Axonal Protection by 17β-Estradiol through Thioredoxin-1 in Tumor Necrosis Factor-Induced Optic Neuropathy
Axonal Protection by 17β-Estradiol through Thioredoxin-1 in Tumor Necrosis Factor-Induced Optic Neuropathy
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DOI：
10.1210/en.2011-0046
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发表时间：
2011-07-01
期刊：
影响因子：
4.8
通讯作者：
Ueno, Satoki
中科院分区：
文献类型：
--
作者：
Kitaoka, Yasushi;Munemasa, Yasunari;Ueno, Satoki
轴突变性常导致神经元细胞体死亡。先前的研究表明，17 -雌二醇（E2）在几种类型的神经元中具有实质性的保护作用。然而，大多数研究检查了细胞体保护，17 β - e2在视网膜神经节细胞轴突变性（RGC）中的作用尚不清楚。在本研究中，我们发现视神经轴突中存在硫氧还蛋白-1 (Trx1)，并发现在玻璃体内注射TNF后，Trx1蛋白水平在离体RGC和视神经中显著降低，这在之前被证明会导致视神经变性和随后的RGC丢失。这些变化伴随着微管的紊乱和神经丝的积累，这些微管被17 β - e2阻断。17 β - e2治疗也完全消除了tnf诱导的离体RGC和视神经中Trx1蛋白水平的下降。与TNF同时注射Trx1小干扰RNA（siRNA）可显著抑制17 β - e2对视神经Trx1的诱导。Trx1 siRNA处理可阻止17 β - e2在RGC-5细胞中上调Trx1。17 β - e2可显著阻止tnf诱导的轴突损失，玻璃体内注射Trx1 siRNA可抑制这种轴突保护作用。微管和神经丝的定量也支持了这一发现。这些结果表明，Trx1在RGC小体及其轴突中的减少可能与tnf诱导的视神经轴突变性有关。17 β - e2的轴突保护作用可能与其对Trx1诱导的调控作用有关。（内分泌学152:2775-2785,2011）
Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies demonstrated the substantial protective role of 17 beta-estradiol (E2) in several types of neuron. However, most studies examined cell body protection, and the role of 17 beta-E2 in axonal degeneration of retinal ganglion cells (RGC) remains unclear. In this study, we showed the presence of thioredoxin-1 (Trx1) in the optic nerve axons and found that the levels of Trx1 protein were significantly decreased in isolated RGC and the optic nerve after intravitreal injection of TNF, which was shown previously to induce optic nerve degeneration and subsequent loss of RGC. These changes were concomitant with disorganization of the microtubules with neurofilament accumulation, which were blocked by 17 beta-E2 implantation. 17 beta-E2 treatment also totally abolished TNF-induced decreases in Trx1 protein levels in isolated RGC and the optic nerve. The induction of Trx1 by 17 beta-E2 in the optic nerve was significantly inhibited by simultaneous injection of Trx1 small interfering RNA(siRNA) with TNF. Up-regulation of Trx1 by 17 beta-E2 in RGC-5 cells was prevented by Trx1 siRNA treatment. 17 beta-E2 significantly prevented TNF-induced axonal loss, and this axonal-protective effect was inhibited by intravitreal injection of Trx1 siRNA. This finding was also supported by the quantification of microtubules and neurofilaments. These results suggest that a Trx1 decrease in RGC bodies and their axons may be associated with TNF-induced optic nerve axonal degeneration. Axonal protection by 17 beta-E2 may be related to its regulatory effect on Trx1 induction. (Endocrinology 152: 2775-2785, 2011)