Abstract

The activity of neural progenitor cells (NPCs) is regulated by various humoral factors. Although prostaglandin D₂ (PGD₂) 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-Δ^12,14-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 EGF-induced proliferation of NPCs; facilitation at low concentrations (around 0.3 μM) and suppression at higher concentrations (0.5 - 10 μM) in vitro. GW9662, an inhibitor of peroxisome proliferator-activated receptor γ (PPARγ), known to be a molecular target for 15d-PGJ₂, failed to abolish the effects of 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 (ROS) and decreased endogenous glutathione (GSH) levels. Furthermore, supplementation with a membrane-permeable analog of glutathione, GSH ethyl ester (GSH-EE) (2 mM), diminished the biphasic effects of 15d-PGJ₂. Finally, cell division in the dentate gyrus of postnatal mice was increased by i.c.v. injection of low-dose (1 ng) 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.