Targeting the gastrin-releasing peptide receptor pathway to treat cognitive dysfunction associated with Alzheimer's Disease

Roesler, Rafael; Luft, Tatiana; Schwartsmann, Gilberto

doi:10.1590/S1980-57642008DN10200002

Abstract

Increasing evidence indicates that bombesin (BB)-like peptides (BLPs), such as the gastrin-releasing peptide (GRP) and its receptor (GRPR), might play a role in neurological and psychiatric disorders. The present study reviews findings from animal and human studies suggesting that the GRPR should be considered a target for the treatment of cognitive dysfunction in patients with Alzheimer's disease (AD). Abnormalities in GRPR-triggered signaling have been described in both fibroblasts from patients with AD, and in transgenic mouse models of AD. Pharmacological and genetic preclinical studies have indicated that BLPs and the GRPR are importantly involved in regulating cognitive function. Moreover, drugs acting at the GRPR have been shown to enhance memory and ameliorate cognitive dysfunction in experimental models of amnesia associated with AD. Taken together, these findings support the view that the GRPR is a novel therapeutic target for the treatment of memory deficits associated with AD.

Key words:
bombesin-like peptides; gastrin-releasing peptide; gastrin-releasing peptide receptor; cognitive enhancers; memory disorders; Alzheimer disease.

Resumo

Estudos recentes indicam que os peptídeos da família da bombesina (BB), como o peptídeo liberador de gastrina (GRP) e seu receptor (GRPR), podem estar envolvidos em doenças neurológicas e psiquiátricas. Este artigo apresenta uma revisão de estudos tanto em humanos como em modelos animais que sugerem que o GRPR deve ser considerado um alvo molecular para o desenvolvimento de novas terapias para o tratamento de déficits cognitivos em pacientes com doença de Alzheimer (DA). Anormalidades na sinalização celular dependente do GRPR têm sido descritas tanto em fibroblastos de pacientes com DA como em modelos de DA em camundongos transgênicos. Além disso, estudos pré-clínicos utilizando estratégias farmacológicas e genéticas indicam que os peptídeos da família da BB e o GRPR estão envolvidos de forma importante na regulação da função cognitiva. Finalmente, resultados recentes mostram que drogas que agem como ligantes do GRPR podem melhorar a memória e prevenir disfunções cognitivas em modelos experimentais de amnésia asssociada à DA. Em conjunto, os dados indicam que o GRPR é um novo alvo terapêutico para o tratamento de déficits de memória associadas à DA.

Palavras-chave:
bombesina; peptídeo liberador de gastrina; receptor do peptídeo liberador de gastrina; facilitadores cognitivos; disfunções de memória; doença de Alzheimer.

