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P3-043: COGNITIVE PROFILE OF S 68890, AN ALLOSTERIC MODULATOR OF ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTORS

2019; Wiley; Volume: 15; Issue: 7S_Part_18 Linguagem: Inglês

10.1016/j.jalz.2019.06.3069

1552-5279

Laurence Danober, G. Das Dores, Caroline Louis, Karine Llopis, Nathalie Dumas, Catherine Liard, Sylvie Girardon, Le Quement Catherine, Marie Bureau, Ali Krazem, Daniel Béracochéa, Thierry Pillot, Thierry Le Diguarher, Marc Bertrand, Alain Benoist, Jean‐Marie Fourquez, Anne‐Marie Chollet, Philippe Gloanec, Ross Jeggo,

Cholinesterase and Neurodegenerative Diseases

Cognitive deficits are associated with several neurodegenerative and mood disorders. Among treatments, agonists and positive allosteric modulators of alpha7 nicotinic acetylcholine receptors (alpha7-nAChRs) have promising therapeutic potentials to enhance cognition. We have recently identified new compounds with a different mechanism of action compared to all previous known allosteric modulators and with a safe profile in vivo. The present study describes the cognitive-enhancing properties of S68890 not only in natural-forgetting conditions but also in amyloidergic-altered memory conditions in rodents*. Plasma and cerebral concentrations were used to determine partition coefficients (Kp) 20 and 60 min after 3 mg/kg acute oral administration of S68890 in mice and rats. S68890 was either orally (po) or intraperitoneally (ip) administrated in animals tested in either natural forgetting conditions (novel object recognition, NOR and spontaneous alternation performed in a T-maze, SAT) or on amyloid β-induced memory deficits observed in spontaneous alternation performed in a Y-maze (SAY). Effects as an add-on therapy with donepezil or using alpha7-nAChRs Knock-out (KO) mice were investigated. Changes in autonomic function, locomotor activity and body temperature were recorded in mice after acute administration. Permeability of the Blood-Brain-Barrier for S68890 was high (Kp ranging from 1.9 in rats and 2.6 in mice). S68890 improved episodic-like memory at very low doses in NOR in rats (0.003−0.1 mg/kg po) and in mice (0.03-3 mg/kg po). The procognitive effect of S68890 was lost in alpha7-nAChRs KO mice. S68890 improved spatial working memory in SAT (0.03−0.3 mg/kg ip), presented additive synergistic effects with donepezil in NOR and reversed memory deficits induced by intracerebroventricular amyloid β infusion in SAY (1-3 mg/kg/j po) in mice. No effects on general behaviour, body temperature and spontaneous locomotor activity were noticed after acute administration in mice (10-100 mg/kg po). Taken together, these results indicate that S68890 displayed potent cognitive-enhancing properties that occurred at very low doses and that were selectively due to alpha7-nAChRs modulation. S68890 could therefore have promising therapeutic potential for the treatment of cognitive impairments in Alzheimer's disease. *Separate abstract on in vitro data of S68890 submitted to AAIC.