Comparative effects of the alpha7 nicotinic partial agonist, S 24795, and the cholinesterase inhibitor, donepezil, against aging-related deficits in declarative and working memory in mice.
BACKGROUND
The comparative effects of a newly described specific alpha7 nAChR partial agonist, S 24795, and a cholinesterase inhibitor, donepezil, currently used as a symptomatic Alzheimer's disease treatment were studied in two mouse models of aging-related memory deficits.


METHODS
We employed radial arm-maze paradigms assessing short-term working memory (STWM, experiment A) and mnemonic flexibility, a cardinal property of long-term declarative (LTDM, experiment B). Both compounds were administered daily at 0.3 and 1 mg/kg subcutaneously (~3 weeks).


RESULTS
In the STWM experiment, vehicle-treated aged mice displayed a severe and persistent deficit in the retention of successive arm visits in comparison to younger controls. S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at 0.3 mg/kg (but not 1 mg/kg) exerted beneficial effects on this deficit: The performance of aged mice treated with these drugs remarkably increased across the testing days and almost reached young adult performance level. In the critical test trials of memory flexibility (i.e., LTDM), in experiment B, S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at the dose of 1 mg/kg (but not 0.3 mg/kg) improved aged mice performance.


CONCLUSIONS
This preclinical demonstration that S 24795 restored specific age-related memory deficits with as much efficacy as donepezil adds to recent literature in highlighting the potential interest of an alpha7 nAChR drug as a symptomatic AD therapeutic.
Marighetto
A
A
Centre Neurosciences Intégratives et Cognitives, Université Bordeaux 1, CNRS 5228, Talence, France. a.marighetto@cnic.u-bordeaux1.fr
Valerio
S
S
Desmedt
A
A
Philippin
J N
JN
Trocmé-Thibierge
C
C
Morain
P
P
D000375:Aging / Q000187:drug effects*; D000544:Alzheimer Disease / Q000523:psychology; D000818:Animals; D002755:Choice Behavior / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects; D004195:Disease Models, Animal; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D007189:Indans / Q000494:pharmacology*; D007266:Inhibition, Psychological; D007279:Injections, Subcutaneous; D018782:Maze Learning / Q000187:drug effects*; D008570:Memory, Short-Term / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D012153:Retention, Psychology / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002800:Cholinesterase Inhibitors; C579166:Chrna7 protein, mouse; D007189:Indans; D018722:Nicotinic Agonists; D018697:Nootropic Agents; D010880:Piperidines; D011726:Pyridinium Compounds; D011978:Receptors, Nicotinic; C524163:S 24795; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000077265:Donepezil