Anti-ischemic and cognition-enhancing properties of NNC-711, a gamma-aminobutyric acid reuptake inhibitor.
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.
O'Connell
A W
AW
Department of Pharmacology, Conway Institute, University College Dublin, Belfield, 4, Dublin, Ireland.
Fox
G B
GB
Kjøller
C
C
Gallagher
H C
HC
Murphy
K J
KJ
Kelly
J
J
Regan
C M
CM
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
D018756:GABA Antagonists; D018696:Neuroprotective Agents; D009557:Nipecotic Acids; D010091:Oximes; C078793:NNC 711; D012601:Scopolamine