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Molecular Pharmacology

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Research ArticleArticle

15-Deoxy-Δ12,14-Prostaglandin J2 Biphasically Regulates the Proliferation of Mouse Hippocampal Neural Progenitor Cells by Modulating the Redox State

Takashi Katura, Takahiro Moriya and Norimichi Nakahata
Molecular Pharmacology April 2010, 77 (4) 601-611; DOI: https://doi.org/10.1124/mol.109.061010
Takashi Katura
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Takahiro Moriya
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Norimichi Nakahata
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Abstract

The activity of neural progenitor cells (NPCs) is regulated by various humoral factors. Although prostaglandin (PG) D2 is known to mediate various physiological brain functions such as sleep, its actions on NPCs have not been fully understood. In the process of investigating the effects of PGD2 on NPCs, we found that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous metabolite of PGD2, exhibits a novel regulation of the proliferation of NPCs derived from mouse hippocampus. 15d-PGJ2 showed biphasic effects on epidermal growth factor-induced proliferation of NPCs; facilitation at low concentrations (∼0.3 μM) and suppression at higher concentrations (0.5–10 μM) in vitro. 2-Chloro-5-nitrobenzanilide (GW9662), an inhibitor of peroxisome proliferator-activated receptor γ, known to be a molecular target for 15d-PGJ2, failed to abolish the effects of 15d-PGJ2. 9,10-dihydro-15d-PGJ2 (CAY10410), a structural analog of 15d-PGJ2 lacking the electrophilic carbon in the cyclopentenone ring, did not show 15d-PGJ2-like actions. Treatment with 15d-PGJ2 increased the levels of reactive oxygen species and decreased endogenous GSH levels. Furthermore, supplementation with a membrane-permeable analog of glutathione, GSH ethyl ester (2 mM), diminished the biphasic effects of 15d-PGJ2. Finally, cell division in the dentate gyrus of postnatal mice was increased by injection of low-dose (1 ng i.c.v.) 15d-PGJ2 and suppressed by high-dose (30 ng) 15d-PGJ2. These results suggest that 15d-PGJ2 regulates the proliferation of NPCs via its electrophilic nature, which enables covalent binding to molecules such as GSH.

Footnotes

    fn-1
  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • fn-2
  • This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas-Molecular Brain Science-from the Ministry of Education, Culture, Sports, Science and Technology of Japan (2002) and by the Nishinomiya Basic Research Fund (Japan).

  • fn-3
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.061010.

  • fn-4
  • ABBREVIATIONS:

    NPC
    neural progenitor cell
    DG
    dentate gyrus
    PG
    prostaglandin
    15d-PGJ2
    15-deoxy-Δ12,14-prostaglandin J2
    PPAR
    peroxisome proliferator-activated receptor
    ROS
    reactive oxygen species
    MHM
    media-hormone mix
    EGF
    epidermal growth factor
    BWA868C
    3-[(2-cyclohexyl-2-hydroxyethyl)amino]-2,5-dioxo-1-(phenylmethyl)-4-imidazolidineheptanoic acid
    CAY10410
    9,10-dehydro-15-deoxy-Δ12,14-prostaglandin J2
    GW9662
    2-chloro-5-nitrobenzanilide
    BrdU
    bromodeoxyuridine
    IgG
    immunoglobulin G
    H2DCFDA
    2′,7′-dichlorodihydrofluorescein diacetate
    GFAP
    anti-glial fibrillary acidic protein
    GSH-EE
    GSH reduced ethyl ester
    WST-8; TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling
    PPAR
    peroxisome proliferator-activated receptor
    PMA
    phorbol 12,13-myristate acetate
    PFA
    paraformaldehyde
    PBS
    phosphate-buffered saline
    PBSGT
    PBS containing 1% normal goat serum and 0.3% Triton X-100
    PB
    phosphate buffer
    ANOVA
    analysis of variance
    MCI-186
    edaravone
    DP1
    prostaglandin D2 receptor type 1
    DP2
    prostaglandin D2 receptor type 2
    Trx
    thioredoxin
    LPS
    lipopolysaccharide.

    • Received September 14, 2009.
    • Accepted January 19, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

15-Deoxy-Δ12,14-Prostaglandin J2 Biphasically Regulates the Proliferation of Mouse Hippocampal Neural Progenitor Cells by Modulating the Redox State

Takashi Katura, Takahiro Moriya and Norimichi Nakahata
Molecular Pharmacology April 1, 2010, 77 (4) 601-611; DOI: https://doi.org/10.1124/mol.109.061010

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Research ArticleArticle

15-Deoxy-Δ12,14-Prostaglandin J2 Biphasically Regulates the Proliferation of Mouse Hippocampal Neural Progenitor Cells by Modulating the Redox State

Takashi Katura, Takahiro Moriya and Norimichi Nakahata
Molecular Pharmacology April 1, 2010, 77 (4) 601-611; DOI: https://doi.org/10.1124/mol.109.061010
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