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首页> 外文期刊>Experimental Eye Research >Negative impact of AQP-4 channel inhibition on survival of retinal ganglion cells and glutamate metabolism after crushing optic nerve
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Negative impact of AQP-4 channel inhibition on survival of retinal ganglion cells and glutamate metabolism after crushing optic nerve

机译：AQP-4通道抑制对视网膜神经节细胞的存活率的负面影响，裂解视神经后谷氨酸代谢

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The purpose of this study was to determine whether inhibition of aquaporin 4 (AQP4) is neuroprotective or neurodestructive after crushing the optic nerve of rats. The left optic nerves of rats were crushed, and TGN-020 (5.0 mg/kg, crush TGN-020) or its vehicle (DMSO, crush placebo) was injected intraperitoneally just after the crushing. As controls, the left optic nerves were exposed but not touched in other rats (sham controls). The retinal damages were determined by the density of retinal ganglion cells (RGCs) and the ratio of BAX/Bcl-2 on day 7. The glutamate level in the optic nerve on day 1 after the crushing was determined. The expressions of glutamine synthetase, glutamate-aspartate transporter (GLAST), and AQP4 were determined on day 3 by immunoblotting. The effects of AQP4 inhibition on the glutamate induced changes of AQP4 expression and on the glutamate uptake were determined for optic nerve astrocytes in culture. The results showed that the density of RGCs was 2040 +/- 913 cells/mm(2) (n = 6) in the sham control, and it was significantly decreased to 1072 +/- 134.3 cells/mm(2) after crushing the optic nerve (P < 0.0001, crush placebo, n = 7; Fisher). An intraperitoneal injection of TGN-020 led to a further significant (P = 0.02, Fisher) decrease of the density of RGCs to 743 +/- 371 cells/mm(2) (crush TGN-020, n = 7). The mRNA level of BAX/Bcl-2 ratio was 0.37 +/- 0.05 in the sham control (n = 6) which was significantly increased to 0.88 +/- 0.10 after crushing the optic nerve (placebo crush, n = 7; P = 0.0001, Scheffe). TGN-020 also significantly increased the BAX/Bcl-2 ratio to 1.29 +/- 0.4 (n = 6) from the crush placebo group (P = 0.04, Scheffe). Immunoblotting showed similar changes in the protein levels. The glutamate level in the optic nerve was significantly increased to 53.7 +/- 6.0 mu M/mg/protein on day 1 (n = 4) from the sham control level of 45.9 +/- 3.1 mu M/mg/protein (n = 4; P = 0.04, t test). TGN-020 significantly (P < 0.05, Scheffe) depressed the expression of glutamate metabolism-related proteins on day 3. Exposure of cultured optic nerve astrocytes to glutamate (1.0 mM, n = 4) significantly increased the expression of AQP4 (P < 0.001, Scheffe) that was depressed by TGN-020 (100 nM, n = 4). In addition, glutamate uptake was inhibited by TGN-020 at 10 nM or higher. These results indicate that an inhibition of AQP4 enhances the loss of RGCs and retinal damages after crushing the optic nerve. Inhibition of AQP4 impairs glutamate metabolism which may account in part for these neurodestructive events. (c) 2016 Elsevier Ltd. All rights reserved.
机译：本研究的目的是确定水素4（AQP4）的抑制是否是在压碎大鼠视神经后的神经保护或神经性的。在破碎后，粉碎大鼠的左视神经和TGN-020（5.0mg / kg，粉碎TGN-020）或其载体（DMSO，Crush Platebo）。作为对照，左视神经暴露但未在其他大鼠（假对照）中触及。视网膜损伤由视网膜神经节细胞（RGC）的密度和第7天的Bax / Bcl-2的比率决定。测定破碎后第1天的视神经中的谷氨酸水平。通过免疫印迹，在第3天确定谷氨酰胺合成酶，谷氨酸 - 天冬氨酸转运蛋白和AQP4的表达。 AQP4抑制对谷氨酸诱导的AQP4表达和谷氨酸摄取变化的影响，用于培养的视神经星形胶质细胞。结果表明，假手术中，RGC的密度为2040 +/- 913细胞/ mm（2）（n = 6），在压碎后，它显着降至1072 +/- 134.3细胞/ mm（2）视神经（P <0.0001，Crush Plationbo，N = 7; Fisher）。腹膜内注射TGN-020导致进一步显着（P = 0.02，Fisher）的RGCs密度降低至743 +/- 371细胞/ mm（2）（粉碎TGN-020，N = 7）。在破碎视神经（安慰剂粉碎，N = 7; P = 7; P = 0.0001，Scheffe）。 TGN-020也显着增加了来自挤压安慰剂组的Bax / Bcl-2比到1.29 +/- 0.4（n = 6）（P = 0.04，Scheffe）。免疫印迹显示出蛋白质水平的类似变化。视神经中的谷氨酸水平显着增加至第1天（n = 4）的53.7 +/- 6.0 mu m / mg /蛋白，来自假手法控制水平为45.9 +/-3.1μm/ m / mg /蛋白（n = 4; p = 0.04，t检验）。 TGN-020显着（P <0.05，Scheffe）在第3天抑制谷氨酸代谢相关蛋白的表达3.培养的视神经星形胶质细胞对谷氨酸（1.0mm，n = 4）的暴露显着增加了AQP4的表达（P <0.001由TGN-020抑制的Scheffe）（100nm，n = 4）。此外，在10nm或更高的TGN-020抑制谷氨酸摄取。这些结果表明，在压碎视神经后，抑制AQP4增强了RGCS和视网膜损伤的损失。 AQP4的抑制损害谷氨酸代谢，这些代谢可以部分地用于这些神经节病事件。 （c）2016 Elsevier Ltd.保留所有权利。

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