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.
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