n-3 Polyunsaturated Fatty Acids Reduce Neonatal Hypoxic/Ischemic Brain Injury by Promoting Phosphatidylserine Formation and Akt Signaling
n-3 Polyunsaturated Fatty Acids Reduce Neonatal Hypoxic/Ischemic Brain Injury by Promoting Phosphatidylserine Formation and Akt Signaling
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n-3 多不饱和脂肪酸通过促进磷脂酰丝氨酸形成和 Akt 信号传导减少新生儿缺氧/缺血性脑损伤
DOI：
10.1161/strokeaha.115.010815
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发表时间：
2015
期刊：
影响因子：
8.3
通讯作者：
Chen Jun
中科院分区：
文献类型：
--
作者：
Zhang Wenting;Liu Jia;Hu Xiaoming;Li Peiying;Leak Rehana K.;Gao Yanqin;Chen Jun
背景与目的ω-3多不饱和脂肪酸（n-3 PUFAs）可减轻新生儿缺氧/缺血（H/I）脑损伤，但其机制尚不完全清楚。本研究测试的假设，即N-3 PUFAs增强Akt依赖的促生存信号通过促进磷脂酰丝氨酸的生物合成在neuronal cell membranes.MethodsDietaryn-3 PUFA补充启动妊娠的第二天在大坝。H/I诱导7日龄大鼠幼仔同侧颈总动脉闭塞，然后缺氧（8%氧气2.5小时）。在H/I后评估神经学结果、脑组织损失、细胞死亡和信号事件的激活。n-3 PUFAs（二十二碳六烯酸和二十碳五烯酸）对氧-葡萄糖剥夺诱导的细胞死亡和保护的基本机制的影响也在原代皮层神经元culture.Resultsn-3 PUFAs减少脑组织损失后7天H/I和改善神经功能的结果，而抑制PI 3 K/Akt信号LY 294002部分废除了这种神经保护作用。二十二碳六烯酸/二十碳五烯酸还通过Akt促存活途径在体外预防缺血性神经元死亡。此外，二十二碳六烯酸/二十碳五烯酸增加生产的磷脂酰丝氨酸，主要的膜结合磷脂，缺血后，在体外和体内。减少膜磷脂酰丝氨酸的shRNA介导的敲低磷脂酰丝氨酸合成酶-1衰减Akt激活和神经元存活后，二十二碳六烯酸/二十碳五烯酸治疗的氧-葡萄糖deprivationmodel.Conclusionsn-3 PUFAs强大的保护H/I诱导的脑损伤新生儿通过激活Akt促生存途径受损的神经元。此外，n-3 PUFA促进膜磷脂酰丝氨酸的形成，从而促进Akt活性并改善细胞存活。
Background and PurposeOmega-3 polyunsaturated fatty acids (n-3PUFAs) attenuate neonatal hypoxic/ischemic (H/I) brain damage, but the underlying mechanisms are not fully understood. This study tested the hypothesis thatn-3PUFAs enhance Akt-dependent prosurvival signaling by promoting the biosynthesis of phosphatidylserine in neuronal cell membranes.MethodsDietaryn-3PUFA supplementation was initiated on the second day of pregnancy in dams. H/I was induced in 7-day-old rat pups by ipsilateral common carotid artery occlusion followed by hypoxia (8% oxygen for 2.5 hours). Neurological outcomes, brain tissue loss, cell death, and the activation of signaling events were assessed after H/I. The effects ofn-3PUFAs (docosahexaenoic acid and eicosapentaenoic acid) on oxygen-glucose deprivation–induced cell death and the underlying mechanism of protection were also examined in primary cortical neuron cultures.Resultsn-3PUFAs reduced brain tissue loss at 7 days after H/I and improved neurological outcomes, whereas inhibition of PI3K/Akt signaling by LY294002 partially abrogated this neuroprotective effect. Docosahexaenoic acid/eicosapentaenoic acid also prevented ischemic neuronal death through the Akt prosurvival pathway in vitro. Furthermore, docosahexaenoic acid/eicosapentaenoic acid increased the production of phosphatidylserine, the major membrane-bound phospholipids, after ischemia both in vitro and in vivo. A reduction in membrane phosphatidylserine by shRNA-mediated knockdown of phosphatidylserine synthetase-1 attenuated Akt activation and neuronal survival after docosahexaenoic acid/eicosapentaenoic acid treatment in the oxygen-glucose deprivation model.Conclusionsn-3PUFAs robustly protect against H/I-induced brain damage in neonates by activating Akt prosurvival pathway in compromised neurons. In addition,n-3PUFAs promote the formation of membrane phosphatidylserine, thereby promoting Akt activity and improving cellular survival.