Cognitive enhancing effects of ghrelin receptor agonists
- 349 Downloads
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.
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.
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.
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.
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.
KeywordsGhrelin Growth hormone secretagogue receptor Novel object recognition Atlantis water maze Scopolamine fear conditioning Rodent cognition Alzheimer’s disease Schizophrenia
The authors would like to thank Paul F Chapman from GlaxoSmithKline Centre for Cognition and Neurodegeneration, Singapore for his advice with regards to the manuscript and Simon Bate and Andrew Lloyd from the GSK Discovery Statistics Department for their advice with respect to the statistical analysis of these data.
- Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR (2004) Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun 313:635–641PubMedCrossRefGoogle Scholar
- Carpino PA, Lefker BA, Toler SM, Pan LC, Hadcock JR, Murray MC, Cook ER, DiBrino JN, DeNinno SL, Chidsey-Frink KL, Hada WA, Inthavongsay J, Lewis SK, Mangano FM, Mullins MA, Nickerson DF, Ng O, Pirie CM, Ragan JA, Rose CR, Tess DA, Wright AS, Yu L, Zawistoski MP, Pettersen JC, DaSilva-Jardine PA, Wilson TC, Thompson DD (2002) Discovery and biological characterization of capromorelin analogues with extended half-lives. Bioorg Med Chem Lett 12:3279–3282PubMedCrossRefGoogle Scholar
- Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649–661PubMedCrossRefGoogle Scholar
- Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Horvath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschop MH, Horvath TL (2006) Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci 9:381–388PubMedCrossRefGoogle Scholar
- Enomoto M, Nagaya N, Uematsu M, Okumura H, Nakagawa E, Ono F, Hosoda H, Oya H, Kojima M, Kanmatsuse K, Kangawa K (2003) Cardiovascular and hormonal effects of subcutaneous administration of ghrelin, a novel growth hormone-releasing peptide, in healthy humans. Clin Sci 105:431–435PubMedCrossRefGoogle Scholar
- Heightman TD, Scott JS, Longley M, Bordas V, Dean DK, Elliott R, Hutley G, Witherington J, Abberley L, Passingham B, Berlanga M, de Los Frailes M, Wise A, Powney B, Muir A, McKay F, Butler S, Winborn K, Gardner C, Darton J, Campbell C, Sanger G (2007) Potent achiral agonists of the ghrelin (growth hormone secretagogue) receptor. Part I: Lead identification. Bioorg Med Chem Lett 17:6584–6587PubMedCrossRefGoogle Scholar
- Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273:974–977PubMedCrossRefGoogle Scholar
- Pan LC, Carpino PA, Lefker BA, Ragan JA, Toler SM, Pettersen JC, Nettleton DO, Ng O, Pirie CM, Chidsey-Frink K, Lu B, Nickerson DF, Tess DA, Mullins MA, MacLean DB, DaSilva-Jardine PA, Thompson DD (2001) Preclinical pharmacology of CP-424, 391, an orally active pyrazolinone-piperidine growth hormone secretagogue. Endocr 14:121–132CrossRefGoogle Scholar
- Patchett AA, Nargund RP, Tata JR, Chen MH, Barakat KJ, Johnston DB, Cheng K, Chan WW, Butler B, Hickey G, Jacks T, Schleim K, Pong SS, Chuang LYP, Chen HY, Frazier E, Leung KH, Chiu SHL, Smith RG (1995) Design and biological activities of L-163, 191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci U S A 92:7001–7005PubMedCrossRefGoogle Scholar
- Santos M, Bastos P, Gonzaga S, Roriz JM, Baptista MJ, Nogueira-Silva C, Melo-Rocha G, Henriques-Coelho T, Roncon-Albuquerque R Jr, Leite-Moreira AF, De Krijger RR, Tibboel D, Rottier R, Correia-Pinto J (2006) Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia. Pediatr Res 59:531–537PubMedCrossRefGoogle Scholar
- Weikel JC, Wichniak A, Ising M, Brunner H, Friess E, Held K, Mathias S, Schmid DA, Uhr M, Steiger A (2003) Ghrelin promotes slow-wave sleep in humans. Am J Physiol - Endocrinol Metabol 284:E407–E415Google Scholar
- Witherington J, Abberley L, Briggs MA, Collis K, Dean DK, Gaiba A, King NP, Kraus H, Shuker N, Steadman JG, Takle AK, Sanger G, Wadsworth G, Butler S, McKay F, Muir A, Winborn K, Heightman TD (2008) Potent achiral agonists of the growth hormone secretagogue (ghrelin) receptor. Part 2: Lead optimisation. Bioorg Med Chem Lett 18:2203–2205PubMedCrossRefGoogle Scholar