中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (1): 87-93.doi: 10.4103/1673-5374.344831

• 综述:视神经损伤修复保护与再生 • 上一篇    下一篇

正常眼压性青光眼视网膜神经节细胞死亡的调控机制及潜在治疗方法

  

  • 出版日期:2023-01-15 发布日期:2022-06-16

Regulatory mechanisms of retinal ganglion cell death in normal tension glaucoma and potential therapies

Wen-Cui Shen1, Bing-Qing Huang2, *, Jin Yang1, *   

  1. 1Tianjin Eye Hospital & Eye Institute, Tianjin Key Laboratory of Ophthalmology and Visual Science, Nankai University, Tianjin, China; 2State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
  • Online:2023-01-15 Published:2022-06-16
  • Contact: Bing-Qing Huang, PhD, huangbingqing@ihcams.ac.cn; Jin Yang, PhD, yangjin979@163.com.
  • Supported by:
    This work was supported in part by the Technology Foundation of Tianjin Eye Hospital of China, No. YKQN1911 (to WCS); Tianjin Health Science and Technology Project, No. TJWJ2021QN071 (to WCS); Translational Medicine Research Project of State Key Laboratory of Experimental Hematology of China, No. Z21-11 (to BQH).

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摘要：

正常眼压性青光眼是一种多因素的视神经病变，其特征是眼压正常、进行性视网膜神经节细胞死亡和青光眼性视野丧失。最近已经有一些研究描述了正常眼压性青光眼发病的潜在机制，而且还有研究报道，除了控制眼压外，神经保护和减少视网膜神经节细胞病变可能是正常眼压性青光眼的有益疗法。①该篇综述总结了调节正常眼压性青光眼的视网膜神经节细胞死亡的主要机制，从自噬、谷氨酸神经毒性、氧化应激、神经炎症和免疫以及血管收缩几个方面进行阐述分析。②视网膜缺氧和轴突损伤可诱导自噬，在此过程中，缺血可导致视神经素突变和核转录因子κB通路激活。③在视网膜神经节细胞中，谷氨酸神经毒性是由谷氨酸过度刺激NMDA膜受体引起的，并诱导进行性青光眼性视神经病变。④氧化应激也参与了正常眼压性青光眼相关的青光眼性视神经病变，一方面，氧化应激通过ASK-JNK途径损害视网膜神经节细胞线粒体和DNA的功能；另一方面，氧化应激上调视网膜神经节细胞的炎症和免疫反应。⑤内皮素1可导致正常眼压性青光眼相关的内皮功能紊乱和眼血流损伤，促进血管痉挛和青光眼性视神经病变。⑥最后，文章还讨论了视网膜神经节细胞保护的潜在疗法和研究进展，其中主要包括TBK1抑制剂调控自噬、NMDA受体拮抗剂调抑制谷氨酸盐毒性、ASK抑制剂调节线粒体功能、抗氧化剂抑制氧化应激过程等。⑦因此，在正常眼压性青光眼中，存在不同且互相交错的网络调控视网膜神经节细胞死亡，并有针对视神经保护的相关治疗靶点，这为正常眼压性青光眼的发病机制和治疗的相关研究都提供了依据。

https://orcid.org/0000-0002-8489-6064 (Bing-Qing Huang); https://orcid.org/0000-0001-9238-730X (Jin Yang)

关键词: 自噬, et-1, 谷氨酸神经毒性, 抑制剂, 正常眼压性青光眼, 神经炎症, 神经再生, 氧化应激, 视网膜神经节细胞, 血管收缩

Abstract: Normal tension glaucoma (NTG) is a multifactorial optic neuropathy characterized by normal intraocular pressure, progressive retinal ganglion cell (RGC) death, and glaucomatous visual field loss. Recent studies have described the mechanisms underlying the pathogenesis of NTG. In addition to controlling intraocular pressure, neuroprotection and reduction of RGC degeneration may be beneficial therapies for NTG. In this review, we summarized the main regulatory mechanisms of RGC death in NTG, including autophagy, glutamate neurotoxicity, oxidative stress, neuroinflammation, immunity, and vasoconstriction. Autophagy can be induced by retinal hypoxia and axonal damage. In this process, ischemia can cause mutations of optineurin and activate the nuclear factor-kappa B pathway. Glutamate neurotoxicity is induced by the over-stimulation of N-methyl-D-aspartate membrane receptors by glutamate, which occurs in RGCs and induces progressive glaucomatous optic neuropathy. Oxidative stress also participates in NTG-related glaucomatous optic neuropathy. It impairs the mitochondrial and DNA function of RGCs through the apoptosis signal-regulating kinase-JUN N-terminal kinase pathway. Moreover, it increases inflammation and the immune response of RGCs. Endothelin 1 causes endothelial dysfunction and impairment of ocular blood flow, promoting vasospasm and glaucomatous optic neuropathy, as a result of NTG. In conclusion, we discussed research progress on potential options for the protection of RGCs, including TANK binding kinase 1 inhibitors regulating autophagy, N-methyl-D-aspartate receptor antagonists inhibiting glutamate toxicity, ASK1 inhibitors regulating mitochondrial function, and antioxidants inhibiting oxidative stress. In NTG, RGC death is regulated by a network of mechanisms, while various potential targets protect RGCs. Collectively, these findings provide insight into the pathogenesis of NTG and potential therapeutic strategies.

Key words: autophagy, endothelin 1, glutamate neurotoxicity, inhibitor, nerve regeneration, neuroinflammation, normal tension glaucoma, oxidative stress, retinal ganglion cell, vasoconstriction