Sustained Na+/H+ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation.
Sustained Na+/H+ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation.
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DOI：
10.1371/journal.pone.0084294
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Sun D
中科院分区：
文献类型：
--
作者：
Cengiz P;Kintner DB;Chanana V;Yuan H;Akture E;Kendigelen P;Begum G;Fidan E;Uluc K;Ferrazzano P;Sun D
缺氧缺血（HI）相关的脑损伤是新生儿长期发病的主要原因。新生儿 HI 的特征之一是海马体中出现反应性星形胶质细胞增生。然而，反应性星形胶质细胞增生对新生儿 HI 后海马损伤的影响尚不完全清楚。在本研究中，我们研究了体外缺血模型（缺氧/葡萄糖剥夺和复氧，OGD/REOX）中 Na+/H+ 交换异构体 1 (NHE1) 蛋白在小鼠反应性海马星形胶质细胞功能中的作用。 2 h OGD 显着增加海马星形胶质细胞中 NHE1 蛋白表达和 NHE1 介导的 H+ 流出。 NHE1 活性在 1-5 小时 REOX 期间保持刺激状态，并在 24 小时 REOX 时恢复到基础水平。海马星形胶质细胞中 NHE1 的激活导致细胞内 Na+ 和 Ca2+ 超载。后者是通过 Na+/Ca2+ 交换的逆转介导的。海马星形胶质细胞在 1-24 小时 REOX 期间还表现出胶质递质（谷氨酸和促炎细胞因子 IL-6 和 TNFα）的强劲释放。有趣的是，用其强效抑制剂 HOE 642 抑制 NHE1 活性不仅可以减少 Na+ 超载，还可以减少海马星形胶质细胞的胶质递质释放。非竞争性兴奋性氨基酸转运蛋白抑制剂 TBOA 在阻断谷氨酸释放方面表现出类似的作用。综上所述，我们得出结论，NHE1 在维持海马星形胶质细胞 H+ 稳态中发挥着重要作用。体外缺血后 NHE1 活性的过度刺激会破坏 Na+ 和 Ca2+ 稳态，从而减少 Na+ 依赖性谷氨酸的摄取，并促进反应性星形胶质细胞释放谷氨酸和细胞因子。因此，阻断反应性星形胶质细胞中 NHE1 的持续激活可能会在 HI 后提供神经保护。
Hypoxia ischemia (HI)-related brain injury is the major cause of long-term morbidity in neonates. One characteristic hallmark of neonatal HI is the development of reactive astrogliosis in the hippocampus. However, the impact of reactive astrogliosis in hippocampal damage after neonatal HI is not fully understood. In the current study, we investigated the role of Na+/H+ exchanger isoform 1 (NHE1) protein in mouse reactive hippocampal astrocyte function in an in vitro ischemia model (oxygen/glucose deprivation and reoxygenation, OGD/REOX). 2 h OGD significantly increased NHE1 protein expression and NHE1-mediated H+ efflux in hippocampal astrocytes. NHE1 activity remained stimulated during 1–5 h REOX and returned to the basal level at 24 h REOX. NHE1 activation in hippocampal astrocytes resulted in intracellular Na+ and Ca2+ overload. The latter was mediated by reversal of Na+/Ca2+ exchange. Hippocampal astrocytes also exhibited a robust release of gliotransmitters (glutamate and pro-inflammatory cytokines IL-6 and TNFα) during 1–24 h REOX. Interestingly, inhibition of NHE1 activity with its potent inhibitor HOE 642 not only reduced Na+ overload but also gliotransmitter release from hippocampal astrocytes. The noncompetitive excitatory amino acid transporter inhibitor TBOA showed a similar effect on blocking the glutamate release. Taken together, we concluded that NHE1 plays an essential role in maintaining H+ homeostasis in hippocampal astrocytes. Over-stimulation of NHE1 activity following in vitro ischemia disrupts Na+ and Ca2+ homeostasis, which reduces Na+-dependent glutamate uptake and promotes release of glutamate and cytokines from reactive astrocytes. Therefore, blocking sustained NHE1 activation in reactive astrocytes may provide neuroprotection following HI.
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影响因子：
15.3
作者：
Brambilla, R;Bracchi-Ricard, V;Hu, WH;Frydel, B;Bramwell, A;Karmally, S;Green, EJ;Bethea, JR
通讯作者：
Bethea, JR
DOI：
10.1007/978-1-62703-520-0_21
发表时间：
2013
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Chen SH;Oyarzabal EA;Hong JS
通讯作者：
Hong JS
影响因子：
3.8
作者：
Bevensee, MO;Weed, RA;Boron, WF
通讯作者：
Boron, WF
影响因子：
6.2
作者：
BOYARSKY, G;RANSOM, B;BORON, WF
通讯作者：
BORON, WF
影响因子：
6.6
作者：
Cengiz, Pelin;Kleman, Neil;Sun, Dandan
通讯作者：
Sun, Dandan