icatibant and Alzheimer-Disease

An Increasing body of evidence supports a critical role of brain inflammation in the pathogenesis of Alzheimer's disease. A principal aspect of the brain immune response to inflammation is the activation of microglia. It has been shown that the kinin system is activated during brain inflammation and previously we demonstrated that bradykinin B1 receptor agonist reduced microglial activation in vitro. The aim of the present study was to investigate the effects of bradykinin B1 or B2 receptor antagonists on microglial release of pro-inflammatory factors in BV2 microglia. In vivo, we focused on the effects of intranasally given kinin antagonists on amyloid burden and microglia/macrophage marker expression in brains of 5X familial Alzheimer's disease mice. The present data show that pharmacological antagonism of B1 receptor (R-715) but not B2 receptor (HOE-140) markedly increased nitric oxide and tumor necrosis factor alpha release from BV2 microglial cells. We also showed that intranasal treatment with R-715 but not HOE-140 of Alzheimer's mice enhanced amyloid beta burden and microglia/macrophages activation. Taken together, our data reveal a possible role for the bradykinin B1 receptor in neuroinflammation and in the control of Abeta accumulation in transgenic mice, possibly through regulation of glial cell responses.

Topics: Administration, Intranasal; Alzheimer Disease; Animals; Bradykinin; Bradykinin Receptor Antagonists; Cells, Cultured; Macrophages; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Structure-Activity Relationship

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

We treated human skin fibroblasts with bradykinin (BK) and observed a concentration-dependent increase in the release of soluble amyloid precursor protein (sAPP). The estimated EC50 for the observed effect is 2.8 nM, which is of the same order of magnitude as the reported Kd of BK binding in human skin fibroblasts. The effect of BK on sAPP secretion appears to be dependent on interaction of the ligand with the B2 type of BK receptors but independent of activation of protein kinase C. We also show that sAPP release after BK treatment in fibroblasts from patients with sporadic Alzheimer's disease is not different from control cells and is paralleled by equivalent levels of inositol trisphosphate production. A discussion of the differences from previously published work focuses on the possible divergent alterations in transduction systems in fibroblasts from patients with familial and sporadic Alzheimer's disease. Our results are the first example of receptor-mediated sAPP release in human skin fibroblasts and the first demonstration of the co-existence of protein kinase C-dependent and -independent mechanisms in these cells.

Topics: Adult; Aged; Alzheimer Disease; Amyloid beta-Protein Precursor; Bradykinin; Bradykinin Receptor Antagonists; Cells, Cultured; Female; Fibroblasts; Humans; Inositol 1,4,5-Trisphosphate; Kinetics; Male; Protein Kinase C; Receptor, Bradykinin B2; Receptors, Bradykinin; Reference Values; Skin