Genetic Deletion of Prostacyclin IP Receptor Exacerbates Transient Global Cerebral Ischemia in Aging Mice.
Genetic Deletion of Prostacyclin IP Receptor Exacerbates Transient Global Cerebral Ischemia in Aging Mice.
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DOI：
10.3390/brainsci3031095
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发表时间：
2013-07-22
期刊：
影响因子：
3.3
通讯作者：
Saleem S
中科院分区：
文献类型：
--
作者：
Shakil H;Saleem S
短暂性全脑缺血导致海马 CA1 区神经元迟发性死亡。它还诱导环氧合酶 2 (COX-2) 上调，从而产生多种花生四烯酸代谢物，称为前列腺素，包括前列腺素 I2 (PGI2)。本研究调查了 PGI2 IP 受体是否在老年小鼠全脑缺血后的脑损伤中发挥重要作用。成年年轻（2-3 个月）和老年（12-15 个月）雄性 C57Bl/6 野生型 (WT) 或 IP 受体敲除 (IP KO) 小鼠接受 12 分钟双侧颈总动脉闭塞 (BCCAO) 或假手术。 BCCAO 后 3 天和 7 天进行行为测试（神经功能缺损和 T 迷宫）。再灌注7天后，通过免疫组织化学方法评估神经元、星形胶质细胞、小胶质细胞、髓过氧化物酶（MPO）和磷酸化CREB（p-CREB）标记物呈阳性的细胞数量。有趣的是，在年轻和老年IP KO缺血小鼠中，与相应的WT对照相比，认知缺陷、海马CA1锥体神经元死亡、小胶质细胞和MPO激活显着增加（p < 0.01），而p-CREB减少。这些数据表明，缺血后，IP 受体缺失会导致 CREB 通路调节的记忆和认知缺陷，并且 IP 受体激动剂治疗可能是预防有害后果的有用目标。
Transient global cerebral ischemia causes delayed neuronal death in the hippocampal CA1 region. It also induces an up regulation of cyclooxygenase 2 (COX-2), which generates several metabolites of arachidonic acid, known as prostanoids, including Prostaglandin I2 (PGI2). The present study investigated whether the PGI2 IP receptor plays an important role in brain injury after global cerebral ischemia in aged mice. Adult young (2–3 months) and aged (12–15 months) male C57Bl/6 wild-type (WT) or IP receptor knockout (IP KO) mice underwent a 12 min bilateral common carotid artery occlusion (BCCAO) or a sham surgery. Behavior tests (neurologic deficit and T-maze) were performed 3 and 7 days after BCCAO. After seven days of reperfusion, the numbers of cells positive for markers of neurons, astrocytes, microglia, myeloperoxidase (MPO) and phosphorylated CREB (p-CREB) were evaluated immunohistochemically. Interestingly, in young and aged IP KO ischemic mice, there was a significant increase (p < 0.01) in cognitive deficit, hippocampal CA1 pyramidal neuron death, microglia and MPO activation, while p-CREB was reduced as compared to their corresponding WT controls. These data suggest that following ischemia, IP receptor deletion contributes to memory and cognitive deficits regulated by the CREB pathway and that treatment with IP receptor agonists could be a useful target to prevent harmful consequences.