icatibant and Cognition-Disorders

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.. 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.. 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.. 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.

Topics: Amyloid beta-Peptides; Analysis of Variance; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Cerebral Cortex; Cognition Disorders; Cyclooxygenase 2; Disease Models, Animal; Drug Administration Schedule; Hippocampus; Imidazoles; Male; Mice; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Peptide Fragments; Spatial Memory; Spiro Compounds; Time Factors; Up-Regulation

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Analysis of Variance; Animals; Behavior, Animal; Bradykinin; Bradykinin B1 Receptor Antagonists; Bradykinin B2 Receptor Antagonists; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Dose-Response Relationship, Drug; Exploratory Behavior; Hippocampus; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Reaction Time; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Time Factors