Oxidative stress is a state in which the balance between reactive oxygen species (ROS) produced in cells and the antioxidant defense system that detoxifies them is disrupted. 2)
ROS include the following types. 2)
The eye is an organ particularly vulnerable to oxidative stress among the whole body. Constant exposure to light energy, high oxygen consumption, and accumulation of photosensitizers (such as A2E) promote ROS production in ocular tissues. 2)Oxidative stress is currently thought to be involved in the onset and progression of more than 100 ophthalmic diseases. 2)
Oxidative stress has been shown to be involved in many major eye diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, cataracts, retinitis pigmentosa (RP), and dry eye. 2)For details, see the “Main Symptoms and Clinical Findings” section.
Oxidative stress does not present with specific symptoms on its own but manifests as symptoms of each underlying disease.
Typical oxidative damage-related findings by disease are shown below.
Glaucoma
Optic disc cupping: Apoptosis of retinal ganglion cells (RGCs) due to ROS.
Elevated intraocular pressure: Aqueous humor outflow obstruction due to oxidative damage to trabecular meshwork cells. 7)
Decreased SOD activity in aqueous humor: Confirmed as an oxidative stress indicator. 7)
Age-related macular degeneration and diabetic retinopathy
Drusen and RPE atrophy: Age-related macular degeneration-like lesions that spontaneously develop in SOD1-deficient mice. Phototoxicity due to A2E accumulation. 2)
Retinal neovascularization: Progression of exudative age-related macular degeneration due to mutual enhancement of VEGF induction and ROS.
Diabetic retinopathy: Enhanced polyol pathway, accumulation of AGEs, and excessive NADPH consumption cause a chain of oxidative damage. 4)
The following summarizes the major oxidative damage mechanisms and findings for each disease.
The oxidative stress mechanisms and major biomarkers for each disease are shown below.
| Disease | Main mechanism | Representative biomarker |
|---|---|---|
| Glaucoma | RGC degeneration / ETC impairment | Serum TAS decreased / Aqueous humor SOD↓7) |
| Age-related macular degeneration | A2E accumulation, SOD1 deficiency | Elevated 8-OHdG and MDA2) |
| Diabetic retinopathy | Polyol pathway, AGEs | Decreased GSH, NADPH consumption4) |
| Retinitis pigmentosa | Rod death → hyperoxia → ROS | Increased oxygen tension around cones6) |
| Cataract | GSH depletion · EMT | Decreased GSH · protein aggregation2) |
| Dry eye | NOX4–inflammation cycle | Increased MDA and 8-OHdG2) |
In RP, degeneration and death of rod photoreceptors occur first. When rods disappear, oxygen consumption in the outer nuclear layer decreases, leading to a local relative hyperoxic state. This excess oxygen produces ROS, which secondarily damages cones. 6) For details, see the “Pathophysiology” section.
Mitochondrial ETC complexes I and III are the main sources of ROS. 1) Dysfunction of complex I is the essence of LHON (Leber hereditary optic neuropathy) and DOA (dominant optic atrophy). 1)
With aging, the activity of endogenous antioxidant enzymes (SOD, catalase, glutathione peroxidase) declines. In the retinal pigment epithelium (RPE), the photosensitizer A2E accumulates in an age-dependent manner and produces ROS upon visible light exposure. 2)
High blood glucose produces large amounts of ROS through the following pathways. 4)
Polymorphisms and mutations in the SOD1, SOD2, and CAT genes create individual differences in antioxidant defense. 2) Nrf2 (nuclear factor erythroid 2-related factor 2) is a master transcriptional regulator of antioxidant genes, and its reduced function directly leads to increased systemic oxidative sensitivity. 2)
Although a gold-standard clinical test for directly measuring oxidative stress has not been established, the following biomarkers are used in research and clinical evaluation.
For each disease, a diagnostic approach combining oxidative markers is used.
