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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 B 1 R and B 2 R 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 B 1 R antagonist des-Arg 9 -[Leu 8 ]-bradykinin (DALBK, 3 nmol), but not the selective B 2 R antagonist D-Arg-[Hyp 3 ,Thi 5 ,D-Tic 7 ,Oic 8 ]-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 B 2 R expression were observed in middle-aged rats. These findings provide new evidence that inappropriate hippocampal B 1 R expression and activation exert a critical role on the spatial learning and memory deficits in middle-aged rats. Therefore, selective B 1 R antagonists, especially orally active non-peptide antagonists, may represent drugs of potential interest to counteract the age-related cognitive decline., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Previous studies have shown that cognitive deficits precede the classical motor symptoms seen in Parkinson's disease (PD) and that physical exercise may exert beneficial effects on PD. We have recently verified that the monoamine-depleting drug reserpine - at doses that do not modify motor function - impairs memory processes in rats. Here, we evaluated the potential of physical exercise to improve cognitive and motor deficits induced by reserpine. Adult Wistar rats were assigned to six groups: (1) untrained-vehicle; (2) untrained-reserpine; (3) running wheel (RW)-vehicle; (4) RW-reserpine; (5) treadmill-vehicle; and (6) treadmill-reserpine. Exercise groups were given free nocturnal access to RW or continuous treadmill exercise (20-25 min/day) for 5 days/week over 4 weeks. The animals were injected subcutaneously with reserpine (1.0 or 5.0mg/kg) or vehicle 48 h after the end of physical program, and 24h later they were tested in a battery of behavioral paradigms. RW and treadmill improved the motor deficits induced by a high reserpine dose (5.0mg/kg), as evaluated in the rotarod and open-field tests. Moreover, untrained rats treated with a low reserpine dose (1.0mg/kg) presented short-term social memory deficits (without motor or olfactory disturbance) that were selectively improved by the exercise training. Our results reinforce the potential of low to moderate physical exercise as a useful tool in the prevention of motor and cognitive impairments associated to CNS monoaminergic depletion.

Muscarinic receptor agonists have been suggested as potential drugs to counteract age-related cognitive decline since critical changes in cholinergic system occur with aging. Recently, we demonstrated that single administration of the non-selective muscarinic receptor agonist pilocarpine prevents age-related spatial learning impairments in rats. In addition, increasing evidence suggests that areas in the central nervous system processing olfactory information are affected at the early stages of age-related diseases, such as Alzheimer's disease, and that specific olfactory testing may represent an important tool in the diagnosis of these diseases. In the present study, olfactory discrimination and short-term social memory of 3 and 24 month-old rats were assessed with the olfactory discrimination and social recognition memory tasks, respectively. The actions of the repeated treatment with pilocarpine (30 mg/kg, i.p.; once per day for 21 days) in relation to age-related effects on olfactory and cognitive functions were also studied. The 24 month-old rats exhibited significantly impaired performance in both models, demonstrating deficits in their odour discrimination and in their ability to recognize a juvenile rat after a short period of time. The treatment with pilocarpine improved in a specific manner these age-related deficits in 24 month-old rats without altering their motor performance. The present results extend the notion of the participation of muscarinic receptors in control of olfactory functions and reinforce the potential of muscarinic receptor agonists for the treatment of age-related cognitive decline.