RT Journal Article
SR Electronic
T1 15-Deoxy-Δ<sup>12,14</sup>-Prostaglandin J<sub>2</sub> Biphasically Regulates the Proliferation of Mouse Hippocampal Neural Progenitor Cells by Modulating the Redox State
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 601
OP 611
DO 10.1124/mol.109.061010
VO 77
IS 4
A1 Katura, Takashi
A1 Moriya, Takahiro
A1 Nakahata, Norimichi
YR 2010
UL http://molpharm.aspetjournals.org/content/77/4/601.abstract
AB 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.Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics