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-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 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.