title: Montelukast rescues primary neurons against Aβ1-42-induced toxicity through inhibiting CysLT1R-mediated NF-κB signaling.
abstract: Amyloid-β peptide (Aβ), 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 Aβ generation. In this study, we investigated rescuing effect of CysLT1R antagonist montelukast on Aβ1-42-induced neurotoxicity in primary neurons. Our data showed that Aβ1-42 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-1β (IL-1β) as well as pro-apoptotic protein Caspase-3 activation and anti-apoptosis protein Bcl-2 reduction. Aβ1-42-mediated increase of CysLT1R expression was associated with Aβ1-42-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 Aβ1-42-induced cytotoxicity. Moreover, blockade of CysLT1R with montelukast reversed Aβ1-42-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 Aβ1-42-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.
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jin'e
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Zhen Lin
authors.initials: ZL
authors.lastname: Mei
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ming Xing
authors.initials: MX
authors.lastname: Miao
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China. Electronic address: haohongchina@hotmail.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D003521:Cyclopropanes; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D018836:Inflammation Mediators / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D018077:Receptors, Leukotriene / Q000187:drug effects* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013440:Sulfides
chemical_list: D000085:Acetates; D016229:Amyloid beta-Peptides; D003521:Cyclopropanes; D016207:Cytokines; D018836:Inflammation Mediators; D020024:Leukotriene Antagonists; D016328:NF-kappa B; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D018077:Receptors, Leukotriene; D013440:Sulfides; C075222:amyloid beta-protein (1-42); D053148:Caspase 3; C083169:leukotriene D4 receptor; C093875:montelukast
keywords: Amyloid-β; Cysteinyl leukotriene receptor 1; Montelukast; NF-κB