**Background:** Optic nerve diseases, including glaucoma, Leber's hereditary optic neuropathy (LHON), anterior ischemic optic neuropathy (AION), and optic neuritis, are characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible vision loss. Glaucoma is the most prevalent, affecting approximately 3.54% of the population aged 40–80 years worldwide. LHON has a prevalence of 2–4 in 100,000 for complete penetrance, while AION (nonarteritic) has a prevalence of approximately 102.87 in 100,000 in individuals over 40. Optic neuritis has a prevalence of around 115 in 100,000 in the age range of 20–45 years. Current treatments are limited and primarily focus on managing risk factors (e.g., intraocular pressure in glaucoma) or providing symptomatic relief (e.g., corticosteroids in optic neuritis). There is a critical need for novel therapeutic strategies. This narrative review aims to explore the role of oxidative stress in the pathophysiology of these diseases and evaluate its potential as a therapeutic target.
**Methods:** This is a narrative review of the literature. The authors synthesized findings from preclinical studies (animal models and cell cultures) and clinical investigations to describe the mechanisms of oxidative stress in optic nerve diseases. They focused on four major conditions: glaucoma, LHON, AION, and optic neuritis, and also briefly discussed traumatic, compressive, infiltrative, congenital, and nutritional/toxic optic neuropathies. The review covers general mechanisms of nitro-oxidative stress, including the generation of reactive oxygen and nitrogen species (ROS/RNS), oxidative damage to DNA, proteins, and lipids, and the role of antioxidant defense systems. For each disease, the authors detail the specific involvement of oxidative stress in pathogenesis and review potential antioxidant therapeutic agents.
**Key Results:** The review presents extensive evidence linking oxidative stress to RGC damage across multiple optic nerve diseases. In glaucoma, studies show elevated levels of oxidative stress biomarkers such as 8-hydroxy-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA) in plasma and aqueous humor, along with decreased total antioxidant status (TAS). A meta-analysis confirmed MDA as a significant biomarker. The pathogenesis involves ROS-induced trabecular meshwork dysfunction, leading to elevated intraocular pressure, and direct RGC apoptosis via pathways including ASK-1/p38/JNK, NF-kB, and mitochondrial dysfunction. In LHON, mitochondrial DNA mutations (m.3460G>A, m.11778G>A, m.14484T>C) cause complex I deficiency, leading to increased ROS production and RGC apoptosis. Studies report elevated 8-OHdG and reduced glutathione reductase activity in LHON cells. In AION, ischemia/reperfusion injury triggers ROS overproduction via NOX2, xanthine oxidase, and dysfunctional electron transport chain. A study in pigs showed that after only 12 minutes of ocular ischemia and 20 hours of reperfusion, endothelial dysfunction, retinal edema, and RGC loss occurred. In optic neuritis, ROS are implicated in myelin phagocytosis, blood-brain barrier disruption, and T-cell infiltration. The review highlights several promising antioxidant compounds tested in preclinical models: resveratrol (activates SIRT1/Nrf2, reduces RGC loss in glaucoma and AION models), idebenone (approved for LHON, acts as an electron carrier and NOX2 inhibitor), EPI-743 (targets NQO1, showed vision improvement in 4/5 LHON patients), astaxanthin (activates Nrf2, reduces RGC loss in glaucoma and AION models), and dimethyl fumarate (Nrf2 activator, reduces optic neuritis severity in EAE models). However, many potential antioxidants have failed to progress beyond phase II clinical trials due to issues with bioavailability, tissue targeting, and toxicity.
**Clinical Implications:** The review underscores the significant potential of targeting oxidative stress as a therapeutic strategy for optic nerve diseases. The approval of idebenone for LHON represents a successful clinical translation. For glaucoma, the high prevalence and economic burden (over £300 million in the UK in 2002) suggest that cost-effective antioxidant therapies could have a major public health impact. However, the authors caution that many preclinical successes have not translated to clinical benefit, likely due to pharmacokinetic limitations and the complexity of oxidative stress pathways. They recommend careful planning of clinical trials, including adaptive designs, and the development of efficient drug delivery systems. The review concludes that while oxidative stress is a suitable therapeutic target, further research is needed to overcome translational barriers and bring effective antioxidant treatments to patients with optic nerve diseases.