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

S. Bretin, A. Krazem, N. Henkous, C. Froger-Colleaux, E. Mocaer, C. Louis, N. Perdaems, A. Marighetto, D. Beracochea
Psychopharmacology. 2017-11-22; 235(3): 771-787
DOI: 10.1007/s00213-017-4792-5

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1. Psychopharmacology (Berl). 2018 Mar;235(3):771-787. doi:
10.1007/s00213-017-4792-5. Epub 2017 Nov 22.

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

Bretin S(1), Krazem A(2), Henkous N(2), Froger-Colleaux C(3), Mocaer E(1), Louis
C(4), Perdaems N(5), Marighetto A(6), Beracochea D(7).

Author information:
(1)Institut de Recherches Internationales Servier, Pôle d’Innovation
Thérapeutique Neuropsychiatrie, Suresnes, France.
(2)Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (INCIA),
Université de Bordeaux, UMR CNRS 5287, Allée Geoffroy Saint-Hilaire, Bat B2,
33613, Pessac, France.
(3)Froger-Colleaux C, Porsolt Research Laboratory, Z.A de Glatiné, 53940, Le
Genest-Saint-Isle, France.
(4)Institut de Recherches Servier, Pôle d’Innovation Thérapeutique
Neuropsychiatrie, Croissy-Sur-Seine, France.
(5)Pôle Expertise en Pharmacocinétique, Orléans, France.
(6)INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale,
U1215, 33077, Bordeaux, France.
(7)Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (INCIA),
Université de Bordeaux, UMR CNRS 5287, Allée Geoffroy Saint-Hilaire, Bat B2,
33613, Pessac, France. .

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.

DOI: 10.1007/s00213-017-4792-5
PMCID: PMC5847048
PMID: 29167913 [Indexed for MEDLINE]


Auteurs Bordeaux Neurocampus