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References

¹
Moody TW, Merali Z. Bombesin-like peptides and associated receptors within the brain: distribution and behavioral implications. Peptides 2004;25:511-520.
²
Ohki-Hamazaki H, Iwabuchi M, Maekawa F. Development and function of bombesin-like peptides and their receptors. Int J Dev Biol 2005;49:293-300.
³
Patel O, Shulkes A, Baldwin GS. Gastrin-releasing peptide and cancer. Biochim Biophys Acta 2006;1766:23-41.
⁴
Roesler R, Henriques JAP, Schwartsmann G. Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. CNS Neurol Disord Drug Targets 2006;5:197-204.
⁵
Moody TW, Pert CB, Rivier J, Brown MR. Bombesin: specific binding to rat brain membranes. Proc Natl Acad Sci USA 1978;75:5372-5376.
⁶
Battey J, Wada E, Corjay M, et al. Molecular genetic analysis of two distinct receptors for mammalian bombesin-like peptides. J Natl Cancer Inst Monogr 1992;13:141-144.
⁷
Battey JF, Way JM, Corjay MH, et al. Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cells. Proc Natl Acad Sci USA 1991;88:395-399.
⁸
Spindel ER, Giladi E, Brehm P, Goodman RH, Segerson TP. Cloning and functional characterization of a complementary DNA encoding the murine fibroblast bombesin/gastrin-releasing peptide receptor. Mol Endocrinol 1990; 4:1956-1963.
⁹
Wolf SS, Moody TW. Receptors for GRP/bombesin-like peptides in the rat forebrain. Peptides 1985;6:111-114.
¹⁰
Wolf SS, Moody TW, O'Donohue TL, Zarbin MA, Kuhar MJ. Autoradiographic visualization of rat brain binding sites for bombesin-like peptides. Eur J Pharmacol 1983;87:163-164.
¹¹
Kamichi S, Wada E, Aoki S, Sekiguchi M, Kimura I, Wada K. Immunohistochemical localization of gastrin-releasing peptide receptor in the mouse brain. Brain Res 2005;1032:162-170.
¹²
Hellmich MR, Ives KL, Udupi V, et al. Multiple protein kinase pathways are involved in gastrin-releasing peptide receptor-regulated secretion. J Biol Chem 1999;274:23901-23909.
¹³
Kim HJ, Evers BM, Litvak DA, Hellmich MR, Townsend CM Jr. Signaling mechanisms regulating bombesin-mediated AP-1 gene induction in the human gastric cancer SIIA. Am J Physiol Cell Physiol 2000;279:C326-334.
¹⁴
Xiao D, Qu X, Weber HC. Activation of extracellular signal-regulated kinase mediates bombesin-induced mitogenic responses in prostate cancer cells. Cell Signal 2003;15:945-953.
¹⁵
Lee K, Dixon AK, Gonzalez I, et al. Bombesin-like peptides depolarize rat hippocampal interneurones through interaction with subtype 2 bombesin receptors. J Physiol 1999;518:791-802.
¹⁶
Roesler R, Luft T, Oliveira SH, et al. Molecular mechanisms mediating gastrin-releasing peptide receptor modulation of memory consolidation in the hippocampus. Neuropharmacology 2006;51:350-357.
¹⁷
Roesler R, Henriques JA, Schwartsmann G. Neuropeptides and anxiety disorders: bombesin receptors as novel therapeutic targets. Trends Pharmacol Sci 2004;25:241-242.
¹⁸
Leissring MA, Akbari Y, Fanger CM, Cahalan MD, Mattson MP, LaFerla FM. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 2000;149:793-798.
¹⁹
Guo Q, Fu W, Sopher BL, et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 1999;5:101-106.
²⁰
Gibson GE, Huang HM. Oxidative stress in Alzheimer's disease. Neurobiol Aging 2005;26:575-578.
²¹
Gibson GE, Vestling M, Zhang H, et al. Abnormalities in Alzheimer's disease fibroblasts bearing the APP670/671 mutation. Neurobiol Aging 1997;18:573-580.
²²
Gibson GE, Zhang H, Toral-Barza L, Szolosi S, Tofel-Grehl B. Calcium stores in cultured fibroblasts and their changes with Alzheimer's disease. Biochim Biophys Acta 1996;1316:71-77.
²³
Huang HM, Chen HL, Xu H, Gibson GE. Modification of endoplasmic reticulum Ca2+ stores by select oxidants produces changes reminiscent of those in cells from patients with Alzheimer disease. Free Radic Biol Med 2005;39:979-989.
²⁴
Ito E, Oka K, Etcheberrigaray R, et al. Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease. Proc Natl Acad Sci USA 1994;91:534-538.
