Chien Jia-Ying, Chou Yu-Yau, Ciou Jhih-Wei, Liu Fang-Yun, Huang Shun-Ping
Institute of Medical Sciences, Tzu Chi University, Hualien 970, Taiwan.
Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970, Taiwan.
Antioxidants (Basel). 2021 Sep 15;10(9):1466. doi: 10.3390/antiox10091466.
Nonarteritic anterior ischemic optic neuropathy (NAION) is one of the most common acute optic neuropathies that affect the over 55-year-old population. NAION causes the loss of visual function, and it has no safe and effective therapy. Bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate; CDDO-Me; RTA 402) is a semisynthetic triterpenoid with effects against antioxidative stress and inflammation in neurodegeneration and kidney disease that activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Moreover, RTA 402 is an FDA-approved compound for the treatment of solid tumors, lymphoid malignancies, melanoma, and chronic kidney disease. Omaveloxolone (RTA 408) is an activator of Nrf2 and an inhibitor of NFκB, possessing antioxidative and anti-inflammatory activities in mitochondrial bioenergetics. RTA 408 is also under clinical investigation for Friedreich ataxia (FA). In this study, a rodent anterior ischemic optic neuropathy (rAION) model induced by photothrombosis was used to examine the therapeutic effects of RTA 402 and RTA 408. Treatment with RTA402 results in antiapoptotic, antioxidative stress, anti-inflammatory, and myelin-preserving effects on retinal ganglion cell (RGC) survival and visual function via regulation of NQO1 and HO-1, reduced IL-6 and Iba1 expression in macrophages, and promoted microglial expression of TGF-β and Ym1 + 2 in the retina and optic nerve. However, these effects were not observed after RTA 408 treatment. Our results provide explicit evidence that RTA 402 modulates the Nrf2 and NFκB signaling pathways to protect RGCs from apoptosis and maintain the visual function in an rAION model. These findings indicate that RTA 402 may a potential therapeutic agent for ischemic optic neuropathy.
非动脉炎性前部缺血性视神经病变（NAION）是影响55岁以上人群的最常见急性视神经病变之一。NAION会导致视觉功能丧失，且尚无安全有效的治疗方法。巴多昔芬甲酯（2-氰基-3,12-二氧代齐墩果-1,9(11)-二烯-28-酸甲酯；CDDO-Me；RTA 402）是一种半合成三萜类化合物，在神经退行性疾病和肾脏疾病中具有抗氧化应激和抗炎作用，可激活核因子红细胞2相关因子2（Nrf2）信号通路。此外，RTA 402是一种经美国食品药品监督管理局（FDA）批准用于治疗实体瘤、淋巴恶性肿瘤、黑色素瘤和慢性肾病的化合物。奥马韦罗酮（RTA 408）是Nrf2的激活剂和NFκB的抑制剂，在线粒体生物能量学中具有抗氧化和抗炎活性。RTA 408也正在进行治疗弗里德赖希共济失调（FA）的临床研究。在本研究中，使用光血栓形成诱导的啮齿动物前部缺血性视神经病变（rAION）模型来研究RTA 402和RTA 408的治疗效果。RTA402治疗通过调节NQO1和HO-1、降低巨噬细胞中IL-6和Iba1的表达以及促进视网膜和视神经中TGF-β和Ym1 + 2的小胶质细胞表达，对视网膜神经节细胞（RGC）存活和视觉功能产生抗凋亡、抗氧化应激、抗炎和保护髓鞘的作用。然而，RTA 408治疗后未观察到这些效果。我们的结果提供了明确的证据，表明RTA 402调节Nrf2和NFκB信号通路以保护RGC免受凋亡，并在rAION模型中维持视觉功能。这些发现表明RTA 402可能是缺血性视神经病变的一种潜在治疗药物。
