Affiliation:
1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center Sun Yat‐sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science Guangzhou China
2. Guangxi Key Laboratory of Eye Health & Guangxi Health Commission Key Laboratory of Ophthalmology and Related Systemic Diseases Artificial Intelligence Screening Technology, Department of Ophthalmology, The People's Hospital of Guangxi Zhuang Autonomous Region, Institute of Ophthalmic Diseases Guangxi Academy of Medical Sciences Nanning China
3. Yale College Yale University New Haven Connecticut USA
Abstract
AbstractNormal tension glaucoma (NTG) is referred to as a progressive degenerative disorder of the retinal ganglion cells (RGCs), resulting in nonreversible visual defects, despite intraocular pressure levels within the statistically normal range. Current therapeutic strategies for NTG yield limited benefits. Excitatory amino acid carrier 1 (EAAC1) knockout (EAAC1−/−) in mice has been shown to induce RGC degeneration without elevating intraocular pressure, mimicking pathological characteristics of NTG. In this study, we explored whether daily oral administration of melatonin could block RGCs loss and prevent retinal morphology and function defects associated with EAAC1 deletion. We also explored the molecular mechanisms underlying EAAC1 deletion‐induced RGC degeneration and the neuroprotective effects of melatonin. Our RNA sequencing and in vivo data indicated EAAC1 deletion caused elevated oxidative stress, activation of apoptosis and cellular senescence pathways, and neuroinflammation in RGCs. However, melatonin administration efficiently prevented these detrimental effects. Furthermore, we investigated the potential role of apoptosis‐ and senescence‐related redox‐sensitive factors in EAAC1 deletion‐induced RGCs degeneration and the neuroprotective effects of melatonin administration. We observed remarkable upregulation of p53, whereas NRF2 and Sirt1 expression were significantly decreased in EAAC1−/− mice, which were prevented by melatonin treatment, suggesting that melatonin exerted its neuroprotective effects possibly through modulating NRF2/p53/Sirt1 redox‐sensitive signaling pathways. Overall, our study provided a solid foundation for the application of melatonin in the management of NTG.