15-Deoxy-Δ^12,14-prostaglandin J₂ biphasically regulates the proliferation of mouse hippocampal neural progenitor cells by modulating the redox state

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-PGJ ₂. 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-PGJ ₂ 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.