²⁵
Huang HM, Zhang H, Ou HC, Chen HL, Gibson GE. alpha-keto-beta-methyl-n-valeric acid diminishes reactive oxygen species and alters endoplasmic reticulum Ca(2+) stores. Free Radic Biol Med 2004;37:1779-1789.
²⁶
Flood JF, Morley JE. Effects of bombesin and gastrin-releasing peptide on memory processing. Brain Res 1988;460:314-322.
²⁷
Rashidy-Pour A, Razvani ME. Unilateral reversible inactivations of the nucleus tractus solitarius and amygdala attenuate the effects of bombesin on memory storage. Brain Res 1998;814:127-132.
²⁸
Martins MR, Reinke A, Valvassori SS, et al. Non-associative learning and anxiety in rats treated with a single systemic administration of the gastrin-releasing peptide receptor antagonist RC-3095. Peptides 2005;26:2525-2529.
²⁹
Presti-Torres J, de Lima MN, Scalco FS, et al. Impairments of social behavior and memory after neonatal gastrin-releasing peptide receptor blockade in rats: Implications for an animal model of neurodevelopmental disorders. Neuropharmacology 2007;52:724-732.
³⁰
Roesler R, Kopschina MI, Rosa RM, Henriques JA, Souza DO, Schwartsmann G. RC-3095, a bombesin/gastrin-releasing peptide receptor antagonist, impairs aversive but not recognition memory in rats. Eur J Pharmacol 2004;486:35-41.
³¹
Roesler R, Lessa D, Venturella R, et al. Bombesin/gastrin-releasing peptide receptors in the basolateral amygdala regulate memory consolidation. Eur J Neurosci 2004;19:1041-1045.
³²
Santo-Yamada Y, Yamada K, Wada E, Goto Y, Wada K. Blockade of bombesin-like peptide receptors impairs inhibitory avoidance learning in mice. Neurosci Lett 2003;340:65-68.
³³
Dantas AS, Luft T, Henriques JA, Schwartsmann G, Roesler R. Opposite effects of low and high doses of the gastrin-releasing peptide receptor antagonist RC-3095 on memory consolidation in the hippocampus: possible involvement of the GABAergic system. Peptides 2006;27:2307-2312.
³⁴
Luft T, Flores DG, Vianna MR, Schwartsmann G, Roesler R, Izquierdo I. A role for hippocampal gastrin-releasing peptide receptors in extinction of aversive memory. Neuroreport 2006;17:935-939.
³⁵
Mountney C, Sillberg V, Kent P, Anisman H, Merali Z. The role of gastrin-releasing peptide on conditioned fear: differential cortical and amygdaloid responses in the rat. Psychopharmacology 2006;189:287-296.
³⁶
Roesler R, Meller CA, Kopschina MI, Souza DO, Henriques JA, Schwartsmann G. Intrahippocampal infusion of the bombesin/gastrin-releasing peptide antagonist RC-3095 impairs inhibitory avoidance retention. Peptides 2003;24:1069-1074.
³⁷
Venturella R, Lessa D, Luft T, Roozendaal B, Schwartsmann G, Roesler R. Dexamethasone reverses the memory impairment induced by antagonism of hippocampal gastrin-releasing peptide receptors. Peptides 2005;26:821-825.
³⁸
Williams CL, McGaugh JL. Enhancement of memory processing in an inhibitory avoidance and radial maze task by post-training infusion of bombesin into the nucleus tractus solitarius. Brain Res 1994;654:251-256.
³⁹
Shumyatsky GP, Tsvetkov E, Malleret G, et al. Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 2002;111:905-918.
⁴⁰
Santo-Yamada Y, Yamada K, Wada K. Posttraining administration of gastrin-releasing peptide improves memory loss in scopolamine- and hypoxia-induced amnesic mice. Physiol Behav 2001;74:139-143.
⁴¹
Dal-Pizzol F, Di Leone LP, Ritter C, et al. Gastrin-releasing peptide receptor antagonist effects on an animal model of sepsis. Am J Respir Crit Care Med 2006;173:84-90.
⁴²
Gutzwiller JP, Drewe J, Hildebrand P, Rossi L, Lauper JZ, Beglinger C. Effect of intravenous human gastrin-releasing peptide on food intake in humans. Gastroenterology 1994;106:1168-1173.
⁴³
Schwartsmann G, DiLeone LP, Horowitz M, et al. A phase I trial of the bombesin/gastrin-releasing peptide (BB/GRP) antagonist RC3095 in patients with advanced solid malignancies. Invest New Drugs 2006;24:403-412.

