title: B₂ receptor blockage prevents Aβ-induced cognitive impairment by neuroinflammation inhibition.
abstract: OBJECTIVE
  Aβ-induced neuronal toxicity and memory loss is thought to be dependent on neuroinflammation, an important event in Alzheimer's disease (AD). Previously, we demonstrated that the blockage of the kinin B2 receptor (B2R) protects against the memory deficits induced by amyloid β (Aβ) peptide in mice. In this study, we aimed to investigate the role of B2R on Aβ-induced neuroinflammation in mice and the beneficial effects of B2R blockage in synapses alterations.
  
  
  METHODS
  The selective kinin B2R antagonist HOE 140 (50 pmol/site) was given by intracerebroventricular (i.c.v.) route to male Swiss mice 2 h prior the i.c.v. injection of Aβ(1-40) (400 pmol/site) peptide. Animals were sacrificed, at specific time points after Aβ(1-40) injection (6 h, 1 day or 8 days), and the brain was collected in order to perform immunohistochemical analysis. Different groups of animals were submitted to behavioral cognition tests on day 14 after Aβ(1-40) administration.
  
  
  RESULTS
  In this study, we report that the pre-treatment with the selective kinin B2R antagonist HOE 140 significantly inhibited Aβ-induced neuroinflammation in mice. B2R antagonism reduced microglial activation and the levels of pro-inflammatory proteins, including COX-2, iNOS and nNOS. Notably, these phenomena were accompanied by an inhibition of MAPKs (JNK and p38) and transcription factors (c-Jun and p65/NF-κB) activation. Finally, the anti-inflammatory effects of B2R antagonism provided significant protection against Aβ(1-40)-induced synaptic loss and cognitive impairment in mice.
  
  
  CONCLUSIONS
  Collectively, these results suggest that B2R activation may play a critical role in Aβ-induced neuroinflammation, one of the most important contributors to AD progression, and its blockage can provide synapses protection.
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, Santa Catarina, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: Bicca
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, Santa Catarina, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Costa
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, Santa Catarina, Brazil.
authors.forename: G
authors.initials: G
authors.lastname: Loch-Neckel
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, Santa Catarina, Brazil.
authors.forename: C P
authors.initials: CP
authors.lastname: Figueiredo
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, Santa Catarina, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, Santa Catarina, Brazil. Electronic address: calixto@farmaco.ufsc.br.
authors.forename: J B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D065094:Bradykinin B2 Receptor Antagonists / Q000378:metabolism / Q000627:therapeutic use*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced* / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000627:therapeutic use; D008297:Male; D051379:Mice; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D065852:Spatial Memory / Q000187:drug effects; D013141:Spiro Compounds / Q000627:therapeutic use; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D065094:Bradykinin B2 Receptor Antagonists; D007093:Imidazoles; C100920:NPC 18688; D010446:Peptide Fragments; D013141:Spiro Compounds; C078592:amyloid beta-protein (1-40); C065679:icatibant; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D001920:Bradykinin
keywords: Alzheimer's disease; Amyloid-beta; B2 receptor; Kinins; Neuroinflammation