Cognitive enhancing effects of ghrelin receptor agonists.
BACKGROUND
Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, has been shown to play a role in multiple physiological processes including appetite regulation, metabolism and, more recently, dendritic spine architecture, long-term potentiation and cognition.


OBJECTIVE
The objective of this study was to determine the effects of two structurally non-peptide ghrelin receptor agonists (GSK894490A and CP-464709-18) on rodent cognition.


METHODS
All experiments were performed in male Lister hooded rats. Effects of the test compounds on rat cognitive performance was determined using the novel object recognition test, a modified water maze paradigm and a scopolamine-induced deficit in cued fear conditioning. These tests were chosen as they each probe a relatively independent cognitive domain and therefore potentially have differing underlying neural substrates.


RESULTS
Both compounds significantly improved performance in the novel object recognition and modified water maze tests but were unable to attenuate a scopolamine deficit in cued fear conditioning.


CONCLUSIONS
These results demonstrate that the small-molecule ghrelin receptor agonists profiled here readily cross the blood/brain barrier and elicit pro-cognitive effects in recognition and spatial learning and memory tests. Based on these observations, the central ghrelin receptor would appear to be a chemically tractable receptor and perhaps should be considered as a new drug target for therapeutic approaches to treat diseases affecting cognition.
Atcha
Zeenat
Z
GlaxoSmithKline R&D China, Centre for Cognition and Neurodegeneration Research, Biopolis at One-North, 11 Biopolis Way, The Helios Building, #03-01/02, Singapore 138667, Singapore. Zeenat.I.Atcha@gsk.com
Chen
Woei-Shin
WS
Ong
Agnes B
AB
Wong
Fong-Kuan
FK
Neo
Aveline
A
Browne
Edward R
ER
Witherington
Jason
J
Pemberton
Darrel J
DJ
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003213:Conditioning, Psychological / Q000187:drug effects; D003463:Cues; D005239:Fear; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D054440:Receptors, Ghrelin / Q000819:agonists*; D021641:Recognition, Psychology / Q000187:drug effects; D012601:Scopolamine; D012694:Serine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D010879:Piperazines; D011725:Pyridines; D054440:Receptors, Ghrelin; D012601:Scopolamine; D012694:Serine; D013449:Sulfonamides; C546352:5-(2-methylalanyl)-O-((2,4difluorophenyl)methyl)-seryl-3-oxo-3a-(2 pyridinylmethyl)-2-(2,2,2 trifluoroethyl)-3,3a,4,5,6,7-hexahydro-2H pyrazolo(4,3-c)pyridine; C546351:N-(5-(3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl)-4-(5-methyl-2-furanyl) benzenesulfonamide; D000096926:Benzenesulfonamides