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Prevention and Reversal of Selenite-Induced Cataracts by N

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Prevention and Reversal of Selenite-Induced Cataracts by N Maddirala et al. BMC Ophthalmology (2017) 17:54 DOI 10.1186/s12886-017-0443-1 RESEARCH ARTICLE Open Access Prevention and reversal of selenite-induced cataracts by N-acetylcysteine amide in Wistar rats Yasaswi Maddirala1†, Shakila Tobwala1†, Humeyra Karacal2 and Nuran Ercal1* Abstract Background: The present study sought to evaluate the efficacy of N-acetylcysteine amide (NACA) eye drops in reversing the cataract formation induced by sodium selenite in male Wistar rat pups. Methods: Forty male Wistar rat pups were randomly divided into a control group, an N-acetylcysteine amide-only group, a sodium selenite-induced cataract group, and a NACA-treated sodium selenite-induced cataract group. Sodium selenite was injected intraperitoneally on postpartum day 10, whereas N-acetylcysteine amide was injected intraperitoneally on postpartum days 9, 11, and 13 in the respective groups. Cataracts were evaluated at the end of week 2 (postpartum day 14) when the rat pups opened their eyes. N-acetylcysteine amide eye drops were administered beginning on week 3 until the end of week 4 (postpartum days 15 to 30), and the rats were sacrificed at the end of week 4. Lenses were isolated and examined for oxidative stress parameterssuchasglutathione,lipid peroxidation, and calcium levels along with the glutathione reductase and thioltransferase enzyme activities. Casein zymography and Western blot of m-calpain were performed using the water soluble fraction of lens proteins. Results: Morphological examination of the lenses in the NACA-treated group indicated that NACA was able to reverse the cataract grade. In addition, glutathione level, thioltransferase activity, m-calpain activity, and m-calpain level (as assessed by Western blot) were all significantly higher in the NACA-treated group than in the sodium selenite-induced cataract group. Furthermore, sodium selenite- injected rat pups had significantly higher levels of malondialdehyde, glutathione reductase enzyme activity, and calcium levels, which were reduced to control levels upon treatment with NACA. Conclusions: The data suggest that NACA has the potential to significantly improve vision and decrease the burden of cataract-related loss of function. Prevention and reversal of cataract formation could have a global impact. Development of pharmacological agents like NACA may eventually prevent cataract formation in high-risk populations and may prevent progression of early-stage cataracts. This brings a paradigm shift from expensive surgical treatment of cataracts to relatively inexpensive prevention of vision loss. Keywords: Cataract, N-acetylcysteine amide (NACA), Glutathione, Calpain, Crystallin, Lens, Sodium selenite Background have had cataract surgery. The NEI and Prevent Blind- Cataract is a progressive loss of transparency of the lens ness America estimate that more than 22 million people that affects vision. It is the most common cause of in the U.S. live with cataracts and, by 2020, this may curable blindness, accounting for more than 50% of exceed 30 million. Although cataract is not associated cases worldwide [1]. Most cataracts are age-related and, with signs such as pain or redness in the eye, it is still according to the National Eye Institute (NEI), by age 80, characterized by symptoms such as blurry vision, double more than half of all Americans either have a cataract or vision, glare of light, and fading of colors. Presently, the only effective treatment option is the surgical removal of * Correspondence: [email protected] the affected lens and replacement with an artificial lens. †Equal contributors 1Department of Chemistry, Missouri University of Science and Technology, However, the cost of surgery and need for highly trained Rolla, MO 65409, USA personnel to perform ocular surgery limit restoration of Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Maddirala et al. BMC Ophthalmology (2017) 17:54 Page 2 of 12 vision in certain parts of the world. Unfortunately, the than NAC, owing to its neutral amide group, which majority of people with vision impairment due to cata- increases its lipophilicity and, consequently, its penetra- racts live in developing countries where access to tion into cell membranes. This has been verified in pre- surgery is limited [2]. Hence, there is an immediate neces- vious studies, as well as its ability to chelate Cu2+, sity for prevention and