Eye Lens in Aging and Diabetes: Effect of Quercetin

REJUVENATION RESEARCH Volume 14, Number 5, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/rej.2011.1170 Eye Lens in Aging and Diabetes: Effect of Quercetin Milan Stefek1 and Cimen Karasu2 Abstract Old age is accompanied by a number of pathological eye conditions. Cataract is the most common age-related eye complication. Because the lens becomes naturally more opaque over time, aging is the most important risk factor for developing cataract, which is a major cause of blindness in the world. Cataractogenesis is also one of the earliest secondary complications of diabetes mellitus. The lens is a closed system with limited capability to repair or regenerate itself. Current evidence supports the view that cataractogenesis is a multifactorial process. Oxidative stress and its sequelae are clearly involved in the etiology of senile cataract, whereas mechanisms related to glucose toxicity, namely oxidative stress, processes of nonenzymatic glycation, and enhanced polyol pathway contribute significantly to the development of the eye complications under conditions of diabetes. There is an urgent need for inexpensive, nonsurgical approaches to the treatment of cataract. Recently, considerable attention has been devoted to the search for phytochemical therapeutics. Several pharmacological actions of natural flavonoids may operate in preventing cataract because flavonoids are capable of affecting multiple mechanisms or etiological factors responsible for the development of sight-threatening ocular diseases. The flavonol quercetin is the most widely consumed flavonoid in the human diet. In this article, quercetin is reviewed as an agent that could reduce the risk of cataract formation via affecting multiple pathways pertinent to eye lens opacification, including oxidative stress, nonenzymatic glycation, the polyol pathway, lens calpain proteases, and epithelial cell signaling. In addition, the bioavailability of quercetin to the lens is considered. Introduction and provide a second level of defense. Compromises of lens function upon aging are associated with, and may be caus- ld age is accompanied by a number of pathological ally related to, depleted or diminished primary antioxidant Oeye conditions. Cataract is the most common age-re- reserves, antioxidant enzyme capabilities, and diminished lated eye complication. Because the lens becomes naturally secondary defenses such as proteases. Environmental stress more opaque over time, aging is the most important risk such as smoking and excessive ultraviolet (UV)-light expo- factor for developing cataract, which is a major cause of sure, appear to provide an additional oxidative challenge blindness in the world.1–3 Current evidence supports the associated with the depletion of antioxidants as well as with view that cataractogenesis is a multifactorial process in enhanced risk for cataract. Other risk factors for cataract which a combination of several events induces an array of formation include diabetes, galactosemia, radiation, life- subtle posttranslational modifications in the lens structural threatening diarrhea, renal failure, and many drugs.1,3,4,8–14 proteins, enhancing their aggregation, fragmentation, and Etiologically, the most common types of cataract are those precipitation, resulting eventually in lens opacification. associated with aging and diabetes.15,16 Cataractogenesis is Human studies as well as in vitro and in vivo animal exper- one of the earliest secondary complications of diabetes mel- iments strongly suggest that there is an association be- litus. Diabetic patients are about 60% more likely to develop tween increased oxidative stress and the development of these eye conditions.17 cataract. Oxidative free-radical damage is considered an People with diabetes also tend to get cataract at a younger initiating or very early event in the overall sequence leading age with a faster progression. The association between to cataract.4–8 diabetes and cataract formation has been shown in clinical The young lens has substantial reserves of antioxidants epidemiological and basic research studies. Because extra- and antioxidant enzymes that may prevent damage. Pro- cellular glucose diffuses into the lens uncontrolled by the teolytic enzymes may selectively remove obsolete proteins hormone insulin, the lens is one of the most affected body 1Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovakia. 2Department of Medical Pharmacology, Faculty of Medicine, Gazi University, Ankara, Turkey. 525 526 STEFEK AND KARASU parts in diabetes mellitus. The proteins of the lens are ex- tremely long-lived, and there is virtually no protein turnover, which provides great opportunities for posttranslational modification to occur.18 Multiple mechanisms have been implicated in the development of cataract in diabetes. To date, the exact sequence of events leading to opacification has not been clearly defined. Thus, the relationship of the opacity to the initiating event may be obscure. What are the molecular changes that are responsible for the increasing level of lens turbidity? How can these changes be arrested? A further problem is that the appearance of opacity in model systems rarely duplicates the cataracts observed in humans.4,5,19 The lens is a closed system with limited capability to repair or regenerate itself. Oxidative stress and its sequelae are clearly involved in the etiology of age-related cataract FIG. 1. Molecular structure of quercetin [2-(3,4-dihydrox- whereas mechanisms related to glucose toxicity, namely yphenyl)-3,5,7-trihydroxy-4H-chromen-4-one]. oxidative stress, processes of nonenzymatic glycation, and enhanced polyol patway, contribute significantly to the development of the eye complications under conditions of Anticataract Action of Quercetin diabetes.4,5,20–25 Treatment recommendations for the general aging pop- Models in vitro ulation emphasize the use of antioxidant micronutrients. Under in vitro conditions, using the rat lens organ culture Several clinical studies have pointed to a diminution of endowed with hydrogen peroxide (H O ), it was demon- human senile cataract incidence after an adequate supply of 2 2 strated that low micromolar levels of quercetin inhibited antioxidants in food.4–6,16,26 Inthecaseofdiabeticpa- oxidation-induced sodium and calcium influx and loss of tients, the need for tight blood glucose control is a key lens transparency.32 As shown later by Cornish et al.,33 prerequisite to reduce the incidence, progression, and se- quercetin was rapidly lost from the medium and readily verity of cataract. Yet periods of hyperglycemia in the daily entered the lens, where it was methylated to 30-O-methyl regimenofadiabeticpatientcannotbeavoided,withtheall quercetin. Both quercetin and its metabolite were active in aforementioned deleterious consequences of glucose toxic- inhibiting oxidative damage in the lens. ity. Therefore, additional adjunct therapy, e.g., including The addition of quercetin (20 mg/mL) to rat lens organ antioxidants, antiglycation agents, and aldose reductase culture supplemented with selenite prevented the formation inhibitors, is needed to attenuate the noxious effects of of opacity as a result of selenite toxic effects.34 The glucoside glucose. of isorhamnetin (methylated quercetin), isolated as a bioac- Recently, considerable attention has been devoted to the tive flavonoid from the leaves of Cochlospermum religiosum search for phytochemical therapeutics. There is epidemio- (silk-cotton tree),35 and flavonoid fraction isolated from fresh logic evidence that a sufficient intake of fruit and vegetables leaves of Vitex negundo (chastetree)34 protected enucleated can lower the risk of cataract in humans.6 A variety of con- rat eye lenses against selenite-induced cataract in an in vitro stituents, like vitamins, minerals, fiber, and numerous phy- culture model. tochemicals, including flavonoids, may contribute to the The flavonoid venoruton, a mixture of mono-, di-, tri-, and protective effect of fruits and vegetables. Indeed, several tetrahydroxyethylrutosides, significantly reduced the degree pharmacological actions of flavonoids may operate in the of opacification and the leakage of lactate dehydrogenase in prevention of both age-related and diabetic cataract, as fla- rat lens organ culture simulating diabetic conditions.36 vonoids are capable of affecting multiple mechanisms or etiological factors responsible for the development of sight- Animal models in vivo threatening ocular diseases.27–29 The flavonol quercetin (Fig. 1) is the most widely con- As early as in 1977, Varma et al.37 studied the effect of sumed flavonoid in the human diet.30,31 Quercetin and other quercetin rhamnoside (quercitrin) on the development of flavonoids have been shown to have protective effects cataract in the rodent Octodon degus (brush-tailed rat or degu) against eye lens opacification. In plants, quercetin is present made diabetic by a single intraperitoneal dose of streptozo- mainly in the form of O-glycosides with a sugar group, tocin. The control diabetic animals not receiving quercitrin such as glucose, galactose, rhamnose, rutinose, or xylose. developed a nuclear opacity by about the tenth day after the The glycosidic structure has a large impact on quercetin onset of hyperglycemia. In contrast, the diabetic animals bioavailability. treated with quercitrin (70 mg/day) did not develop cata- In this article, quercetin is reviewed as an agent that racts, even 25 days after the onset of diabetes, although they could reduce the risk

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