15-deoxy-Δ 12,14-prostaglandin J 2 biphasically regulates the proliferation of mouse hippocampal neural stem cells by modulating the redox state

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-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 factorinduced proliferation of NPCs; facilitation at low concentrations ( 0.3 M) and suppression at higher concentrations (0.5–10 M) in vitro. 2-Chloro-5-nitrobenzanilide (GW9662), an inhibitor of peroxisome proliferator-activated receptor , 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) 15dPGJ2. These results suggest that 15d-PGJ2 regulates the proliferation of NPCs via its electrophilic nature, which enables covalent binding to molecules such as GSH. Recent extensive studies have elucidated that three cell types in the brain (neurons, astrocytes, and oligodendrocytes) originate from immature precursor cells referred to as neural progenitor cells (NPCs) (Weiss et al., 1996; Gage, 2000). During development, NPCs primarily undergo extensive selfrenewal and then generate neurons; later, they sequentially generate astrocytes and oligodendrocytes (Miller and Gauthier, 2007). NPCs are located not only in the developing mammalian brain but also in the adult brain and are especially abundant in the anterior subventricular zone and subgranular zone of the hippocampal dentate gyrus (DG) (Eriksson et al., 1998). The self-renewal and multipotential activities of NPCs are dynamically regulated by various humoral factors under physiological and pathophysiological conditions, such as ischemia (Nakatomi et al., 2002), seizure (Parent et al., 1997), and sleep (Guzman-Marin et al., 2003). The elucidation of signaling molecules regulating NPC activity may contribute not only to the understanding of neurogenesis but also to the development of new therapies against nervous system disorders; however, the cellular mechanisms underlying regulation of NPC activity have not been fully understood. Prostaglandins (PGs) are a group of 20-carbon fatty acids 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). Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.109.061010. □S The online version of this article (available at http://molpharm. aspetjournals.org) contains supplemental material. ABBREVIATIONS: NPC, neural progenitor cell; DG, dentate gyrus; PG, prostaglandin; 15d-PGJ2, 15-deoxy-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-deoxyprostaglandin 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. 0026-895X/10/7704-601–611$20.00 MOLECULAR PHARMACOLOGY Vol. 77, No. 4 Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics 61010/3572707 Mol Pharmacol 77:601–611, 2010 Printed in U.S.A.