Department of Ophthalmology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, 216-8511, Kanagawa, Japan.
Department of Molecular Neuroscience, St. Marianna University Graduate School of Medicine, Kawasaki, Japan.
Neurochem Res. 2019 Jul;44(7):1726-1735. doi: 10.1007/s11064-019-02804-6. Epub 2019 May 13.
Tacrolimus, a calcineurin (CaN) inhibitor, has been used for treatment of refractory allergic ocular disease, although its role in optic nerve degeneration remains to be elucidated. In this study, we investigated whether tacrolimus modulates tumor necrosis factor (TNF)-mediated axonal degeneration and whether it alters nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. Immunoblot analysis showed no significant difference in CaNAα protein levels in optic nerve on day 3, 7, or 14 after TNF injection compared with PBS injection. However, a significant increase in NFATc1 protein level was observed in optic nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. Administration of tacrolimus alone did not change the NFATc1 protein level in comparison to that observed after PBS injection. A significant increase in TNF protein level was observed in optic nerve 14 days after TNF injection and this increase was prevented by tacrolimus. Immunohistochemical analysis showed the immunoreactivity of NFATc1 to be increased in optic nerve after TNF injection. This increased immunoreactivity was colocalized with glial fibrillary acidic protein and was suppressed by tacrolimus. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss. These results suggest that tacrolimus is neuroprotective against axon loss in TNF-induced optic neuropathy and that the effect arises from suppression of the CaN/NFATc1 pathway.
他克莫司是一种钙调神经磷酸酶（CaN）抑制剂，已被用于治疗难治性过敏性眼病，但它在视神经变性中的作用仍需阐明。在这项研究中，我们研究了他克莫司是否调节肿瘤坏死因子（TNF）介导的轴突变性，以及它是否改变核因子活化 T 细胞（NFATc），CaN 信号的下游效应物。免疫印迹分析显示，与 PBS 注射相比，TNF 注射后第 3、7 或 14 天视神经中 CaNAα 蛋白水平无明显差异。然而，在 TNF 注射后 7 天观察到 NFATc1 蛋白水平显著增加。他克莫司的同时给药可消除这种增加。与 PBS 注射后观察到的水平相比，单独给予他克莫司不会改变 NFATc1 蛋白水平。在 TNF 注射后 14 天观察到 TNF 蛋白水平显著增加，他克莫司可预防这种增加。免疫组织化学分析显示，TNF 注射后视神经中 NFATc1 的免疫反应性增加。这种增加的免疫反应性与神经胶质纤维酸性蛋白共定位，并被他克莫司抑制。他克莫司治疗可显著改善 TNF 介导的轴突丢失。这些结果表明，他克莫司对 TNF 诱导的视神经病变中的轴突丢失具有神经保护作用，其作用源于对 CaN/NFATc1 途径的抑制。