Antioxidant supplement therapy for age-related macular degeneration is the only approach with established evidence. 2)
AREDS2 formula (daily dose): Vitamin C 500 mg, Vitamin E 400 IU, Lutein 10 mg, Zeaxanthin 2 mg, Zinc 80 mg, Copper 2 mg. It reduces the risk of progression from intermediate to advanced age-related macular degeneration by about 25%. 2)
The following antioxidants are used as adjunctive therapy for mitochondrial ETC disorders. 1)
Coenzyme Q10
NAC and Nicotinamide
N-acetylcysteine (NAC): A glutathione precursor. It has shown neuroprotective effects. 1)
Nicotinamide (vitamin B3): Supports ETC complex I through NAD⁺ supplementation. 1)
Lipoic acid/EPI-743: Regeneration support in antioxidant chain reaction. Clinical trial stage. 1)
LBP is a natural polysaccharide extracted from goji berries (Lycium barbarum). It activates the Nrf2 pathway, exhibiting antioxidant and neuroprotective effects. 3)
AREDS2 has shown efficacy in patients with intermediate age-related macular degeneration (many medium-sized drusen, or one or more large drusen). 2) Its effect in healthy eyes or patients with only early drusen has not been established. It should be used based on an ophthalmologist’s diagnosis.
Complexes I and III of the electron transport chain (ETC) embedded in the inner mitochondrial membrane produce large amounts of O₂⁻ through electron leakage. 1) Superoxide dismutase (SOD) converts O₂⁻ to H₂O₂, and catalase and glutathione peroxidase detoxify H₂O₂. 2) When this multi-step defense fails, oxidative damage cascades.
There are three isoforms of SOD. 2)
The blood-retinal barrier (BRB) is composed of the internal limiting membrane and tight junctions of retinal vascular endothelial cells. 9) Oxidative stress modifies tight junction proteins (claudin, occludin, ZO-1), disrupting the BRB and leading to inflammatory infiltration and plasma protein leakage. 4)
Activation of NF-κB and MAPK pathways amplifies BRB disruption, establishing a chronic low-grade inflammatory state called “para-inflammation.” 4) In this state, complete tissue repair does not occur, and degeneration progresses latently.
The primary lesion in RP is degeneration of rod photoreceptors due to genetic mutations, but eventually cones also degenerate. 6)
The mechanism of cone degeneration is as follows. 6)
A2E (N-retinylidene-N-retinylethanolamine), a component of RPE lipofuscin, is a photosensitizer that produces ROS upon blue light irradiation. 2) A2E also impairs lysosomal function, hindering the phagocytosis and degradation of photoreceptor outer segments by RPE. This vicious cycle promotes the progression to drusen accumulation and geographic atrophy.
Under hyperglycemia, aldose reductase converts glucose to sorbitol and fructose, consuming NADPH. 4) Since NADPH is a coenzyme for glutathione reductase, its depletion directly impairs intracellular antioxidant capacity. Simultaneously, PKC, NF-κB, and MAPK pathways are activated, increasing VEGF and TNF-α production, leading to breakdown of the blood-retinal barrier (BRB). 4)
A phase II trial of oral NAC for cone degeneration in RP is ongoing.
Schiff et al. (2021) conducted a 24-week trial in 24 RP patients with NAC starting at 600 mg/day and gradually increasing to 1800 mg/day. 6)Improvements in visual field sensitivity and OCT cone layer thickness were observed. Currently, a phase II RCT (NCT05537220, NAC Attack trial) is underway. 6)
Subretinal administration of an AAV vector encoding Nrf2 in an RP animal model showed significant protective effects on cone photoreceptors. 5)
In the AAV-NRF2-treated group, cone electroretinogram amplitudes and cone cell counts remained significantly higher compared to the untreated group. 5)Nrf2 induces a battery of antioxidant enzymes through target genes (HO-1, NQO1, GPx, GCL), making it a promising retinal protection strategy via single-gene therapy. 5)
A drug discovery platform using iPS cell-derived retinal ganglion cells (iPSC-RGC) for LHON and DOA has been established, and evaluation of candidate drugs such as NAC, CoQ10, and EPI-743 is ongoing. 1)
The multiple sclerosis drug DMF (BG-12) is a potent Nrf2 activator, and protective effects have been reported in retinal degeneration models. 2) Its potential application in ophthalmology is suggested, but evaluation of systemic side effects (lymphopenia) remains a challenge.
Interventions that enhance miR-26a-5p have been shown to increase gene expression of SOD and catalase, reducing retinal oxidative damage in diabetic retinopathy models.8)miRNA-targeted therapy is under investigation as a molecular treatment option for diabetic retinopathy.
Multiple disease-specific clinical trials using Lycium barbarum polysaccharides (LBP) are ongoing, and accumulation of long-term safety data is expected.3)
NAC is sold as a supplement, but its use for RP is currently in clinical trials, and its efficacy and safety have not been established.6)Avoid long-term high-dose self-administration, and if considering use, always consult an ophthalmologist.