Publication Dates

Publication in this collection
Apr-Jun 2007

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ¹
Moody TW, Merali Z. Bombesin-like peptides and associated receptors within the brain: distribution and behavioral implications. Peptides 2004;25:511-520.

[2] ²
Ohki-Hamazaki H, Iwabuchi M, Maekawa F. Development and function of bombesin-like peptides and their receptors. Int J Dev Biol 2005;49:293-300.

[3] ³
Patel O, Shulkes A, Baldwin GS. Gastrin-releasing peptide and cancer. Biochim Biophys Acta 2006;1766:23-41.

[4] ⁴
Roesler R, Henriques JAP, Schwartsmann G. Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. CNS Neurol Disord Drug Targets 2006;5:197-204.

[5] ⁵
Moody TW, Pert CB, Rivier J, Brown MR. Bombesin: specific binding to rat brain membranes. Proc Natl Acad Sci USA 1978;75:5372-5376.

[6] ⁶
Battey J, Wada E, Corjay M, et al. Molecular genetic analysis of two distinct receptors for mammalian bombesin-like peptides. J Natl Cancer Inst Monogr 1992;13:141-144.

[7] ⁷
Battey JF, Way JM, Corjay MH, et al. Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cells. Proc Natl Acad Sci USA 1991;88:395-399.

[8] ⁸
Spindel ER, Giladi E, Brehm P, Goodman RH, Segerson TP. Cloning and functional characterization of a complementary DNA encoding the murine fibroblast bombesin/gastrin-releasing peptide receptor. Mol Endocrinol 1990; 4:1956-1963.

[9] ⁹
Wolf SS, Moody TW. Receptors for GRP/bombesin-like peptides in the rat forebrain. Peptides 1985;6:111-114.

[10] ¹⁰
Wolf SS, Moody TW, O'Donohue TL, Zarbin MA, Kuhar MJ. Autoradiographic visualization of rat brain binding sites for bombesin-like peptides. Eur J Pharmacol 1983;87:163-164.

[11] ¹¹
Kamichi S, Wada E, Aoki S, Sekiguchi M, Kimura I, Wada K. Immunohistochemical localization of gastrin-releasing peptide receptor in the mouse brain. Brain Res 2005;1032:162-170.

[12] ¹²
Hellmich MR, Ives KL, Udupi V, et al. Multiple protein kinase pathways are involved in gastrin-releasing peptide receptor-regulated secretion. J Biol Chem 1999;274:23901-23909.

[13] ¹³
Kim HJ, Evers BM, Litvak DA, Hellmich MR, Townsend CM Jr. Signaling mechanisms regulating bombesin-mediated AP-1 gene induction in the human gastric cancer SIIA. Am J Physiol Cell Physiol 2000;279:C326-334.

[14] ¹⁴
Xiao D, Qu X, Weber HC. Activation of extracellular signal-regulated kinase mediates bombesin-induced mitogenic responses in prostate cancer cells. Cell Signal 2003;15:945-953.

[15] ¹⁵
Lee K, Dixon AK, Gonzalez I, et al. Bombesin-like peptides depolarize rat hippocampal interneurones through interaction with subtype 2 bombesin receptors. J Physiol 1999;518:791-802.

[16] ¹⁶
Roesler R, Luft T, Oliveira SH, et al. Molecular mechanisms mediating gastrin-releasing peptide receptor modulation of memory consolidation in the hippocampus. Neuropharmacology 2006;51:350-357.

[17] ¹⁷
Roesler R, Henriques JA, Schwartsmann G. Neuropeptides and anxiety disorders: bombesin receptors as novel therapeutic targets. Trends Pharmacol Sci 2004;25:241-242.

[18] ¹⁸
Leissring MA, Akbari Y, Fanger CM, Cahalan MD, Mattson MP, LaFerla FM. Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice. J Cell Biol 2000;149:793-798.

[19] ¹⁹
Guo Q, Fu W, Sopher BL, et al. Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice. Nat Med 1999;5:101-106.

[20] ²⁰
Gibson GE, Huang HM. Oxidative stress in Alzheimer's disease. Neurobiol Aging 2005;26:575-578.

[21] ²¹
Gibson GE, Vestling M, Zhang H, et al. Abnormalities in Alzheimer's disease fibroblasts bearing the APP670/671 mutation. Neurobiol Aging 1997;18:573-580.

[22] ²²
Gibson GE, Zhang H, Toral-Barza L, Szolosi S, Tofel-Grehl B. Calcium stores in cultured fibroblasts and their changes with Alzheimer's disease. Biochim Biophys Acta 1996;1316:71-77.

[23] ²³
Huang HM, Chen HL, Xu H, Gibson GE. Modification of endoplasmic reticulum Ca2+ stores by select oxidants produces changes reminiscent of those in cells from patients with Alzheimer disease. Free Radic Biol Med 2005;39:979-989.

[24] ²⁴
Ito E, Oka K, Etcheberrigaray R, et al. Internal Ca2+ mobilization is altered in fibroblasts from patients with Alzheimer disease. Proc Natl Acad Sci USA 1994;91:534-538.

[25] ²⁵
Huang HM, Zhang H, Ou HC, Chen HL, Gibson GE. alpha-keto-beta-methyl-n-valeric acid diminishes reactive oxygen species and alters endoplasmic reticulum Ca(2+) stores. Free Radic Biol Med 2004;37:1779-1789.

[26] ²⁶
Flood JF, Morley JE. Effects of bombesin and gastrin-releasing peptide on memory processing. Brain Res 1988;460:314-322.

