Agmatine attenuates depressive-like behavior and hippocampal oxidative stress following amyloid ß (Aß1-40) administration in mice.

Depression is one of the most common psychiatric symptoms in Alzheimer's disease (AD), and several studies have shown that oxidative stress plays a key role in the etiopathology of both AD and depression. Clinical studies indicate reduced efficacy of the current antidepressants for the treatment of depression in AD. In this regard, agmatine emerges as a neuroprotective agent that presents diverse effects, including antidepressant and antioxidant properties. Here we investigated the antioxidant and antidepressant-like effects of agmatine in a mouse model of AD induced by a single intracerebroventricular (i.c.v.) administration of amyloid-ß 1-40 (Aß). Mice were treated with agmatine (10 mg/kg, intraperitoneally) once a day during seven consecutive days. The first administration of agmatine was 24 h before the i.c.v. injection of aggregated Aß 1-40 (400 pmol/mouse). Ten days after Aß injection, mice were evaluated in the forced swimming test (FST) and open field test for assessment of depressive-like behavior and locomotor activity, respectively. Oxidative parameters were evaluated in the hippocampus of mice 24 h after Aß injection. Agmatine prevented Aß-induced increase in hippocampal lipid peroxidation levels and Aß-induced decrease in catalase activity. In addition, agmatine prevented the increase in immobility time in the FST and the decrease in the latency to the first immobility episode induced by Aß, without changing locomotion in the open field test. These results demonstrate the antioxidant and antidepressant-like effects of agmatine in a mouse model of AD, indicating the potential of agmatine for the treatment of depression associated to AD.

Blockade of hippocampal bradykinin B1 receptors improves spatial learning and memory deficits in middle-aged rats.

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.