TSPO activation modulates the effects of high pressure in a rat ex vivo glaucoma model.
TSPO activation modulates the effects of high pressure in a rat ex vivo glaucoma model.
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DOI：
10.1016/j.neuropharm.2016.09.001
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发表时间：
2016-12
影响因子：
4.7
通讯作者：
Izumi Y
中科院分区：
文献类型：
--
作者：
Ishikawa M;Yoshitomi T;Covey DF;Zorumski CF;Izumi Y
我们之前报道过，在离体大鼠视网膜中，血压升高会引起轴突肿胀，并促进神经类固醇异孕酮（AlloP）的合成。外源性应用AlloP可减轻轴突肿胀，提示神经类固醇对青光眼压力性损伤具有神经保护作用，尽管神经类固醇形成的机制尚未明确。本研究的目的是确定同种异体蛋白的合成是否涉及转运蛋白18kd （TSPO）的激活，以及TSPO是否调节压力性视网膜损伤。将离体大鼠视网膜暴露于不同压力（10、35或75 mmHg）下24小时。采用实时定量RT-PCR、ELISA、免疫组织化学和LC-MS/MS检测TSPO、5α-还原酶（5aRD）和AlloP的表达。我们还研究了TSPO配体对同种异体蛋白合成和视网膜损伤的影响。在这个急性模型中，实时定量RT-PCR和ELISA分析显示，血压升高促进了TSPO的表达。同样，这些方法也检测到5aRD增强（主要是II型），在视网膜神经节细胞（RGC）和内核层（INL）中观察到。Atriol是一种TSPO拮抗剂，当血压升高时，可以抑制压力介导的AlloP合成，并在内视网膜引起更严重的组织学变化。PK11195是一种TSPO配体，可以促进同种异体蛋白的合成，显著减少压力介导的视网膜变性。这些结果表明，在离体青光眼模型中，同种异体素的合成是由TSPO和5aRD的顺序激活诱导的，TSPO激动剂可能作为预防压力性视网膜损伤的潜在治疗药物。
We previously reported that elevated pressure induces axonal swelling and facilitates the synthesis of the neurosteroid, allopregnanolone (AlloP), in the ex vivo rat retina. Exogenously applied AlloP attenuates the axonal swelling, suggesting that the neurosteroid plays a neuroprotective role against glaucomatous pressure-induced injuries, although mechanisms underlying neurosteroidogenesis have not been clarified. The aim of this study was to determine whether AlloP synthesis involves activation of translocator protein 18 kD (TSPO) and whether TSPO modulates pressure-induced retinal injury. Ex vivo rat retinas were exposed to various pressures (10, 35, or 75 mmHg) for 24 hours. Expression of TSPO, 5α-reductase (5aRD), and AlloP was examined by quantitative real-time RT-PCR, ELISA, immunohistochemistry, and LC-MS/MS. We also examined the effects of TSPO ligands on AlloP synthesis and retinal damage. In this acute model, quantitative real-time RT-PCR and ELISA analyses revealed that elevated pressure facilitated TSPO expression. Similarly, these methods also detected enhanced 5aRD (mostly type II), which was observed in retinal ganglion cells (RGC) and the inner nuclear layer (INL). Atriol, a TSPO antagonist, suppressed pressure mediated AlloP synthesis and induced more severe histological changes in the inner retina when combined with elevated pressure. PK11195, a TSPO ligand that facilitates AlloP synthesis by itself, remarkably diminished pressure-mediated retinal degeneration. These results suggest that AlloP synthesis is induced by sequential activation of TSPO and 5aRD in an ex vivo glaucoma model, and that TSPO agonists may serve as potential therapeutic agents for the prevention of pressure-induced retinal damage.