title: CysLT1R downregulation reverses intracerebroventricular streptozotocin-induced memory impairment via modulation of neuroinflammation in mice.
abstract: Our previous studies showed that cysteinyl leukotrienes receptor 1 (CysLT1R) is upregulated in amyloid-β (Aβ)-induced neurotoxicity and that administration of CysLT1R antagonists such as pranlukast or montelukast can ameliorate memory impairment in mice. In the current study, we sought to explore the role of CysLT1R in intracerebroventricular streptozotocin (STZ-ICV)-induced mouse model of memory impairment and neuroinflammation through shRNA-mediated knockdown of CysLT1R and also its pharmacological blockade by pranlukast. ICR mice were infused with STZ (3.0mg/kg) by a single bilateral stereotaxic ICV microinjection followed by administration of CysLT1R-shRNA (intra-hippocampal) or pranlukast (intragastric, IG). After 21days, a set of behavioral and biochemical tests were performed in order to assess the degree of memory impairment and neuroinflammation in mice. STZ-infused mice spent less time in the target quadrant of Morris water maze test and took more time to find the shock-free arm in modified Y-maze test, which were rescued in the CysLT1R-knockdowned or pranlukast-treated mice. STZ-induced memory impairment was also accompanied by an elevated level of hippocampal CysLT1R, microglial activation, increased IL-1β, and TNF-α. Such elevation of these factors was found to be mediated through the classical NF-κB pathway and administration of CysLT1R-shRNA or pranlukast for 21days reversed all these parameters, suggesting a role of CysLT1R in STZ-induced memory deficit and neuroinflammation.
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
authors.forename: Arijit
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Chen
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, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, 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, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, 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, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China.
authors.forename: Ling-Yi
authors.initials: LY
authors.lastname: Kong
authors.affiliation: Department of Pharmacology, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu, China. Electronic address: honghao@cpu.edu.cn.
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002867:Chromones / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004660:Encephalitis / Q000209:etiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000150:complications*; D051379:Mice; D008813:Mice, Inbred ICR; D008840:Microfilament Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000627:therapeutic use; D018077:Receptors, Leukotriene / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013311:Streptozocin / Q000633:toxicity; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: C491049:Aif1 protein, mouse; D018927:Anti-Asthmatic Agents; D000903:Antibiotics, Antineoplastic; D002135:Calcium-Binding Proteins; D002867:Chromones; D016207:Cytokines; D006657:Histones; D008840:Microfilament Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018077:Receptors, Leukotriene; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D013311:Streptozocin; C083169:leukotriene D4 receptor; C047681:pranlukast
keywords: Cysteinyl leukotrienes receptor 1; Memory; Neuroinflammation; Pranlukast; STZ ICV; Stereotaxic injection