title: Anti-ischemic and cognition-enhancing properties of NNC-711, a gamma-aminobutyric acid reuptake inhibitor.
abstract: NNC-711 [1-(2-((diphenylmethylene)amino)oxy)ethyl)-1,2,4,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride], a gamma-aminobutyric acid (GABA) reuptake inhibitor with anticonvulsant activity, was investigated with respect to its cognition-enhancing and neuroprotective potency. In the rat, administration of NNC-711 immediately prior to training prevented amnesia for a passive avoidance task induced by the acetylcholine receptor antagonist scopolamine. NNC-711 was also effective in protecting against ischemia-induced death of CA1 pyramidal neurons in a model of bilateral common carotid artery occlusion in the gerbil. In addition to a neuroprotective activity, NNC-711 exhibited significant cognition-enhancing actions. Daily administration of NNC-711, immediately prior to a spatial learning task, significantly reduced escape latencies in the water maze paradigm in both mature (postnatal day 80) and aged (28 months) rats. All of the above actions exhibited a bell-shaped response with an optimal dose of 0.5-1.0 mg/kg. These investigations with NNC-711 and previous clinical observations on the structurally related anticonvulsant tiagabine confirm the potential of GABA reuptake inhibitors as anti-amnesia and cognition-enhancing agents.
authors.affiliation: Department of Pharmacology, Conway Institute, University College Dublin, Belfield, 4, Dublin, Ireland.
authors.forename: A W
authors.initials: AW
authors.lastname: O'Connell
authors.forename: G B
authors.initials: GB
authors.lastname: Fox
authors.forename: C
authors.initials: C
authors.lastname: Kjøller
authors.forename: H C
authors.initials: HC
authors.lastname: Gallagher
authors.forename: K J
authors.initials: KJ
authors.lastname: Murphy
authors.forename: J
authors.initials: J
authors.lastname: Kelly
authors.forename: C M
authors.initials: CM
authors.lastname: Regan
mesh_terms: D000647:Amnesia / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003071:Cognition / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology*; D005849:Gerbillinae; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D002546:Ischemic Attack, Transient / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology*; D010091:Oximes / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000008:administration & dosage
chemical_list: D018756:GABA Antagonists; D018696:Neuroprotective Agents; D009557:Nipecotic Acids; D010091:Oximes; C078793:NNC 711; D012601:Scopolamine