Psychopharmacology

, Volume 180, Issue 1, pp 177–190

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

  • Debby Van Dam
  • Dorothee Abramowski
  • Matthias Staufenbiel
  • Peter Paul De Deyn
Original Investigation

DOI: 10.1007/s00213-004-2132-z

Cite this article as:
Van Dam, D., Abramowski, D., Staufenbiel, M. et al. Psychopharmacology (2005) 180: 177. doi:10.1007/s00213-004-2132-z

Abstract

Rationale

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.

Objectives

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.

Keywords

Transgenic mouse modelAlzheimer’s diseaseCognitionMorris water mazeCholinergic hypothesisAcetylcholinesteraseExcitotoxicityAcetylcholinesterase inhibitorsNMDA receptor antagonist

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Debby Van Dam
    • 1
  • Dorothee Abramowski
    • 2
  • Matthias Staufenbiel
    • 2
  • Peter Paul De Deyn
    • 1
    • 3
  1. 1.Laboratory of Neurochemistry and Behaviour, Born-Bunge Institute, Department of Biomedical SciencesUniversity of AntwerpWilrijkBelgium
  2. 2.Novartis Institutes of Biomedical Research BaselBaselSwitzerland
  3. 3.Department of Neurology/Memory clinicMiddelheim General HospitalAntwerpBelgium