Role of the glucose-dependent insulinotropic polypeptide and its receptor in the central nervous system: therapeutic potential in neurological diseases Cla ´udia P. Figueiredo a,c , Fabrı ´cio A. Pamplona b,c , Ta ˆ nia L. Mazzuco f , Aderbal S. Aguiar Jr b , Roger Walz c,d,e and Rui Daniel Schro ¨ der Prediger b,c Glucose-dependent insulinotropic polypeptide (GIP) is a 42-amino acid hormone, secreted from the enteroendocrine K cells, which has insulin-releasing and extra-pancreatic actions. GIP and its receptor present a widespread distribution in the mammalian brain where they have been implicated with synaptic plasticity, neurogenesis, neuroprotection and behavioral alterations. This review attempts to provide a comprehensive picture of the role of GIP in the central nervous system and to highlight recent findings from our group showing its potential involvement in neurological illnesses including epilepsies, Parkinson’s disease and Alzheimer’s disease. Behavioural Pharmacology 21:394–408  c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Behavioural Pharmacology 2010, 21:394–408 Keywords: Alzheimer’s disease, animal models, central nervous system, GIP receptor, glucose-dependent insulinotropic polypeptide, mesial temporal lobe epilepsy related to hippocampal sclerosis, neurological diseases, neuroplasticity, Parkinson’s disease a Programa de Po ´ s-Graduac ¸a ˜ o em Neurocie ˆ ncias, Departamento de Cie ˆ ncias Fisiolo ´ gicas, b Departamento de Farmacologia, Centro de Cie ˆ ncias Biolo ´ gicas, c Centro de Neurocie ˆ ncias Aplicadas, Hospital Universita ´ rio, d Departamento de Clı ´nica Me ´ dica, Hospital Universita ´ rio, Universidade Federal de Santa Catarina, UFSC, e Centro de Epilepsia de Santa Catarina, Hospital Governador Celso Ramos, Floriano ´ polis, Santa Catarina and f Servic ¸ o de Endocrinologia, Departamento de Clı ´nica Me ´ dica, Hospital Universita ´ rio, Universidade Estadual de Londrina, UEL, Londrina, Parana ´ , Brazil Correspondence to Dr Rui Daniel Schro ¨ der Prediger, PhD, Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Trindade, 88049-900, Floriano ´ polis, Santa Catarina, Brazil E-mail: ruidsp@hotmail.com Received 2 April 2010 Accepted as revised 24 May 2010 Introduction The glucose-dependent insulinotropic polypeptide or gastric inhibitory peptide (GIP) is a peripheral hormone, secreted from the enteroendocrine K cells, which posi- tively modulates the release of insulin contributing to the regulation of circulating glucose levels (Brown et al., 1975; Ross et al., 1977). Apart from that, GIP and its receptor (GIPR) present a ubiquitous distribution in the mamma- lian brain (Nyberg et al., 2007), where they have been implicated with synaptic plasticity, neurogenesis, neuro- protection and behavioral alterations. This review attempts to provide a comprehensive view of the role of GIP in the central nervous system (CNS) and to highlight recent findings from our group showing its potential involvement in neurological illnesses including epilepsies, Parkinson’s disease (PD) and Alzheimer’s disease (AD). The incretin concept and the discovery of glucose-dependent insulinotropic polypeptide The gastrointestinal tract contains a multitude of regu- latory peptides transmitting information within the gut and its associated organs, as well as to other sites, in- cluding the CNS. Historically, the investigation of endo- genous molecules produced by the gut modulating the secretion of the pancreatic juice began in the early 1900s, when the field of endocrinology was originated by the hypothesis that blood glucose could be controlled by some ‘internal secretion’ (Girard, 2008). Physiological studies of the effect of crude intestinal extracts on the stimulation of digestive enzyme secretion allowed an understanding of the pancreatic exocrine function. Never- theless, that ‘secretin’ extract contained another humoral substance that reduced blood glucose levels. Then, the term ‘incretin’ (internal secretion) was created to desig- nate endogenous substances that stimulate the endocrine pancreatic secretion (LaBarre and Still, 1930). However, it was not until the development of the radioimmunoas- say in the 1960’s that the insulinotropic effects of duodenal extracts were studied (Yalow and Berson, 1960). The GIP, discovered during the search for chemical regulators of gastric acid secretion, was subsequently shown to stimulate insulin secretion and therefore renamed ‘glucose-dependent insulinotropic polypeptide’, being the first incretin hormone identified (Brown et al., 1975; Ross et al., 1977). However, studies had suggested that GIP, although important, was not the only incretin, as the blockade of the putative GIP binding sites by antibodies only partially reduced the incretin effects (Creutzfeldt, 1979). Isolation of a second incretin emerged from the characterization of the proglucagon gene in the era of recombinant DNA technology, when two molecular forms of the peptide were identified and are now both referred to as glucagon-like peptide (GLP-1) (Bell et al., 1983). Glucose-dependent insulinotropic polypeptide expression and tissue distribution GIP is a member of the vasoactive intestinal peptide/ secretin/glucagon family of neuroregulatory polypep- tides, which also comprises the pituitary adenylate 394 Review article 0955-8810  c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/FBP.0b013e32833c8544 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.