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|Title:||Genetic deletion or antagonism of kinin B-1 and B-2 receptors improves cognitive deficits in mouse a model of Alzheimer's disease|
|Authors:||Prediger, R. D. S.|
Duarte, F. S.
Passos, G. F.
Pesquero, J. B. [UNIFESP]
Campos, M. M.
Calixto, J. B.
Takahashi, R. N.
Universidade Federal de Santa Catarina (UFSC)
Universidade Federal de São Paulo (UNIFESP)
Pontificia Univ Catolica Rio Grande Do Sul
B-1 and B-2 receptor
spatial learning and memory
|Citation:||Neuroscience. Oxford: Pergamon-Elsevier B.V., v. 151, n. 3, p. 631-643, 2008.|
|Abstract:||Increased brain deposition of amyloid beta protein (A beta) and cognitive deficits are classical signs of Alzheimer's disease (AD) that have been widely associated to inflammatory response. We have recently shown that a single i.c.v. injection of aggregated beta-amyloid peptide-(1-40) (A beta(1-40)) (400 pmol/mouse) results in marked deficits of learning and memory in mice which are related to oxidative stress and synaptic dysfunction. in the present study, we investigated by means of genetic or pharmacological approaches the role of kinin system in the A beta(1-40) cognitive effects on the water maze paradigm. Spatial learning and memory deficits observed at 7 days following A beta(1-40) treatment were significantly reduced by the i.c.v. administration of the selective kinin B-2 receptor antagonist D-Arg-[Hyp(3),Thi(5),D-TiC7,OiC(8)]-BK (Hoe 140). A similar effect was found in mice lacking kinin B2 receptor. On the other hand, genetic deletion of the inducible kinin B-1 receptor or its blockage by i.c.v. injection of des-Arg(9)-[Leu(8)]-BK antagonist attenuated only the long-term (30 days after treatment) cognitive deficits induced by A beta(1-40). Moreover, treatment with A beta(1-40) resulted in a sustained increase in the expression of the kinin B-1 receptor in the hippocampus and prefrontal cortex of mice, while it did not alter the expression of the kinin B-2 receptor in these brain areas. These findings provide convincing evidence that kinins acting via activation of B-1 and B-2 receptors in the CNS exert a critical role in the spatial learning and memory deficits induced by A beta peptide in mice. Therefore, selective kinin receptor antagonists, especially the new orally active non-peptide antagonists, might represent drugs of potential interest for the treatment of AD. (c) 2007 IBRO. Published by Elsevier B.V. All rights reserved.|
|Appears in Collections:||Em verificação - Geral|
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