Sorbitol-linked osmotic stress in lens epithelium cells has recently been reported to induce ER stress that leads to the generation of ROS.

Since opacities do not rapidly form in vitro when rat lenses are with glucose, xylose was substituted for glucose because xylose is more rapidly reduced to xylitiol by AR. Similarly, control lenses cultured for 24 hr in TC fructose media remained clear. This expression was reduced in lenses treated with either compounds 4 , 8 , or AL Samples were loaded onto the gel in different order than the graph.

Therefore, fructose and xylose lanes had to be cut and flipped horizontally using Adobe Photoshop. Pixel intensity was analyzed by ImageJ software. Age-related cataracts are considered to be multi-factorial in origin, with ROS mediated oxidative damage considered to be a common factor [7] , [35] , [36].

Iron concentrations also increase in the ageing lens and a major route to damaging ROS formation is through the Fenton reaction, which produces hydroxyl radicals using iron as the catalyst [37].

In the present study two multi-functional antioxidants 4 and 8 , which independently scavenge free radicals and chelate iron [25] , [38] , [39] , [40] , [41] , [42] have been evaluated for their ability to delay cataract formation in two animal models where oxidative stress has been reported [10] , [11] , [12] , [13] , [19] , [20].

Rat exposed to at least 2 Gy of whole head gamma radiation form cataracts after a dose-dependent latency period [11] , [12] , [13]. Of these reactive oxygen species, the hydroxyl radicals are considered to be the primary initiators of oxidative damage, while superoxide and hydrogen peroxide typically lack the sufficient reactivity to oxidize critical biological macromolecules [15].

Gamma radiation-generated superoxide has also been shown to cause release of iron from ferritin, which can enhance production of hydroxyl radicals through the Fenton and Haber-Weiss reactions leading to DNA, protein, and lipid damage [14]. As expected, 15 Gy of whole head irradiation resulted in damage to the salivary glands.

Since pantethine has been used as a radioprotectant, these compounds could potentially be co-administered with pantethine to synergistically protect against radiation. However, further studies are required to confirm this observation. Radiation damage to the lens is typically first observed as PSC opacities [43] , [44].

In pigmented animals, PSC opacities were observed after a latency period of eight weeks, compared to the 5 weeks typically seen in albino animals [27]. This extended latency period may be due in part to the pigment of the iris, but may also reflect strain differences in the lens, as suggested by observations that lenses from pigmented animals are more tolerant to UV radiation in vitro [45].

Initial lens changes appeared as a diffuse PSC clouding haze which progressed to dense PSC opacification and punctate opacities that blocked visualization of the retina. At the end of the study, total lens opacification, but not mature cataracts, were present.

A number of studies have reported the use of antioxidants and phase transition inhibitors to delay radiation-induced cataracts in albino rats [10] , [26] , [27] , [46] , [47] , [48] , [49] , [50]. In the present studies using pigmented rats, treatment with pantethine and multi-functional antioxidants 4 and 8 delayed the appearance of lens opacities.

However, the delay by pantethine was minimal, unlike the marked delay observed in irradiated albino animals [26]. The observed delay by the multi-functional antioxidants correlated with the lenticular presence of multi-functional 4 and 8 in the lens.

Another common model for cataract formation is the diabetic rat. This process is initiated when glucose is reduced to its sugar alcohol, sorbitol, by the enzyme AR [18]. Hyperosmotic effects result from the accumulation of sorbitol in the lens epithelium and initiate ER stress [19] , [20].

As sorbitol accumulates primarily in the epithelium and superficial lens fibers of the diabetic lens, free radical production is increased and natural antioxidant defenses are compromised. This results in increased oxidative stress [21] , [22] , [23] and apoptotic signaling.

Inhibiting sorbitol induced osmotic stress in the rat lens by the administration of ARIs prevents the biochemical changes associated with diabetic cataract formation [18]. Reducing oxidative stress can only delay cataract formation as demonstrated by the antioxidants butylated hydroxytoluene BHT [53] , [54] , Trolox 6-hydroxy-2,5,7,8-tetramethyl-chromancarboxylic acid [55] , and vitamin E [56].

Antioxidants cannot prevent sorbitol accumulation; however, the overall shift of the treated graphs to the right in Figure 8 indicates a delay in cataract progression presumably by reducing the effects of generated ROS. The absence of cataract formation in ALtreated animals is consistent with previously published reports on the effects of ARI treatment on ocular pathology in diabetic animals [57].

Compounds 4 and 8 were able to delay cataract formation without affecting blood sugars Table 1 or lenticular sorbitol levels Figure The presence of compounds 4 and 8 in the lens strongly suggests that the delays in cataract formation observed in both animal models are linked to their lenticular levels.

These proof of concept studies represent the first step in the potential development of these compounds as therapeutics agents. Efficacy studies where the time to catraract formation pharmacological endpoint of these compounds at their ED 50 is determined, requires repeating the present study at a minimum of three additional doses so that a dose-response curve can be constructed for estimating the ED These dose-response curves would also allow us to estimate the minimal therapeutic dose MTD.

