1-HydroxyPGE1 reduces infarction volume in mouse transient cerebral ischemia
1-HydroxyPGE1 reduces infarction volume in mouse transient cerebral ischemia
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DOI：
10.1111/j.1460-9568.2005.04540.x
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发表时间：
2006-01-01
影响因子：
3.4
通讯作者：
Doré, S
中科院分区：
文献类型：
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作者：
Ahmad, M;Saleem, S;Doré, S
已观察到前列腺素 E-2 激活 G 蛋白偶联前列腺素 E (EP) 受体导致不同的神经系统结果。在这里，我们研究了 EP4/EP3 激动剂 1-羟基PGE(1) (1-OHPGE(1)) 在调节短暂性缺血性脑损伤中的作用。 C57BL/6小鼠在大脑中动脉短暂闭塞前50分钟通过脑室内注射1-OHPGE(1)(0.1、0.2、2.0nmol/0.2μL)进行预处理。再灌注后 4 天的脑损伤（根据梗塞体积估计）在两个较高剂量组中使用 1-OHPGE(1) 显着减少了 19% 以上（P < 0.05）。为了进一步确定保护是否也扩展到神经元，将原代小鼠培养的神经元细胞暴露于 N-甲基-D-天冬氨酸。与 1-OHPGE(1) 联合治疗可产生显着的神经保护作用（P < 0.05）。为了更好地了解潜在的作用机制并测试环磷酸腺苷 (cAMP) 水平和下游信号传导的变化是否具有神经保护作用，我们测量了原代神经元细胞中的 cAMP 水平。短暂暴露于 1-OHPGE(1) 会使 cAMP 水平增加两倍以上，并增加 Thr-202/Tyr-204 位点的细胞外调节激酶的磷酸化。在另一组动物中，所有测试剂量的 1-OHPGE(1) 对药物治疗后观察到的核心体温、平均动脉压和相对脑血流量等生理参数均没有产生显着影响。总之，这些结果表明，用 1-OHPGE(1) 治疗引起的 PGE(2) 受体调节可增加 cAMP 水平并激活细胞外调节激酶 1/2，可以预防局灶性缺血引起的神经元损伤。
Differential neurological outcomes due to prostaglandin E-2 activating G-protein-coupled prostaglandin E (EP) receptors have been observed. Here, we investigated the action of the EP4/EP3 agonist 1-hydroxyPGE(1) (1-OHPGE(1)) in modulating transient ischemic brain damage. C57BL/6 mice were pretreated 50 min before transient occlusion of the middle cerebral artery with an intraventricular injection of 1-OHPGE(1) (0.1, 0.2, 2.0 nmol/0.2 mu L). Brain damage 4 days after reperfusion, as estimated by infarct volume, was significantly reduced by more than 19% with 1-OHPGE(1) in the two higher-dose groups (P < 0.05). To further address whether protection also was extended to neurons, primary mouse cultured neuronal cells were exposed to N-methyl-D-aspartate. Co-treatment with 1-OHPGE(1) resulted in significant neuroprotection (P < 0.05). To better understand potential mechanisms of action and to test whether changes in cyclic adenosine monophosphate (cAMP) levels and downstream signaling would be neuroprotective, we measured cAMP levels in primary neuronal cells. Brief exposure to 1-OHPGE(1) increased cAMP levels more than twofold and increased the phosphorylation of extracellular-regulated kinases at positions Thr-202/Tyr-204. In a separate cohort of animals, 1-OHPGE(1) at all doses tested produced no significant effect on the physiological parameters of core body temperature, mean arterial pressure and relative cerebral blood flow observed following drug treatment. Together, these results suggest that modulation of PGE(2) receptors that increase cAMP levels and activate extracellular-regulated kinases 1/2 caused by treatment with 1-OHPGE(1) can be protective against neuronal injury induced by focal ischemia.