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Protective effect of pranlukast on Aβ₁₋₄₂-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1.

Abstract

Deposition of extracellular amyloid-β (Aβ) peptide is one of the pathological hallmarks of Alzheimer's disease (AD). Accumulation of Aβ is thought to associate with cognition deficits, neuroinflammation and apoptosis observed in AD. However, effective neuroprotective approaches against Aβ neurotoxicity are unavailable. In the present study, we analysed the effects of pranlukast, a selective cysteinyl leukotriene receptor 1 (CysLT₁R) antagonist, on the impairment of learning and memory formation induced by Aβ and the probable underlying electrophysiological and molecular mechanisms. We found that bilateral intrahippocampal injection of Aβ₁₋₄₂ resulted in a significant decline of spatial learning and memory of mice in the Morris water maze (MWM) and Y-maze tests, together with a serious depression of in vivo hippocampal long-term potentiation (LTP) in the CA1 region of the mice. Importantly, this treatment caused significant increases in CysLT₁R expression and subsequent NF-κB signaling, caspase-3 activation and Bcl-2 downregulation in the hippocampus or prefrontal cortex. Oral administration of pranlukast at 0.4 or 0.8 mg/kg for 4 wk significantly reversed Aβ₁₋₄₂-induced impairments of cognitive function and hippocampal LTP in mice. Furthermore, pranlukast reversed Aβ₁₋₄₂-induced CysLT₁R upregulation, and markedly suppressed the Aβ₁₋₄₂-triggered NF-κB pathway, caspase-3 activation and Bcl-2 downregulation in the hippocampus and prefrontal cortex in mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay confirmed its presence in the brain after oral administration of pranlukast in mice. These data disclose novel findings about the therapeutic potential of pranlukast, revealing a previously unknown therapeutic possibility to treat memory deficits associated with AD.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

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    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

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    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

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    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

    ,

    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

    ,

    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

    ,

    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

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    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

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    Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.

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    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

    ,

    Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.

    Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, China.

    Source

    MeSH

    Amyloid beta-Peptides
    Animals
    Behavior, Animal
    CA1 Region, Hippocampal
    Chromones
    Cognition Disorders
    Disease Models, Animal
    Down-Regulation
    Hippocampus
    Learning
    Leukotriene Antagonists
    Long-Term Potentiation
    Male
    Memory
    Mice, Inbred ICR
    Peptide Fragments
    Prefrontal Cortex
    Receptors, Leukotriene

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    24229499

    Citation

    Tang, Su-Su, et al. "Protective Effect of Pranlukast On Aβ₁₋₄₂-induced Cognitive Deficits Associated With Downregulation of Cysteinyl Leukotriene Receptor 1." The International Journal of Neuropsychopharmacology, vol. 17, no. 4, 2014, pp. 581-92.
    Tang SS, Ji MJ, Chen L, et al. Protective effect of pranlukast on Aβ₁₋₄₂-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1. Int J Neuropsychopharmacol. 2014;17(4):581-92.
    Tang, S. S., Ji, M. J., Chen, L., Hu, M., Long, Y., Li, Y. Q., ... Hong, H. (2014). Protective effect of pranlukast on Aβ₁₋₄₂-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1. The International Journal of Neuropsychopharmacology, 17(4), pp. 581-92. doi:10.1017/S1461145713001314.
    Tang SS, et al. Protective Effect of Pranlukast On Aβ₁₋₄₂-induced Cognitive Deficits Associated With Downregulation of Cysteinyl Leukotriene Receptor 1. Int J Neuropsychopharmacol. 2014;17(4):581-92. PubMed PMID: 24229499.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Protective effect of pranlukast on Aβ₁₋₄₂-induced cognitive deficits associated with downregulation of cysteinyl leukotriene receptor 1. AU - Tang,Su-Su, AU - Ji,Miao-jin, AU - Chen,Lan, AU - Hu,Mei, AU - Long,Yan, AU - Li,Yong-qi, AU - Miao,Ming-xing, AU - Li,Jia-chang, AU - Li,Ning, AU - Ji,Hui, AU - Chen,Xi-jing, AU - Hong,Hao, Y1 - 2013/11/11/ PY - 2013/11/16/entrez PY - 2013/11/16/pubmed PY - 2015/2/13/medline SP - 581 EP - 92 JF - The international journal of neuropsychopharmacology JO - Int. J. Neuropsychopharmacol. VL - 17 IS - 4 N2 - Deposition of extracellular amyloid-β (Aβ) peptide is one of the pathological hallmarks of Alzheimer's disease (AD). Accumulation of Aβ is thought to associate with cognition deficits, neuroinflammation and apoptosis observed in AD. However, effective neuroprotective approaches against Aβ neurotoxicity are unavailable. In the present study, we analysed the effects of pranlukast, a selective cysteinyl leukotriene receptor 1 (CysLT₁R) antagonist, on the impairment of learning and memory formation induced by Aβ and the probable underlying electrophysiological and molecular mechanisms. We found that bilateral intrahippocampal injection of Aβ₁₋₄₂ resulted in a significant decline of spatial learning and memory of mice in the Morris water maze (MWM) and Y-maze tests, together with a serious depression of in vivo hippocampal long-term potentiation (LTP) in the CA1 region of the mice. Importantly, this treatment caused significant increases in CysLT₁R expression and subsequent NF-κB signaling, caspase-3 activation and Bcl-2 downregulation in the hippocampus or prefrontal cortex. Oral administration of pranlukast at 0.4 or 0.8 mg/kg for 4 wk significantly reversed Aβ₁₋₄₂-induced impairments of cognitive function and hippocampal LTP in mice. Furthermore, pranlukast reversed Aβ₁₋₄₂-induced CysLT₁R upregulation, and markedly suppressed the Aβ₁₋₄₂-triggered NF-κB pathway, caspase-3 activation and Bcl-2 downregulation in the hippocampus and prefrontal cortex in mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay confirmed its presence in the brain after oral administration of pranlukast in mice. These data disclose novel findings about the therapeutic potential of pranlukast, revealing a previously unknown therapeutic possibility to treat memory deficits associated with AD. SN - 1469-5111 UR - https://www.unboundmedicine.com/medline/citation/24229499/Protective_effect_of_pranlukast_on_Aβ₁₋₄₂_induced_cognitive_deficits_associated_with_downregulation_of_cysteinyl_leukotriene_receptor_1_ L2 - https://academic.oup.com/ijnp/article-lookup/doi/10.1017/S1461145713001314 DB - PRIME DP - Unbound Medicine ER -