B2 receptor blockage prevents Aβ-induced cognitive impairment by neuroinflammation inhibition

Background and purpose: A beta-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 B-2 receptor (B2R) protects against the memory deficits induced by amyloid beta (A beta) peptide in mice. In this study, we aimed to investigate the role of B2R on A beta-induced neuroinflammation in mice and the beneficial effects of B2R blockage in synapses alterations. Experimental approach: 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 A beta(1-40) (400 pmol/site) peptide. Animals were sacrificed, at specific time points after A beta(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 A beta(1-40) administration. Key results: In this study, we report that the pre-treatment with the selective kinin B2R antagonist HOE 140 significantly inhibited A beta-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-kappa B) activation. Finally, the anti-inflammatory effects of B2R antagonism provided significant protection against A beta(1-40)-induced synaptic loss and cognitive impairment in mice. Conclusions and implications: Collectively, these results suggest that B2R activation may play a critical role in A beta-induced neuroinflammation, one of the most important contributors to AD progression, and its blockage can provide synapses protection. (C) 2014 Elsevier B.V. All rights reserved.