Prostaglandin FP receptor inhibitor reduces ischemic brain damage and neurotoxicity.
Prostaglandin FP receptor inhibitor reduces ischemic brain damage and neurotoxicity.
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DOI：
10.1016/j.nbd.2012.06.003
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发表时间：
2012-10
影响因子：
6.1
通讯作者：
Dore, Sylvain
中科院分区：
文献类型：
--
作者：
Kim, Yun Tai;Moon, Sang Kwan;Maruyama, Takayuki;Narumiya, Shuh;Dore, Sylvain
据报道，前列腺素等生物活性脂质在急性和慢性神经系统疾病中具有多种细胞保护或毒性特性。 PGF2α及其受体（FP）在缺血性脑损伤发病机制中的作用尚不清楚。考虑到这种 G 蛋白偶联受体与细胞内钙调节有关，我们假设其阻断将具有保护性。我们在体内和体外中风模型中使用 FP 拮抗剂 (AL-8810) 和 FP 受体敲除 (FP−/−) 小鼠。在永久性大脑中动脉闭塞 (pMCAO) 48 小时后，用 AL-8810 治疗的小鼠的神经功能障碍减少了 35.7 ± 6.3%，梗死体积比用媒介物治疗的小鼠减少了 36.4 ± 6.0%； FP−/− 小鼠在 pMCAO 后的结果也有所改善。阻断 FP 受体还可以防止切片培养物中氧糖剥夺 (OGD) 诱导的细胞死亡和活性氧形成。最后，我们发现 FP 受体激动剂剂量依赖性地增加培养神经元中的细胞内 Ca2+ 水平，并确定 FP 相关的 Ca2+ 信号传导与兰尼碱受体信号传导相关。这些结果表明FP受体参与脑缺血引起的损伤，并可以促进治疗中风和急性神经退行性疾病的药物的开发。
Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles of PGF2α and its receptor (FP) are not clear in the pathogenesis of ischemic brain injury. Considering that this G-protein coupled receptor has been linked to intracellular calcium regulation, we hypothesized that its blockade would be protective. We used FP antagonist (AL-8810) and FP receptor knockout (FP−/−) mice in in vivo and in vitro stroke models. Mice that were treated with AL-8810 had 35.7 ± 6.3% less neurologic dysfunction and 36.4 ± 6.0% smaller infarct volumes than did vehicle-treated mice after 48 hours of permanent middle cerebral artery occlusion (pMCAO); FP−/− mice also had improved outcomes after pMCAO. Blockade of the FP receptor also protected against oxygen-glucose deprivation (OGD)-induced cell death and reactive oxygen species formation in slice cultures. Finally, we found that an FP receptor agonist dose dependently increased intracellular Ca2+ levels in cultured neurons and established that FP-related Ca2+ signaling is related to ryanodine receptor signaling. These results indicate that the FP receptor is involved in cerebral ischemia-induced damage and could promote development of drugs for treatment of stroke and acute neurodegenerative disorders.
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影响因子：
8.3
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影响因子：
3.3
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影响因子：
3.3
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