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Symptomatic effect of donepezil, rivastigmine, galantamine and memantine on cognitive deficits in the APP23 model

Bibliographic

Year of Publication:
2005
Contact PI Name:
Debby Van Dam
Contact PI Affiliation:
Laboratory of Neurochemistry and Behaviour, Born-Bunge Institute, Department of Biomedical Sciences, University of Antwerp, Wilrijk, Belgium
Co-Authors:
Dorothee Abramowski, Matthias Staufenbiel, Peter Paul De Deyn
Primary Reference (PubMED ID):
Funding Source:
Medical Research Foundation Antwerp
The Research Foundation-Flanders/Fonds voor Watenschappelijk Onderzoek-Vlaanderen (FWO)
Study Goal and Principal Findings:

A valid animal model should respond to therapeutic interventions in an equivalent manner as human patients. The rationale of this study was to further validate the APP23 model by comparing the symptomatic efficacy of four, internationally approved compounds for symptomatic treatment of human AD (galantamine, rivastigmine, donepezil, memantine), under identical testing conditions and testing protocol (Morris Water Maze).  Four-month-old APP23 mice and control littermates were administered sham treatment or 1 of the above mentioned compounds. Tg and wild type animals were tested at an age at which untreated APP23 mice display severe deficits in visual–spatial learning. The APP23-sham group was unable to learn the position of the hidden platform as efficient as the WT-sham group; this inferior performance could not be attributed to decreased motor performance, and therefore can (at least partly) be explained by cognitive deficits of the Tg mice. The efficacy studies using Tg mice found that 1 week of treatment with the 3 cholinesterase inhibitors (galantamine, rivastigmine, donepezil) was sufficient to reduce the cognitive deficit with the following optimal 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 previously described for cholinomimetics. The symptomatic efficacy of memantine on cognition was mild compared to that observed with the cholinesterase inhibitors. Comparison of performance in the Morris Water Maze of all WT groups (sham and drug-treated) failed to show a significant effect of drug treatment. The fact that symptomatic intervention was able to diminish cognitive impairment in the APP23 mice, substantially adds to the validity of the model as a valuable tool to evaluate future therapeutic approaches.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Memantine
Therapeutic Target:
NMDA Receptor
Therapy Type:
Small Molecule
Therapeutic Agent:
Donepezil
Therapeutic Target:
Acetylcholinesterase
Therapy Type:
Small Molecule
Therapeutic Agent:
Rivastigmine
Therapeutic Target:
Acetylcholinesterase
Therapy Type:
Small Molecule
Therapeutic Agent:
Galantamine
Therapeutic Target:
Acetylcholinesterase

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Strain/Genetic Background:
Not Reported
Species:
Mouse
Model Type:
Non-transgenic
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Experiment Notes

Dosages were chosen to ensure sufficient inhibition of ChE (and in case of galantamine, significant APL activity), and clinical relevance compared to human dosages based on dosage per kg of body weight and plasma levels. See the following references for details: Fishkin RJ, Ince ES, Carlezon WA Jr, Dunn RW (1993) D-Cycloserine attenuates scopolamine-induced learning and memory deficits in rats. Behav Neural Biol 59:150–157; Camacho F, Smith CP, Vargas HM, Winslow JT (1996) Alpha 2-adrenoceptor antagonists potentiate acetylChE inhibitor effects on passive avoidance learning in the rat. Psychopharmacology (Berl) 124:347–354; Misztal M, Frankiewicz T, Parsons CG, Danysz W (1996) Learning deficits induced by chronic intraventricular infusion of quinolinic acid–protection by MK-801 and memantine. Eur J Pharmacol 296:1–8

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Morris Water Maze
Motor Function
Path Length