However, such efficacy studies are also directly linked to the turnover of drug in the lens. In the present experiments, similar lens levels of compounds were achieved Figure 6 despite different doses being administered, This suggests that the lenticular half-life of compounds 4 and 8 is a key factor in determining the MTD.

Since the synthesis of compounds 4 and 8, as described by Jin et al. In the present studies, the study durations versus the amount of synthesized drug on hand limited the doses utilized for each study. Therefore, chow containing 0. Since the pharmacokinetics of the compounds have not been determined, rats orally received compounds mixed in chow rather than receiving a fixed dose by gavage daily to reduce the potential effects of systemic half-life differences.

Rats typically eat when active awake. While clearly additional studies are required to define the pharmacokinetics and specific efficacy of these compounds, the present study presents a proof of concept that multi-functional antioxidants show promise in significantly delaying ROS generated components of cataract development.

Conceived and designed the experiments: JR PK. Performed the experiments: JR PZ JM KB. Analyzed the data: JR PZ. Wrote the paper: JR PK. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field.

Article Authors Metrics Comments Media Coverage Reader Comments Figures. Abstract Background Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals.

Introduction Cataract is a major worldwide health care problem that especially affects the elderly. Download: PPT. Figure 1. Structure of multi-functional compounds 4 left and 8 right. Materials and Methods Materials All reagents used were of reagent grade.

Animal Care All procedures were performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and approved by the Institutional Animal Care and Use Committee of UNMC Permit Number: In vivo Irradiated Studies in Rats Whole head gamma irradiation was conducted on 24 male pigmented Long Evans — g rats.

Lenticular Levels of Compounds 4 and 8 Lenses from diabetic and irradiated rats were homogenized in ground glass homogenizers with 2 mL of PBS containing 0. Determination Lenticular Sorbitol Levels Individual lenses from each of the in vivo groups were homogenized in a ground glass homogenizer containing 2 mL of PBS and three micromoles of the internal standard, xylitol.

Endoplasmic Reticulum Stress Determination The thawed capsules from the cultured lenses were homogenized in ground glass homogenizers containing a mixture of RIPA buffer Cell Signaling Technology, Danvers, MA and Halt Protease and Phosphatase Inhibitor Cocktails VWR International, West Chester, PA.

Statistical Analyses Calculations were conducted using Microsoft Excel Microsoft, Redmond, WA. Figure 2. Comparison of weights of untreated, 4-treated, 8-treated, and pantethine-treated Long Evans rats post-irradiation.

Figure 3. Progression of radiation-induced cataract formation. Figure 4. Percentage of animals progressing to PSC clouding cataract score of 1. Figure 5. Figure 6. Lenticular levels of investigational compounds 4 and 8. Figure 7. Average weights of non-diabetic control and untreated, 4-treated, 8-treated, and ALtreated diabetic Sprague Dawley rats.

Figure 8. Figure 9. Figure Effect of Compounds 4 and 8 on Endoplasmic Reticulum Stress In Vitro Sorbitol-linked osmotic stress in lens epithelium cells has recently been reported to induce ER stress that leads to the generation of ROS. Discussion Age-related cataracts are considered to be multi-factorial in origin, with ROS mediated oxidative damage considered to be a common factor [7] , [35] , [36].

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Genetics of retinitis pigmentosa and other hereditary retinal disorders in Western Switzerland. Suggested Reading Four Years of Observation to Evaluate Autonomy and Quality of Life after Implantation of a High-Add Intraocular Lens in Age-Related Macular Degeneration Patients Case Rep Ophthalmol August, Oxidative Damage and the Prevention of Age-Related Cataracts Ophthalmic Res September, Mutational Screening of EFNA5 in Chinese Age-Related Cataract Patients Ophthalmic Res October, Lens Epithelial Surface Disorders in Exfoliation Syndrome: A Scanning and Transmission Electron Microscopy Study Ophthalmic Res May, Online ISSN Print ISSN Karger International S.

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Eur J Ophthalmol 18 5 — Download references. Institute of Biochemistry, Medical Faculty Pristina, Anri Dinan Street bb, , Kosovska Mitrovica, Serbia. Clinic for Eye Diseases, Medical Faculty Pristina, Anri Dinan Street bb, , Kosovska Mitrovica, Serbia. You can also search for this author in PubMed Google Scholar.

Correspondence to Bojana Kisic. Department of Pharmacology and Therapeutics, University of British Colombia, Vancouver, British Columbia, Canada.

Reprints and permissions. Kisic, B. Free Radical Biology of Eye Diseases. In: Laher, I. eds Systems Biology of Free Radicals and Antioxidants. Springer, Berlin, Heidelberg.

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Keywords Cataracts Free radicals Glaucoma Macular degeneration Oxidative stress. Buying options Chapter EUR eBook EUR 1, Hardcover Book EUR 2, Tax calculation will be finalised at checkout Purchases are for personal use only Learn about institutional subscriptions.

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