RATIONALE: 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.
RATIONALE: 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 scopolaminedeficit 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.
Authors: L C Pan; P A Carpino; B A Lefker; J A Ragan; S M Toler; J C Pettersen; D O Nettleton; O Ng; C M Pirie; K Chidsey-Frink; B Lu; D F Nickerson; D A Tess; M A Mullins; D B MacLean; P A DaSilva-Jardine; D D Thompson Journal: Endocrine Date: 2001-02 Impact factor: 3.633
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Authors: M Binn; C Albert; A Gougeon; H Maerki; B Coulie; M Lemoyne; R Rabasa Lhoret; C Tomasetto; P Poitras Journal: Peptides Date: 2006-01-19 Impact factor: 3.750
Authors: Michael Lutter; Ichiro Sakata; Sherri Osborne-Lawrence; Sherry A Rovinsky; Jason G Anderson; Saendy Jung; Shari Birnbaum; Masashi Yanagisawa; Joel K Elmquist; Eric J Nestler; Jeffrey M Zigman Journal: Nat Neurosci Date: 2008-06-15 Impact factor: 24.884
Authors: A A Patchett; R P Nargund; J R Tata; M H Chen; K J Barakat; D B Johnston; K Cheng; W W Chan; B Butler; G Hickey Journal: Proc Natl Acad Sci U S A Date: 1995-07-18 Impact factor: 11.205
Authors: Paul J Wellman; P Shane Clifford; Juan Rodriguez; Samuel Hughes; Shoshana Eitan; Luc Brunel; Jean-Alain Fehrentz; Jean Martinez Journal: Regul Pept Date: 2011-09-06
Authors: Luís F Ribeiro; Tatiana Catarino; Sandra D Santos; Marion Benoist; J Fiona van Leeuwen; José A Esteban; Ana Luísa Carvalho Journal: Proc Natl Acad Sci U S A Date: 2013-12-23 Impact factor: 11.205