Toll-like receptor 4 inhibitor protects against retinal ganglion cell damage induced by optic nerve crush in mice
Toll-like receptor 4 inhibitor protects against retinal ganglion cell damage induced by optic nerve crush in mice
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DOI：
10.1016/j.jphs.2017.02.012
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发表时间：
2017-03-01
影响因子：
3.5
通讯作者：
Hara, Hideaki
中科院分区：
文献类型：
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作者：
Nakano, Yukimichi;Shimazawa, Masamitsu;Hara, Hideaki
Toll样受体4（TLR 4）在先天性免疫应答和炎症反应中起关键作用。TAK-242（resatorvid）是一种小分子环己烯衍生物，可选择性抑制TLR 4信号通路并抑制炎症反应。在此，我们研究了TAK-242对小鼠视神经挤压（ONC）诱导轴突损伤（如青光眼）的保护作用。ONC后立即玻璃体内注射TAK-242。通过测量ONC后10天荧光金标记的视网膜神经节细胞（RGC）数量，评价TAK-242的作用。Western blotting法检测磷酸化核因子-κ B（p-NF-κ B）和磷酸化p38（p-p38）的表达水平。此外，我们通过免疫染色检查了活化的星形胶质细胞。TAK-242显著消除了与ONC相关的RGC丢失。此外，TAK-242处理显著降低了p-NF-κ B和p-p38的表达水平。此外，与溶剂处理相比，TAK-242和C34（一种TLR 4抑制剂）显著降低了神经节细胞和内网状层中的星形胶质细胞活化。这些结果表明，TAK-242不仅抑制TLR 4信号传导通路，而且抑制该通路下游的星形胶质细胞活化，表明抑制TLR 4信号传导是治疗青光眼的一种有前景的候选药物。(C)2017作者由Elsevier B. V.代表日本药理学会制作和主办。这是一个在CC BY-NC-ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Toll-like receptor 4 (TLR4) plays key roles in innate immune responses and inflammatory reactions. TAK-242 (resatorvid) is a small-molecule cyclohexene derivative that selectively inhibits TLR4 signaling pathways and suppresses inflammatory reactions. Here we investigated the protective effects of TAK-242 against optic nerve crush (ONC) which induces axonal injury like glaucoma in mice. TAK-242 was injected intravitreally immediately after ONC. The effect of TAK-242 was evaluated by measuring the number of fluorogold-labeled retinal ganglion cells (RGCs) at 10 days after ONC. Furthermore, the expression levels of phosphorylated-nuclear factor-kappa B (p-NF-kappa B) and phosphorylated-p38 (p-p38) were measured by Western blotting. In addition, we examined activated astrocytes by immunostaining. TAK-242 significantly abrogated the loss of RGCs associated with ONC. Moreover, the expression levels of p-NF-kappa B and p-p38 were significantly reduced by TAK-242 treatment. Furthermore, TAK-242 and C34, a TLR4 inhibitor, significantly reduced astrocyte activation in the ganglion cell and inner plexiform layers, compared with vehicle treatment. These findings indicate that TAK-242 inhibits not only the TLR4 signaling pathway but also astrocyte activation downstream of this pathway, suggesting that the inhibition of TLR4 signaling is a promising candidate for the treatment of glaucoma. (C) 2017 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).