title: Genetic deletion or antagonism of kinin B(1) and B(2) receptors improves cognitive deficits in a mouse model of Alzheimer's disease.
abstract: Increased brain deposition of amyloid beta protein (Abeta) 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) (Abeta(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 Abeta(1-40) cognitive effects on the water maze paradigm. Spatial learning and memory deficits observed at 7 days following Abeta(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-Tic(7),Oic(8)]-BK (Hoe 140). A similar effect was found in mice lacking kinin B(2) 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 Abeta(1-40). Moreover, treatment with Abeta(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 Abeta 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.
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Florianópolis SC 88049-900, Brazil. ruidsp@hotmail.com
authors.forename: R D S
authors.initials: RD
authors.lastname: Prediger
authors.forename: R
authors.initials: R
authors.lastname: Medeiros
authors.forename: P
authors.initials: P
authors.lastname: Pandolfo
authors.forename: F S
authors.initials: FS
authors.lastname: Duarte
authors.forename: G F
authors.initials: GF
authors.lastname: Passos
authors.forename: J B
authors.initials: JB
authors.lastname: Pesquero
authors.forename: M M
authors.initials: MM
authors.lastname: Campos
authors.forename: J B
authors.initials: JB
authors.lastname: Calixto
authors.forename: R N
authors.initials: RN
authors.lastname: Takahashi
mesh_terms: D000544:Alzheimer Disease / Q000150:complications; D016229:Amyloid beta-Peptides; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D002540:Cerebral Cortex / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D043783:Receptor, Bradykinin B1 / Q000172:deficiency* / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D010446:Peptide Fragments; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; C075222:amyloid beta-protein (1-42); C051090:bradykinin, Leu(8)-des-Arg(9)-; C065679:icatibant; D001920:Bradykinin