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.

Keywords: Alzheimer’s disease; B(1) receptor; Bradykinin; Cortex; Hippocampus; Learning and memory; Middle age; Rat.