[27] ²⁷
Rashidy-Pour A, Razvani ME. Unilateral reversible inactivations of the nucleus tractus solitarius and amygdala attenuate the effects of bombesin on memory storage. Brain Res 1998;814:127-132.

[28] ²⁸
Martins MR, Reinke A, Valvassori SS, et al. Non-associative learning and anxiety in rats treated with a single systemic administration of the gastrin-releasing peptide receptor antagonist RC-3095. Peptides 2005;26:2525-2529.

[29] ²⁹
Presti-Torres J, de Lima MN, Scalco FS, et al. Impairments of social behavior and memory after neonatal gastrin-releasing peptide receptor blockade in rats: Implications for an animal model of neurodevelopmental disorders. Neuropharmacology 2007;52:724-732.

[30] ³⁰
Roesler R, Kopschina MI, Rosa RM, Henriques JA, Souza DO, Schwartsmann G. RC-3095, a bombesin/gastrin-releasing peptide receptor antagonist, impairs aversive but not recognition memory in rats. Eur J Pharmacol 2004;486:35-41.

[31] ³¹
Roesler R, Lessa D, Venturella R, et al. Bombesin/gastrin-releasing peptide receptors in the basolateral amygdala regulate memory consolidation. Eur J Neurosci 2004;19:1041-1045.

[32] ³²
Santo-Yamada Y, Yamada K, Wada E, Goto Y, Wada K. Blockade of bombesin-like peptide receptors impairs inhibitory avoidance learning in mice. Neurosci Lett 2003;340:65-68.

[33] ³³
Dantas AS, Luft T, Henriques JA, Schwartsmann G, Roesler R. Opposite effects of low and high doses of the gastrin-releasing peptide receptor antagonist RC-3095 on memory consolidation in the hippocampus: possible involvement of the GABAergic system. Peptides 2006;27:2307-2312.

[34] ³⁴
Luft T, Flores DG, Vianna MR, Schwartsmann G, Roesler R, Izquierdo I. A role for hippocampal gastrin-releasing peptide receptors in extinction of aversive memory. Neuroreport 2006;17:935-939.

[35] ³⁵
Mountney C, Sillberg V, Kent P, Anisman H, Merali Z. The role of gastrin-releasing peptide on conditioned fear: differential cortical and amygdaloid responses in the rat. Psychopharmacology 2006;189:287-296.

[36] ³⁶
Roesler R, Meller CA, Kopschina MI, Souza DO, Henriques JA, Schwartsmann G. Intrahippocampal infusion of the bombesin/gastrin-releasing peptide antagonist RC-3095 impairs inhibitory avoidance retention. Peptides 2003;24:1069-1074.

[37] ³⁷
Venturella R, Lessa D, Luft T, Roozendaal B, Schwartsmann G, Roesler R. Dexamethasone reverses the memory impairment induced by antagonism of hippocampal gastrin-releasing peptide receptors. Peptides 2005;26:821-825.

[38] ³⁸
Williams CL, McGaugh JL. Enhancement of memory processing in an inhibitory avoidance and radial maze task by post-training infusion of bombesin into the nucleus tractus solitarius. Brain Res 1994;654:251-256.

[39] ³⁹
Shumyatsky GP, Tsvetkov E, Malleret G, et al. Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 2002;111:905-918.

[40] ⁴⁰
Santo-Yamada Y, Yamada K, Wada K. Posttraining administration of gastrin-releasing peptide improves memory loss in scopolamine- and hypoxia-induced amnesic mice. Physiol Behav 2001;74:139-143.

[41] ⁴¹
Dal-Pizzol F, Di Leone LP, Ritter C, et al. Gastrin-releasing peptide receptor antagonist effects on an animal model of sepsis. Am J Respir Crit Care Med 2006;173:84-90.

[42] ⁴²
Gutzwiller JP, Drewe J, Hildebrand P, Rossi L, Lauper JZ, Beglinger C. Effect of intravenous human gastrin-releasing peptide on food intake in humans. Gastroenterology 1994;106:1168-1173.

[43] ⁴³
Schwartsmann G, DiLeone LP, Horowitz M, et al. A phase I trial of the bombesin/gastrin-releasing peptide (BB/GRP) antagonist RC3095 in patients with advanced solid malignancies. Invest New Drugs 2006;24:403-412.

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