition. A valid animal model should respond to therapeutic interventions in an equivalent manner as human patients.


OBJECTIVE
To further validate the APP23 model, we examined whether cognitive deficits could be antagonised by donepezil, rivastigmine, galantamine or memantine, which are approved drugs for symptomatic treatment of dementia.


METHODS
Animals were tested at an age at which untreated APP23 mice display severe deficits in visual-spatial learning. Four-month-old APP23 mice and control littermates were administered donepezil (0.3 or 0.6 mg kg(-1)), rivastigmine (0.5 or 1.0 mg kg(-1)), galantamine (1.25 or 2.5 mg kg(-1)), memantine (2 or 10 mg kg(-1)) or saline through daily i.p. injections. After 1 week of treatment, acquisition phase commenced, with daily treatment continuing during cognitive testing.


RESULTS
All cholinesterase inhibitors reduced cognitive deficits with the following optimal daily doses: galantamine 1.25 mg kg(-1), rivastigmine 0.5 mg kg(-1) and donepezil 0.3 mg kg(-1). Higher dosages often did not exert beneficial effects in accordance with inverted U-shaped dose-response curves described for cholinomimetics. Symptomatic efficacy of memantine on cognition was mild, with significant amelioration manifesting during probe trial.


CONCLUSIONS
This is the first study to simultaneously evaluate the efficacy of therapeutically relevant doses of these four compounds in one particular learning and memory paradigm, being the Morris water maze. The fact that symptomatic intervention was able to diminish cognitive impairment, substantially adds to the validity of the APP23 model as a valuable tool to evaluate future therapeutic approaches.
Van Dam
Debby
D
Laboratory of Neurochemistry and Behaviour, Born-Bunge Institute, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Abramowski
Dorothee
D
Staufenbiel
Matthias
M
De Deyn
Peter Paul
PP
D000544:Alzheimer Disease / Q000188:drug therapy*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D005702:Galantamine / Q000627:therapeutic use; D006801:Humans; D007189:Indans / Q000627:therapeutic use; D008297:Male; D008559:Memantine / Q000627:therapeutic use; D051379:Mice; D008817:Mice, Mutant Strains; D048448:Phenylcarbamates / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D000068836:Rivastigmine; D012680:Sensitivity and Specificity
D016564:Amyloid beta-Protein Precursor; D002800:Cholinesterase Inhibitors; D007189:Indans; D048448:Phenylcarbamates; D010880:Piperidines; D005702:Galantamine; D000077265:Donepezil; D000068836:Rivastigmine; D008559:Memantine