Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity.
Contribution of PGE2 EP1 receptor in hemin-induced neurotoxicity.
复制标题
DOI：
10.3389/fnmol.2013.00031
复制
发表时间：
2013
影响因子：
4.8
通讯作者：
Doré S
中科院分区：
文献类型：
--
作者：
Mohan S;Glushakov AV;Decurnou A;Narumiya S;Doré S
尽管氯化血红素介导的神经毒性与自由基和谷氨酸兴奋性毒性的产生有关，但前列腺素E2（PGE 2）-EP 1受体的作用仍不清楚。神经元中EP 1受体的激活会导致细胞内钙水平增加;因此，我们假设EP 1受体的阻断会降低氯高铁血红素的神经毒性。使用从野生型（WT）和EP 1 −/−小鼠培养的出生后原代皮层神经元，我们研究了EP 1受体在通过乳酸脱氢酶（LDH）细胞存活测定测量的氯化血红素神经毒性中的作用。氯化血红素（75 μM）诱导WT神经元LDH释放（34.7 ± 4.5%）高于EP 1 −/−神经元（27.6 ± 3.3%）。在EP 1受体拮抗剂SC-51089的存在下，氯化血红素诱导的LDH释放减少。为了进一步研究潜在的作用机制，我们测量了用17-苯基三去甲前列腺素E2（17-pt-PGE 2）（一种选择性EP 1激动剂）治疗后细胞内钙水平[Ca 2 +]i的变化。在WT神经元中，17-pt-PGE 2剂量依赖性地增加[Ca 2 +]i。然而，在EP 1 −/−神经元中，[Ca 2 +]i显著减弱。我们还发现，氯化血红素剂量依赖性地增加WT神经元中的[Ca 2 +]i，同时EP 1 −/−神经元中的[Ca 2 +]i显著减少。N-甲基-D-天冬氨酸（NMDA）受体和兰尼碱受体阻断剂可阻断17-pt-PGE 2和氯化血红素诱导的[Ca 2 +]i。这些结果表明，在体外阻断EP 1受体可能是对氯化血红素神经毒性的保护。我们推测氯化血红素神经元死亡的机制涉及[Ca ~（2+）]i介导的NMDA酸受体介导的细胞外Ca ~（2+）内流和EP 1受体介导的细胞内释放从ryanodine受体操作的Ca ~（2+）库。因此，阻断EP 1受体可用于减少暴露于超生理水平的氯化血红素后的神经元损伤。
Although hemin-mediated neurotoxicity has been linked to the production of free radicals and glutamate excitotoxicity, the role of the prostaglandin E2 (PGE2)-EP1 receptor remains unclear. Activation of the EP1 receptor in neurons results in increased intracellular calcium levels; therefore, we hypothesize that the blockade of the EP1 receptor reduces hemin neurotoxicity. Using postnatal primary cortical neurons cultured from wild-type (WT) and EP1−/− mice, we investigated the EP1 receptor role in hemin neurotoxicity measured by lactate dehydrogenase (LDH) cell survival assay. Hemin (75 μM) induced greater release of LDH in WT (34.7 ± 4.5%) than in EP1−/− (27.6 ± 3.3%) neurons. In the presence of the EP1 receptor antagonist SC-51089, the hemin-induced release of LDH decreased. To further investigate potential mechanisms of action, we measured changes in the intracellular calcium level [Ca2+]i following treatment with 17-phenyl trinor PGE2 (17-pt-PGE2) a selective EP1 agonist. In the WT neurons, 17-pt-PGE2 dose-dependently increased [Ca2+]i. However, in EP1−/− neurons, [Ca2+]i was significantly attenuated. We also revealed that hemin dose-dependently increased [Ca2+]i in WT neurons, with a significant decrease in EP1−/− neurons. Both 17-pt-PGE2 and hemin-induced [Ca2+]i were abolished by N-methyl-D-aspartic (NMDA) acid receptor and ryanodine receptor blockers. These results suggest that blockade of the EP1 receptor may be protective against hemin neurotoxicity in vitro. We speculate that the mechanism of hemin neuronal death involves [Ca2+]i mediated by NMDA acid receptor-mediated extracellular Ca2+ influx and EP1 receptor-mediated intracellular release from ryanodine receptor-operated Ca2+ stores. Therefore, blockade of the EP1 receptor could be used to minimize neuronal damage following exposure to supraphysiological levels of hemin.
登录
查看更多内容
DOI：
10.1038/jcbfm.2008.88
发表时间：
2009-01
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
影响因子：
3
作者：
KOH, JY;CHOI, DW
通讯作者：
CHOI, DW
影响因子：
1.7
作者：
Atlante, A;Gagliardi, S;Calissano, P
通讯作者：
Calissano, P
影响因子：
21.3
作者：
Ferris, CD;Jaffrey, SR;Snyder, SH
通讯作者：
Snyder, SH
影响因子：
25
作者：
Hardingham, GE;Fukunaga, Y;Bading, H
通讯作者：
Bading, H