Montelukast rescues primary neurons against Aβ1-42-induced toxicity through inhibiting CysLT1R-mediated NF-κB signaling

Amyloid-beta peptide (A beta), which can invoke a cascade of inflammatory responses, is considered to play a causal role in the development and progress of Alzheimer's disease (AD). Montelukast, known as a cysteinyl leukotriene receptor 1 (CysLT(1)R) antagonist, is currently used for treatment of inflammatory diseases such as asthma. We have previously reported that CysLT(1)R activation is involved in A beta generation. In this study, we investigated rescuing effect of CysLT(1)R antagonist montelukast on A beta(1-42)-induced neurotoxicity in primary neurons. Our data showed that A beta(1-42) elicited a marked increase of CysLT(1)R expression in primary mouse neurons. This increment of CysLT(1)R expression was accompanied by increases of inflammatory factors such as NF-kappa B p65, tumor necrosis factor-alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) as well as pro-apoptotic protein Caspase-3 activation and anti-apoptosis protein Bcl-2 reduction. A beta(1-42)-mediated increase of CysLT(1)R expression was associated with A beta(1-42)-induced cytotoxicity as measured by MTT reduction assay and lactate dehydrogenase (LDH) release assay. This observation was confirmed with treatment of montelukast, a selective CysLT(1)R antagonist, which had significant effect on A beta(1-42)-induced cytotoxicity. Moreover, blockade of CysLT(1)R with montelukast reversed A beta(1-42)-mediated increase of CysLT(1)R expression, and concomitant changes of the pro-inflammatory factors and the apoptosis-related proteins. The results demonstrate that montelukast rescued neurons against A beta(1-42)-induced neurotoxicity, neuroinflammation and apoptosis by down-regulating CysLT(1)R-mediated NF-kappa B signaling, suggesting that CysLT1R may be a potential target for AD, and its antagonist may have beneficial effects for treatment of AD. (C) 2014 Elsevier Ltd. All rights reserved.