title: Montelukast ameliorates streptozotocin-induced cognitive impairment and neurotoxicity in mice.
abstract: Extensive studies have demonstrated that neuroinflammation is associated with Alzheimer's disease (AD) and cysteinyl leukotriene receptor 1 (CysLT1R) was involved in neuroinflammation. Montelukast, a highly selective CysLT1R antagonist, has been reported to attenuate learning and memory impairments in the amyloid-β-induced mouse model of AD. However, whether montelukast also exerts beneficial effects on streptozotocin (STZ)-induced memory deficits in mice is not well known. In the present study, we aimed to investigate the effects of montelukast on STZ-induced cognitive impairment, neuroinflammation and apoptosis in mice. Our data showed that intra-hippocampal microinfusion of STZ resulted in learning and memory impairments, including increased escape latency during acquisition trials and decreased exploratory activities in the probe trial in Morris watermaze (MWM) task, and decreased number of correct choices and increased latency to enter the shock-free compartment in Y-maze test, and caused neuroinflammatory and apoptotic responses, evidenced by increments of nuclear NF-κB p65, TNF-α, IL-1β, cleaved caspase-3, Bax as well as decreased expression of Bcl-2 in hippocampus. Interestingly, STZ treatment led to up-regulation of protein and mRNA of CysLT1R in hippocampus. Of note, consecutive oral administration of montelukast (1 or 2mg/kg, 3 weeks) remarkably attenuated these effects induced by STZ. However, montelukast had no effect on normal mice. These results suggest that montelukast improves memory impairment and inhibits neuroinflammation and apoptosis in mice exposed to STZ. Montelukast may provide a novel strategy for treating or preventing AD.
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Chun Teng
authors.initials: CT
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jing Ran
authors.initials: JR
authors.lastname: Lin
authors.affiliation: School of Pharmacy, Nantong University, Nantong 226001, Jiangsu, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China; Department of Health Technology & Informatics, The Hong Kong Polytechnic University, Kowloon, HKSAR, Hong Kong.
authors.forename: Arijit
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Su Su
authors.initials: SS
authors.lastname: Tang
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Hong Bin
authors.initials: HB
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China. Electronic address: honghao@cpu.edu.cn.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
mesh_terms: D000085:Acetates / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000139:chemically induced* / Q000188:drug therapy*; D003521:Cyclopropanes; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000209:etiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D018077:Receptors, Leukotriene / Q000378:metabolism; D013311:Streptozocin / Q000633:toxicity*; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: D000085:Acetates; D003521:Cyclopropanes; D053583:Interleukin-1beta; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; D013440:Sulfides; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D013311:Streptozocin; D053148:Caspase 3; C083169:leukotriene D4 receptor; C093875:montelukast
keywords: Cysteinyl leukotriene receptor 1; Memory; Montelukast; Neurotoxicity; Streptozotocin