Zhou Ping, Qian Liping, Chou Tsu, Iadecola Costantino
Division of Neurobiology, Weill Cornell Medical College, New York, NY 10021, USA.
Neurobiol Dis. 2008 Mar;29(3):543-51. doi: 10.1016/j.nbd.2007.11.010. Epub 2007 Dec 4.
The prostanoid synthesizing enzyme cyclooxygenase-2 (COX-2) is involved in the mechanisms of cerebral ischemia, an effect mediated by prostaglandin E2 through activation of EP1 receptors. Thus, inhibition of EP1 receptors is neuroprotective in models of ischemic stroke, but the molecular mechanisms of the effect have not been fully elucidated. We used oxygen glucose deprivation (OGD) in hippocampal slices as an injury model to investigate whether the neuroprotection afforded by EP1 receptor inhibition involves the PI3K/AKT survival pathway. EP1 receptor inhibition with SC51089 or SC51322 reduced the hippocampal damage produced by ODG by 28+/-2% and 32+/-3%, respectively (p<0.05). OGD induced a transient reduction of AKT activity that was partly counteracted by SC51089. LY294002 blocked the increase in phospho-AKT evoked by SC51089 and abolished the associated protective effect. The AKT activation induced by SC51089 was associated with phosphorylation of PTEN, the phosphatase that negatively regulates AKT. Furthermore, SC51089 attenuated the mitochondrial translocation of the proapoptotic protein BAD. These data indicate that EP1 receptor inhibition improves the survival of hippocampal slices by preventing the attenuation in AKT activity induced by OGD, and by reducing the mitochondrial translocation of BAD. The findings provide evidence for a link between EP1 receptors and the PI3K/AKT survival pathway and shed light on the molecular mechanisms of the prosurvival effect of EP1 receptor inhibition.
前列腺素合成酶环氧合酶-2（COX-2）参与脑缺血机制，该效应由前列腺素E2通过激活EP1受体介导。因此，在缺血性中风模型中，抑制EP1受体具有神经保护作用，但该效应的分子机制尚未完全阐明。我们使用海马脑片氧糖剥夺（OGD）作为损伤模型，以研究抑制EP1受体所提供的神经保护是否涉及PI3K/AKT存活途径。用SC51089或SC51322抑制EP1受体可分别将OGD引起的海马损伤降低28±2%和32±3%（p<0.05）。OGD诱导AKT活性短暂降低，SC51089可部分抵消该降低。LY294002阻断了SC51089引起的磷酸化AKT增加，并消除了相关的保护作用。SC51089诱导的AKT激活与PTEN（负向调节AKT的磷酸酶）的磷酸化有关。此外，SC51089减弱了促凋亡蛋白BAD的线粒体易位。这些数据表明，抑制EP1受体可通过防止OGD诱导的AKT活性降低以及减少BAD的线粒体易位来提高海马脑片的存活率。这些发现为EP1受体与PI3K/AKT存活途径之间的联系提供了证据，并揭示了抑制EP1受体促存活效应的分子机制。
