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Arachidonic acid (ARA) and docosahexaenoic acid (DHA), which are the dominant polyunsaturated fatty acids in the brain, have crucial roles in brain development and function. Recent studies have shown that ARA and DHA promote postnatal neurogenesis. However, the direct effects of ARA on neural stem ⁄ progenitor cells (NSPCs) and the effects of ARA and DHA on NSPCs at the neurogenic and subsequent gliogenic stages are still unknown. Here, we analyzed the effects of ARA and DHA on neurogenesis, specifically maintenance and differentiation, using neurosphere assays. We confirmed that primary neurospheres are neurogenic NSPCs and that tertiary neurospheres are gliogenic NSPCs. Regarding the effects of ARA and DHA on neurogenic NSPCs, ARA and DHA increased the number of neurospheres, whereas neither ARA nor DHA had a detectable effect on NSPCs in the differentiation condition. In gliogenic NSPCs, DHA increased the number of neurospheres, whereas ARA had no such effect. In contrast, ARA increased the number of astrocytes, whereas DHA increased the number of neurons in the differentiation condition. These results suggest that ARA promotes the maintenance of neurogenic NSPCs and might induce the glial differentiation of gliogenic NSPCs and that DHA promotes the maintenance of both neurogenic and gliogenic NSPCs and might lead to the neuronal differentiation of gliogenic NSPCs.

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The activity of neural progenitor cells (NPCs) is regulated by various humoral factors. Although prostaglandin (PG) D 2 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 PGD 2 on NPCs, we found that 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), an endogenous metabolite of PGD 2 , exhibits a novel regulation of the proliferation of NPCs derived from mouse hippocampus. 15d-PGJ 2 showed biphasic effects on epidermal growth factorinduced proliferation of NPCs; facilitation at low concentrations (ϳ0.3 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-PGJ 2 , failed to abolish the effects of 15d-PGJ 2 . 9,10-dihydro-15d-PGJ 2 (CAY10410), a structural analog of 15d-PGJ 2 lacking the electrophilic carbon in the cyclopentenone ring, did not show 15d-PGJ 2 -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-PGJ 2 . Finally, cell division in the dentate gyrus of postnatal mice was increased by injection of low-dose (1 ng i.c.v.) 15d-PGJ 2 and suppressed by high-dose (30 ng) 15d-PGJ 2 . These results suggest that 15d-PGJ 2 regulates the proliferation of NPCs via its electrophilic nature, which enables covalent binding to molecules such as GSH.

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