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Review
. 2007 Apr-Jun;1(2):118-123.
doi: 10.1590/s1980-57642008dn10200002.

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

Rafael Roesler  1   2 , Tatiana Luft  1   3 , Gilberto Schwartsmann  2   4
Affiliations
Review

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

Rafael Roesler et al. Dement Neuropsychol. 2007 Apr-Jun.

Abstract
in English, Portuguese

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.

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.

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

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Figures

Figure
Figure
Proposed signaling pathways associated with the gastrinreleasing peptide receptor (GRPR) in the central nervous system. Gastrin-releasing peptide (GRP) released from synaptic terminals binds to the Gq protein-coupled GRPR at postsynaptic sites. GRPR activation induces an increase in [Ca2+] and triggers activation of the phospholipase C (PLC)/protein kinase C (PKC) pathway, which, in turn, can activate mitogen-activated protein kinase (MAPK). The dopamine D1/D5 receptor (D1R) is coupled to Gs protein (Gs) and adenylyl cyclase (AC) activation. The D1R-induced cAMP signal might be synergistically potentiated by [Ca2+]-induced stimulation of [Ca2+]-responsive types of AC, leading to increased activation of protein kinase A (PKA). Reproduced from [16], with permission.
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