non-invasive treatment of cataracts. scavenge free-radicals, and protect against oxidative The pathogenesis of cataracts is multifactorial, involv- stress [29–36]. Our lab has demonstrated NACA’s ing mechanisms that are not fully understood, with improved antioxidant ability compared to that of NAC oxidative stress being the foremost cause in initiating [33, 37]. Furthermore, NACA is effective at lower cataract formation [3–9]. Oxidative stress implies an concentrations than NAC, which helps to prevent the imbalance between the rate of oxidant production and various adverse effects that are associated with adminis- the rate of detoxification, with the rate of production tration of higher doses of NAC [26, 31, 38–40]. being significantly higher compared to that of detoxifica- Based on these results, the primary objective of this tion by antioxidants [10]. An organism counteracts this study was to assess the ability of NACA to prevent and/ condition with its natural antioxidant defense systems, or reverse selenite-induced cataract formation in Wistar but with age, oxidants accumulate while antioxidant rats. We demonstrated that NACA, when injected intra- defenses gradually diminish, which is likely the most im- peritoneally on postpartum days 9, 11, and 13 helped to portant mechanism in age-related cataract formation. prevent dense nuclear cataract formation [41, 42]. Furthermore, Shearer [11] proposed the involvement of Continuous NACA administration (from postpartum oxidative stress in selenite-induced cataract and the day 15 to 30) as an eye drop formulation reversed the sequence of events leading to cataract formation. It was density of the cataract. Our results demonstrate that hypothesized that the oxidative damage caused by selen- NACA administration bolstered antioxidant defenses of ite possibly involves oxidation of critical sulfhydryl selenite-dosed animals by replenishing GSH, inhibiting groups on calcium ATPase or ion channels. [11] This lipid peroxidation, preventing accumulation of calcium, may lead to altered metabolism in lens epithelium and thereby preventing activation of m-calpain and eventu- loss of calcium ATPase activity and, hence, an accumula- ally preserving the lens crystallin proteins. Therefore, tion of calcium in the nucleus of the lens, which could NACA shows promise as a candidate for development activate m-calpain. Activation of m-calpain initiates the into a drug-based cataract treatment. proteolysis of β-crystallins, leading to the insolubilization of both proteolyzed β- and α-crystallins, co-precipitation Methods of γ-crystallins, and ultimately the formation of Materials cataracts. Since oxidative stress is implicated in cataract Sodium selenite (Na2SeO3, Cat no: 214,485, ≥99% pure) formation, application of an antioxidant capable of suc- and N-(1-pyrenyl) maleimide (NPM, Cat no: P7908, cessfully penetrating the lens tissue represents a logical ≥98.5% pure) were purchased from Sigma-Aldrich (St. approach to counteract oxidation-related cataractogen- Louis, MO, USA). N-acetylcysteine amide (NACA, esis. Several compounds with antioxidant properties ≥99.9% pure) was provided by Dr. Glenn Goldstein have been reported to prevent selenite-induced (David Pharmaceuticals, New York, NY, USA). Casein cataracts, such as resveratrol [12], saffron [13], ellagic zymogram gels (12% Ready Gel, Cat no: 161–1168) were acid [14], garlic [15], melatonin [16], drevogenin D [17], purchased from Bio-Rad (Hercules, CA, USA). Rabbit caffeine [18], ebselen [19], lycopene in vivo [20], m-calpain Antibody (Cat no: 2539S), GAPDH Rabbit N-acetyl-L-carnitine in vitro and in vivo [21–23], and mAb (Cat no: 2118S), and Anti-rabbit IgG, HRP-linked Ocimum sanctum in vivo and ex vivo [24]. In fact, Antibody (Cat no: 7074S) were purchased from Cell N-acetylcysteine (NAC), a glutathione (GSH) prodrug, Signaling Technology (Beverly, MA, USA). All other has previously been tried in selenite-induced cataracts in chemicals were purchased from Sigma-Aldrich, unless vivo [25] and was shown to prevent oxidative damage to stated otherwise. the lens, slowing down cataractogenesis. Use of antioxidants in treating or preventing oxidative Animal study design stress-related disorders is becoming more popular, with Lactating female Wistar rats with 40 2-day-old male thiol antioxidants, such as GSH, cysteine, and NAC, pups were purchased from the breeding facility at showing some protection [26–28]. However, the negative Charles River and were housed in a temperature- and charge on the NAC molecule at physiological
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