Effects of S 18986-1, a novel cognitive enhancer, on memory performances in an object recognition task in rats.
(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxi de (S 18986-1) is a new compound that facilitates post-synaptic responses by modulating alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated synaptic responses and thus promotes long-term potentiation and potentiates (S)-AMPA-induced release of noradrenaline in rat brain slices. In the present study, the effects of S 18986-1 were evaluated on cognitive functions by using a one-trial object-recognition test in the Wistar rat, a test which measures a form of episodic memory in rodents. Recognition was measured by the ability of treated rats to discriminate between a familiar and a new object after a 24-h retention delay. Oral administrations with S 18986-1 (0.3 to 100 mg/kg) 1 h before each session of the test improved object recognition at concentrations as low as 0.3 mg/kg. Under the same conditions, the nootropic drug aniracetam was active at a dose of 10 mg/kg by i.p. route. S 18986-1 was still effective on the object-recognition test when it was administered 4 h before each of the three sessions. Furthermore, subchronic oral pretreatment (7 days) with S 18986-1 (0.3 to 30 mg/kg) also increased the recognition of the familiar object indicating that the animals failed to develop tolerance to repeated administrations with S 18986-1. Finally, the recognition of the familiar object was improved when S 18986-1 was administered before the recognition trial whereas the rats failed to recognise the familiar object when S 18986-1 was administered before the sample presentation trial only. Taken together, the results indicated that S 18986-1 facilitated a form of episodic memory in the rat, by improving the recognition of a familiar information (retention). Furthermore, S 18986-1 was long-acting and demonstrated a good oral bioavailability. These data confer on S 18986-1, a potential role in improving episodic memory impaired in neurodegenerative diseases and during aging.
Division of Cerebral Pathology, Institut de Recherches Servier, 125, Chemin de Ronde, 78290 Croissy-sur-Seine, France. lebrun@netgrs.com
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D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D008297:Male; D008568:Memory / Q000187:drug effects*; D018697:Nootropic Agents / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects*; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D001581:Benzothiadiazines; D018697:Nootropic Agents; D011760:Pyrrolidinones; C414205:S18986-1; C036466:aniracetam