Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice

Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging. In fact, administration of S 47445 at 0.3 mg/kg (s.c.) reversed the age-induced deficits of the working memory model whatever the retention interval. Moreover, in the contextual task, S 47445 also reversed the age-induced deficit at all tested doses (from 0.03 to 0.3 mg/kg, p.o.). Since donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer's disease patients, an alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both glutamatergic AMPA receptors and cholinergic pathways by combining pharmacological treatments. The present study further examined such effects by assessing combinations of S 47445 and donepezil given orally during 9 days in aged C57/Bl6J mice using contextual memory task (CSD) and the working memory model of serial alternation task (AT). Interestingly, a significant synergistic memory-enhancing effect was observed with the combination of donepezil at 0.1 mg/kg with S 47445 at 0.1 mg/kg p.o. in the CSD or with S 47445 at 0.1 and 0.3 mg/kg in AT in comparison to compounds given alone and without any pharmacokinetic interaction.