The optic neuropathies are various groups of disorders characterized by visual loss resulting from optic nerve dysfunction. According to the World Health Organization, a form of optic neuropathy is responsible for approximately 15% of the global burden of visual impairment . The importance of oxidative stress in the etiopathogenesis of neurological diseases—like multiple sclerosis; Alzheimer’s, Parkinson’s , and Huntington’s diseases ; and Graves’ ophthalmopathy  -is well known. Iyer et al.  report the role of oxidative stress in the etiopathogenesis of Leber’s hereditary optic neuropathy, and antioxidants are recommended for treating this disease. In animal studies, significant differences in MDA, 8-OHdG, GSH, and SOD, along with interleukin-1β, tumor necrosis factor-alpha, and myeloperoxidase levels were reported in methanol-induced optic neuropathy. They also observe that these changes can be prevented with an effective anti-inflammatory and antioxidant therapy . However, clinical studies on the connection between optic neuropathy and oxidative damage mostly focus on glaucoma, a specific form of optic neuropathy. Oxidative damage plays a key role in the common pathway of various glaucoma types [2, 21]. It is a valid working hypothesis that a special form of ischemia is the reason for ganglion cell death in glaucoma . On the other hand, the mechanisms responsible for ischemic optic neuropathy include oxidative stress, excitotoxicity, angiogenesis, neuroinflammation, and apoptosis following retinal ischemia .
A random-effects meta-analysis of Parkinson’s disease, conducted by Wei et al., has shown that patients with Parkinson’s have significantly higher levels of blood oxidative stress markers-ferritin, 8-OHdG, nitrite, and MDA-compared with healthy subjects. In contrast, concentrations of UA, catalase, tGSH, and total cholesterol are significantly lower in Parkinson’s patients compared with healthy subjects. Interestingly, blood levels of Mn, Cu, Zn, Fe, SOD, albumin, GSH, vitamin E, Cp, triglycerides, LDL-cholesterol, lactoferrin, transferrin, and HDL-cholesterol show no significant differences between Parkinson’s patients and healthy subjects. In peripheral blood, significant heterogeneity is reported for 21 of the 22 oxidative stress markers, except for lactoferrin . In comparing the blood biochemistry and oxidative stress parameters between the patient and control groups in the present study, only vitamin E and MDA showed statistically significant increments. This finding is highly concordant with both the meta-analysis of Wei et al. and a similar study carried out by the first author and another research group in 2010. 31 healthy individuals and 160 glaucoma patients were included in the latter multicenter case–control study. SOD and GSH were found to be decreased, and MDA and vitamins A and E were found to be increased, in the patient group. For vitamin E and MDA, this increase was determined to be very significant . Serum MDA levels are increased, not only in the cataract patients , but also in primary angle closure glaucoma (PACG) patients . These reports are significant regarding nerve tissue damage, for MDA is an oxidation degradation product and is the most important marker of lipid oxidative damage [1, 24]. The increased vitamin E levels reported in patients with optic neuropathy can be explained with the existence of sensitive mechanisms for regulating tissue levels vitamin E. Discovery of membrane receptors and cytosolic transfer proteins specifically tuned to the tocopherol transfer protein, α-tocopherol, strengthens the thesis that vitamin E derivatives act as neurohormones and initiate various intracellular conduction pathways with a lock-and-key model 25. In addition to their antioxidative properties, however, molecules of the vitamin E family exert neuroprotective and anti-inflammatory activities [25, 26]. Due to the antioxidative and neuroprotective potential of vitamin E, protecting lipids from membrane peroxidation, vitamin E supplementation has been suggested as beneficial in many pathologies, including those grounded in neural tissue. Reviewing a large number of meta-analysis, epidemiological, and prospective cohort studies, as well as randomized clinical trials on plasma vitamin E levels and the subsequent risk of developing Alzheimer’s disease, Browne et al.  concluded that reduced plasma vitamin E status has been associated with increased future risk of developing Alzheimer’s, and vitamin E supplementation has been offered for this disease.
All those articles also imply that the significant and very significant interactions between vitamin E, MDA and cholesterol observed in the present study are noteworthy. In a systematic review of 14 observational and seven randomized controlled clinical trials, vitamin E was found to correlate significantly with MDA and SOD . In a clinical study carried out in Africa, patients demonstrated higher plasma atherogenic indices and higher levels of total cholesterol, along with at least 1,334-fold of MDA concentration above normal levels. Also, in the same patients, the higher atherogenic plasmatic index significantly (p<0.05) increased with MDA concentration . Sole supplementation of vitamin E, on the other hand, may act as a stimulant to HMG-CoA activity and, therefore, demonstrate hypercholesterolemic activity . The hypocholesterolemic effects of vitamin E, however, are also well known via several membrane proteins  and SREBP/SCAP system . Moreover, significant positive correlation between vitamin E and total cholesterol in lung cancer patients was reported .
In correlation analysis between the clinical and bochemical data, significant correlations between color vision and age, as well as between RNFL and vision, are consistent with current clinical knowledge and the extant literature . Prominent results related with vitamins E and B12 were observed in the correlation analysis of oxidative stress parameters with clinical and biochemical data, as well as other oxidative stress parameters in the patient group. Vitamin E was found to significantly correlated with IOP in NAION patients. Engin et al. have reported that α-tocopherol exert vasoregulatory effects on the retina, which is important for avoiding ischemia . Another parameter significantly corelated with IOP -UA- is also known to exert protective effects against oxidative damage in the central nervous system. Negative association between UA levels and disease severity has been shown in PACG  patients. Significantly higher UA levels, however, have been reported in NTG patients .
