title: Blockade of hippocampal bradykinin B1 receptors improves spatial learning and memory deficits in middle-aged rats.
abstract: Previous studies have demonstrated that targeting bradykinin receptors is a promising strategy to counteract the cognitive impairment related with aging and Alzheimer's disease (AD). The hippocampus is critical for cognition, and abnormalities in this brain region are linked to the decline in mental ability. Nevertheless, the impact of bradykinin signaling on hippocampal function is unknown. Therefore, we sought to determine the role of hippocampal bradykinin receptors B1R and B2R on the cognitive decline of middle-aged rats. Twelve-month-old rats exhibited impaired ability to acquire and retrieve spatial information in the Morris water maze task. A single intra-hippocampal injection of the selective B1R antagonist des-Arg9-[Leu8]-bradykinin (DALBK, 3 nmol), but not the selective B2R antagonist D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]-BK (Hoe 140, 3 nmol), reversed the spatial learning and memory deficits on these animals. However, both drugs did not affect the cognitive function in 3-month-old rats, suggesting absence of nootropic properties. Molecular biology analysis revealed an up-regulation of B1R expression in the hippocampal CA1 sub-region and in the pre-frontal cortex of 12-month-old rats, whereas no changes in the B2R expression were observed in middle-aged rats. These findings provide new evidence that inappropriate hippocampal B1R expression and activation exert a critical role on the spatial learning and memory deficits in middle-aged rats. Therefore, selective B1R antagonists, especially orally active non-peptide antagonists, may represent drugs of potential interest to counteract the age-related cognitive decline.
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.
authors: Rafael M
authors: RM
authors: Bitencourt
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.
authors: Ana C
authors: AC
authors: Guerra de Souza
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.
authors: Maíra A
authors: MA
authors: Bicca
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil; Instituto D'Or de Pesquisa e Ensino, Rio de Janeiro, Brazil.
authors: Fabrício A
authors: FA
authors: Pamplona
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.
authors: Nelson
authors: N
authors: de Mello
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil; Departamento de Biotecnologia Farmacêutica, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors: Giselle F
authors: GF
authors: Passos
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.
authors: Rodrigo
authors: R
authors: Medeiros
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.
authors: Reinaldo N
authors: RN
authors: Takahashi
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil.
authors: João B
authors: JB
authors: Calixto
authors: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, UFSC, Florianópolis, SC, Brazil. Electronic address: ruidsp@hotmail.com.
authors: Rui D
authors: RD
authors: Prediger
mesh_terms: D000375:Aging / Q000187:drug effects; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists / Q000494:pharmacology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000188:drug therapy / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000378:metabolism*; D065853:Spatial Learning / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D065169:Bradykinin B1 Receptor Antagonists; D043783:Receptor, Bradykinin B1; C051090:bradykinin, Leu(8)-des-Arg(9)-; D001920:Bradykinin
keywords: Alzheimer’s disease; B(1) receptor; Bradykinin; Cortex; Hippocampus; Learning and memory; Middle age; Rat