Bicca M A, Costa R, Loch-Neckel G, Figueiredo C P, Medeiros R, Calixto J B
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, Santa Catarina, Brazil.
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, Santa Catarina, Brazil.
Behav Brain Res. 2015 Feb 1;278:482-91. doi: 10.1016/j.bbr.2014.10.040. Epub 2014 Nov 3.
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.
β淀粉样蛋白（Aβ）诱导的神经元毒性和记忆丧失被认为依赖于神经炎症，这是阿尔茨海默病（AD）中的一个重要事件。此前，我们证明阻断缓激肽B2受体（B2R）可保护小鼠免受淀粉样β（Aβ）肽诱导的记忆缺陷。在本研究中，我们旨在探讨B2R在Aβ诱导的小鼠神经炎症中的作用以及B2R阻断对突触改变的有益影响。
在脑室内（i.c.v.）注射Aβ（1-40）（400 pmol/部位）肽前2小时，通过脑室内途径给雄性瑞士小鼠注射选择性缓激肽B2R拮抗剂HOE 140（50 pmol/部位）。在注射Aβ（1-40）后的特定时间点（6小时、1天或8天）处死动物，并收集大脑以进行免疫组织化学分析。在给予Aβ（1-40）后第14天，对不同组的动物进行行为认知测试。
在本研究中，我们报告用选择性缓激肽B2R拮抗剂HOE 140预处理可显著抑制Aβ诱导的小鼠神经炎症。B2R拮抗作用减少了小胶质细胞活化以及促炎蛋白的水平，包括COX-2、诱导型一氧化氮合酶（iNOS）和神经元型一氧化氮合酶（nNOS）。值得注意的是，这些现象伴随着丝裂原活化蛋白激酶（JNK和p38）和转录因子（c-Jun和p65/NF-κB）活化的抑制。最后，B2R拮抗作用的抗炎作用为小鼠提供了显著的保护，使其免受Aβ（1-40）诱导的突触丧失和认知障碍。
总体而言，这些结果表明B2R激活可能在Aβ诱导的神经炎症中起关键作用，而神经炎症是AD进展的最重要因素之一，其阻断可提供突触保护。
