Prostaglandin EN receptor agonist protects against acute neurotoxicity
Prostaglandin EN receptor agonist protects against acute neurotoxicity
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DOI：
10.1016/j.brainres.2005.10.068
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发表时间：
2005-12-20
期刊：
影响因子：
2.9
通讯作者：
Doré, S
中科院分区：
文献类型：
--
作者：
Ahmad, AS;Ahmad, M;Doré, S
在各种异常的生理条件下，谷氨酸门控离子通道受体家族成员（包括NMDA受体）的过度活化导致考克斯-2表达增加并产生洋地黄素。PGE（2）主要通过其前列腺素（EP）受体发挥生理作用。在本研究中，EN受体对NMDA诱导的兴奋毒性的作用进行了研究。使用EP 4受体激动剂ONO-AE 1 -329（其对鼠EP受体具有分别> 1000：210：120：1的EP 1：EP 2：EP 3：EP 4的相对选择性），我们质疑EN受体的激活是否具有减轻脑损伤的潜力。通过脑室内注射不同剂量的ONO-AE 1 -329（0.1、1和10 nmol; n = 9/组）预处理小鼠，20 min后，通过单次单侧纹状体内注射NMDA（15 nmol，n = 12）。注射NMDA在同侧纹状体中产生显著损伤。在用ONO-AE 1 -329预处理的组中，该病变体积显著减小，在10 nmol时具有超过32%的最大保护。这是第一项揭示ONO-AE 1 -329在脑兴奋性毒性急性模型中的保护作用的研究，并且它表明EP 4受体的优先刺激减弱了兴奋性毒性脑损伤。(c)2005 Elsevier B. V.保留所有权利。
Under various abnormal physiologic conditions, overactivation of glutamate-gated ion channel receptor family members, including NMDA receptors, causes increase in COX-2 expression and generation of prostaglandins. PGE(2) exerts its physiologic actions mainly through its PGE(2) prostanoid (EP) receptors. In the present study, the role of the EN receptor against NMDA-induced excitotoxicity was investigated. Using the EP4 receptor agonist ONO-AE1-329, which has relative selectivity toward murine EP receptors on the order of EP1:EP2:EP3:EP4 of > 1000:210:120:1, respectively, we questioned whether activation of the EN receptors has the potential to attenuate injury in brain. Mice were pretreated by intracerebroventricular injection with different doses of ONO-AE1-329 (0.1, 1, and 10 nmol; n = 9/group) and, after 20 min, by a single unilateral intrastriatal injection of NMDA (15 nmol, n = 12). NMDA injection produced a significant lesion in the ipsilateral striatum. This lesion volume was significantly reduced in groups that were pretreated with ONO-AE1-329, with maximum protection of more than 32% at 10 nmol. This is the first study revealing the protective effect of ONO-AE1-329 in an acute model of excitotoxicity in brain, and it suggests that preferential stimulation of EP4 receptors attenuates excitotoxic brain injury. (c) 2005 Elsevier B.V. All rights reserved.