Montelukast rescues primary neurons against Aß1-42-induced toxicity through inhibiting CysLT1R-mediated NF-κB signaling.

Amyloid-ß peptide (Aß), 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 (CysLT1R) antagonist, is currently used for treatment of inflammatory diseases such as asthma. We have previously reported that CysLT1R activation is involved in Aß generation. In this study, we investigated rescuing effect of CysLT1R antagonist montelukast on Aß1-42-induced neurotoxicity in primary neurons. Our data showed that Aß1-42 elicited a marked increase of CysLT1R expression in primary mouse neurons. This increment of CysLT1R expression was accompanied by increases of inflammatory factors such as NF-κB p65, tumor necrosis factor-α (TNFα) and interleukin-1ß (IL-1ß) as well as pro-apoptotic protein Caspase-3 activation and anti-apoptosis protein Bcl-2 reduction. Aß1-42-mediated increase of CysLT1R expression was associated with Aß1-42-induced cytotoxicity as measured by MTT reduction assay and lactate dehydrogenase (LDH) release assay. This observation was confirmed with treatment of montelukast, a selective CysLT1R antagonist, which had significant effect on Aß1-42-induced cytotoxicity. Moreover, blockade of CysLT1R with montelukast reversed Aß1-42-mediated increase of CysLT1R expression, and concomitant changes of the pro-inflammatory factors and the apoptosis-related proteins. The results demonstrate that montelukast rescued neurons against Aß1-42-induced neurotoxicity, neuroinflammation and apoptosis by down-regulating CysLT1R-mediated NF-κB signaling, suggesting that CysLT1R may be a potential target for AD, and its antagonist may have beneficial effects for treatment of AD.

Montelukast targeting the cysteinyl leukotriene receptor 1 ameliorates Aß1-42-induced memory impairment and neuroinflammatory and apoptotic responses in mice.

Montelukast, known as a cysteinyl leukotriene receptor 1 (CysLT1R) 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-ß (Aß). The data demonstrated that intracerebroventrical infusions of aggregated Aß1-42 (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-κB p65, TNF-α and IL-1ß as well as pro-apoptotic molecule caspase-3 activation and anti-apoptotic protein Bcl-2 downregulation in hippocampus and cortex. Interestingly, this treatment resulted in upregulation of protein or mRNA of CysLT1R in both hippocampus and cortex. Blockade of CysLT1R by repeated treatment with montelukast (1 or 2 mg/kg, ig, 4 weeks) reduced Aß1-42-induced CysLT1R expression and also suppressed Aß1-42-induced increments of NF-κB p65, TNF-α, IL-1ß and caspase-3 activation, and Bcl-2 downregulation in the hippocampus and cortex. Correspondingly, montelukast treatment significantly improved Aß1-42-induced memory impairment in mice, but had little effect on normal mice. Our results show that montelukast may ameliorate Aß1-42-induced memory impairment via inhibiting neuroinflammation and apoptosis mediated by CysLT1R signaling, suggesting that CysLT1R antagonism represents a novel treatment strategy for Alzheimer's disease.