Dexamethasone protects neonatal hypoxic-ischemic brain injury via L-PGDS-dependent PGD2-DP1-pERK signaling pathway.
Dexamethasone protects neonatal hypoxic-ischemic brain injury via L-PGDS-dependent PGD2-DP1-pERK signaling pathway.
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DOI：
10.1371/journal.pone.0114470
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Gonzalez-Rodriguez PJ;Li Y;Martinez F;Zhang L
糖皮质激素预处理对新生儿缺氧缺血性脑损伤具有保护作用。然而，其分子机制尚不清楚。我们通过刺激Lipocalin型前列腺素D合成酶(Lipocalin型前列腺素D合成酶，Lipocalin型前列腺素D合成酶地塞米松和抑制剂通过侧脑室(i.c.v)注射到10日龄大鼠脑内。免疫印迹法检测L-前列腺素D2、D-前列腺素受体1/2和前列腺素D2的表达。观察10日龄大鼠缺氧缺血后48h脑损伤情况。地塞米松处理显著上调L-PGDS的表达和PGD2的生物合成。地塞米松还选择性地增加新生大鼠大脑中异构体PERK-44的水平。L-PGDS(SeCl4)、DP1(MK-0524)和MAPK(PD98059)的抑制剂分别阻断地塞米松诱导的PERK-44水平的升高。重要的是，这些抑制剂还阻断了地塞米松介导的对新生大鼠脑缺血缺氧性脑损伤的神经保护作用。糖皮质激素-GR信号通路和L-PGDS-PGD2-DP1-PERK通路的相互作用是地塞米松预处理对新生儿缺氧缺血性脑损伤保护作用的基础。
Glucocorticoids pretreatment confers protection against neonatal hypoxic-ischemic (HI) brain injury. However, the molecular mechanism remains poorly elucidated. We tested the hypothesis that glucocorticoids protect against HI brain injury in neonatal rat by stimulation of lipocalin-type prostaglandin D synthase (L-PGDS)-induced prostaglandin D2 (PGD2)-DP1-pERK mediated signaling pathway. Dexamethasone and inhibitors were administered via intracerebroventricular (i.c.v) injections into 10-day-old rat brains. Levels of L-PGD2, D prostanoid (DP1) receptor, pERK1/2 and PGD2 were determined by Western immunoblotting and ELISA, respectively. Brain injury was evaluated 48 hours after conduction of HI in 10-day-old rat pups. Dexamethasone pretreatment significantly upregulated L-PGDS expression and the biosynthesis of PGD2. Dexamethasone also selectively increased isoform pERK-44 level in the neonatal rat brains. Inhibitors of L-PGDS (SeCl4), DP1 (MK-0524) and MAPK (PD98059) abrogated dexamethasone-induced increases in pERK-44 level, respectively. Of importance, these inhibitors also blocked dexamethasone-mediated neuroprotective effects against HI brain injury in neonatal rat brains. Interaction of glucocorticoids-GR signaling and L-PGDS-PGD2-DP1-pERK mediated pathway underlies the neuroprotective effects of dexamethasone pretreatment in neonatal HI brain injury.
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发表时间：
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影响因子：
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