Montelukast targeting the cysteinyl leukotriene receptor 1 ameliorates Aβ1-42-induced memory impairment and neuroinflammatory and apoptotic responses in mice

Montelukast, known as a cysteinyl leukotriene receptor 1 (CysLT(1)R) antagonist, is currently used for treatment of inflammatory diseases such as asthma. Here, we investigated effects of montelukast on neuroinflammatory, apoptotic responses, and memory performance following intracerebral infusions of amyloid-beta (A beta). The data demonstrated that intracerebroventrical infusions of aggregated A beta(1-42) (410 pmol/mouse) produced deficits in learning ability and memory, as evidenced by increase in escape latency during acquisition trials and decreases in exploratory activities in the probe trial in Morris water maze (MWM) task, and by decrease in the number of correct choices and increase in latency to enter the shock-free compartment in Y-maze test, and caused significant increases in pro-inflammatory cytokines such as NF-kappa B p65, TNF-alpha and IL-1 beta as well as pro-apoptotic molecule caspase-3 activation and antiapoptotic protein Bcl-2 downregulation in hippocampus and cortex. Interestingly, this treatment resulted in upregulation of protein or mRNA of CysLT(1)R in both hippocampus and cortex. Blockade of CysLT(1)R by repeated treatment with montelukast (1 or 2 mg/kg, ig, 4 weeks) reduced A beta(1-42)-induced CysLT(1)R expression and also suppressed A beta(1-42)-induced increments of NF-kappa B p65, TNF-alpha, IL-1 beta and caspase-3 activation, and Bcl-2 downregulation in the hippocampus and cortex. Correspondingly, montelukast treatment significantly improved A beta(1-42)-induced memory impairment in mice, but had little effect on normal mice. Our results show that montelukast may ameliorate A beta(1-42)-induced memory impairment via inhibiting neuroinflammation and apoptosis mediated by CysLT(1)R signaling, suggesting that CysLT(1)R antagonism represents a novel treatment strategy for Alzheimer's disease. (C) 2014 Elsevier Ltd. All rights reserved.