15-Deoxy-Δ12,14-Prostaglandin J2 Biphasically Regulates the Proliferation of Mouse Hippocampal Neural Progenitor Cells by Modulating the Redox State
15-Deoxy-Δ12,14-Prostaglandin J2 Biphasically Regulates the Proliferation of Mouse Hippocampal Neural Progenitor Cells by Modulating the Redox State
复制标题
DOI：
10.1124/mol.109.061010
复制
发表时间：
2010-04-01
影响因子：
3.6
通讯作者：
Nakahata, Norimichi
中科院分区：
文献类型：
--
作者：
Katura, Takashi;Moriya, Takahiro;Nakahata, Norimichi
神经祖细胞（neural progenitor cells, npc）的活性受多种体液因子的调控。虽然已知前列腺素（PG） D-2介导多种生理脑功能，如睡眠，但其对npc的作用尚未完全了解。在研究PGD(2)对NPCs的影响过程中，我们发现PGD(2)的内源性代谢产物15-deoxy-Delta(12,14)-prostaglandin J(2) （15d-PGJ(2)）对小鼠海马源NPCs的增殖具有新的调控作用。15d-PGJ(2)对表皮生长因子诱导的NPCs增殖具有双相作用；低浓度（类似于0.3 μ M）促进和高浓度（0.5-10 μ M）抑制。2- chloro -5-nitrobenzanilide （GW9662）是过氧化物酶体增殖体激活受体γ的抑制剂，已知是15d-PGJ的分子靶标(2)，但未能消除15d-PGJ的作用(2)。9,10-二氢-15d-PGJ(2) （CAY10410）是15d-PGJ(2)的结构类似物，缺乏环戊酮环上的亲电碳，没有表现出类似15d-PGJ(2)的作用。15d-PGJ(2)增加了活性氧水平，降低了内源性GSH水平。此外，补充谷胱甘肽的膜渗透性类似物，谷胱甘肽乙酯（2 mM），减少了15d-PGJ的双相效应(2)。最后，小剂量（1 ng c.c.v）注射可促进出生后小鼠齿状回细胞分裂。15d-PGJ(2)并被高剂量（30 ng） 15dPGJ 2抑制。这些结果表明，15d-PGJ(2)通过其亲电性质调节npc的增殖，从而使其能够与GSH等分子形成共价结合。
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-Delta(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 factor-induced proliferation of NPCs; facilitation at low concentrations (similar to 0.3 mu M) and suppression at higher concentrations (0.5-10 mu M) in vitro. 2-Chloro-5-nitrobenzanilide (GW9662), an inhibitor of peroxisome proliferator-activated receptor gamma, 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) 15dPGJ 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.