Along with MDA and cholesterol, Vitamin A was the third molecule to show very significant correlation with vitamin E in this study. Vitamins A and E are fat soluble vitamins absorbed in the small intestine through different, but interrelated, mechanisms. Similar to vitamin E, vitamin A possess antioxidative properties and the ability to regulate gene expression by interacting with the retinoic acid receptors and the retinoid X receptors, acting as transcription factors . An enhanced dietary intake of both vitamin E and A have been reported to be associated with reduced Alzheimer’s risk . Furthermore, the antioxidant properties of vitamin E is shown to help to prevent vitamin A oxidation and, therefore, serve to enhance vitamin A absorption when there is concomitant consumption of vitamin A and E . Negative correlation of vitamin A with glucose was found to be weak but significant. It is evident that hepatic glucose and lipid metabolism are regulated by vitamin A metabolites at many different levels .
A significant negative correlation between tGSH and SOD have been observed in this study. After screening 12 articles with 646 long-lived participants and 1,052 controls Belenguer-Varea et al. have presented significantly lower SOD and higher glutathione reductase activities in elderly individuals , concordant with the present results. Low intake of folate and vitamin B12 has also been found to be associated with reduced levels of tGSH in patients with type 2 diabetes mellitus . In this study, tGSH showed negative and positive significant correlations with both vitamin B12 and MMA, respectively. MMA was also significantly correlated with Cp. Cp is the carrier of the Cu++ ion, which is a cofactor of oxidation enzymes, and its deficiency affects optic nerve function, and the nervous system in general . Vitamin B12 is another antioxidant whose deficiency causes antioxidant response disorders related to the glutathione system. However, vitamin B12 deficiency can be difficult to diagnose. Due to the lack of a clear association between serum vitamin B12 and its deficiency, it has been proposed that functional vitamin B12 deficiency can occur at any serum level. Morover, it was stated that normal or high serum vitamin B12 levels can sometimes be seen in a vitamin B12 deficient state . Vitamin B12 is required for MMA to be converted to succinyl-CoA. Therefore, a deficiency of vitamin B12 at the tissue level can lead to elevation of MMA . In certain circumstances, however, serum vitamin B12 and MMA levels may not be correlated, and high levels of MMA has been identified as a better indicator of B12 deficiency than the actual serum B12 level itself . On the other hand, vitamin B12 deficiency is reported to be related to both symptomatic and asymptomatic small fiber loss and retinal nerve fiber thickness in glaucomatous other non-glaucomatous optic neuropathies , which highlights the very significant negative correlation of vitamin B12 with the c/d ratio. In this study, MD showed significant negative correlations with both MMA and Cp. It has been reported on the association of copper deficiency with the development of concomitant neurologic deficits manifested as peripheral neuropathies and myeloneuropathy indistinguishable from the clinical and T2-weighted MRI findings seen in vitamin B12 deficiency .
MDA is an important end product for lipid peroxidation and 8-OHdG is a critical marker for DNA damage, and increases in both MDA an 8-OHdG, implying oxidative damage in lipid tissue, have been reported in PACG  patients. Although MDA and 8-OHdG are products of lipid oxidation, damage can occur at various organelles and levels, depending on the composition of the tissue or organ from which the oxidation originates. On the other hand, these two compounds are elements of a complex mechanism and interact with each other. MDA is a known mutagenic and carcinogenic  and reacts physiologically with forming deoxyguanosines, including 8-OHdG . Despite MDA being significantly increased among the NAION patients in the present study, neither increase nor correlations of 8-OHdG were statistically significant, -except for a negative correlation with glucose. Although 8-OHdG are identified as important biomarkers in the pathogenesis process of type 2 diabetes mellitus, understandably enhances in blood level as the disease progress . Because reviewing clinical studies on 8-OHdG currently generates interest concerning whether it is an actual marker of DNA damage in lipid tissue due to oxidative stress, variable reports are encountered. 8-OHdG has been reported to be increased in the plasma of Leber’s hereditary optic neuropathy  and in both the aqueous humor and plasma of POAG patients . Yuki et al., however, studied urine samples in NTG cases and reported decreased urine 8-OHdG/creatinine ratio, which is concordant with the present research .
In a recent study among 18 newly diagnosed NAION patients and 17 healthy subjects, along with serum total oxidant and antioxidant status, solely advanced oxidation protein products were studied, and no significant differences were reported between the patients and the control group . The present study is much more comprehensive, with a larger NAION series. Furthermore, the researchers have specifically focused on the products and defense dynamics of lipid oxidation using more sophisticated assay techniques. This study not only obtained clear information regarding oxidative damage and antioxidant response in a frequent form of optic neuropathy, but it also pointed out specific interactions between neuromodulators, like vitamin E, and intracellular signaling and regulation mechanisms. Better reading of these connections and focusing on oxidative nerve tissue damage may aid the development of more suitable diagnosis, follow-up and treatment criteria and strategies, alongside a fuller understanding of NAION.