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Antioxidant Defense Network in the Lens and Benefits of Glutathione Prodrugs in Cataracts

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Book cover Studies on the Cornea and Lens

Abstract

Cataract, the opacification of an eye lens, is a common pathological abnormality of the lens that accounts for approximately 50 % of all blindness. Over 40 % of all visits to ophthalmologists by Medicare patients are associated with cataracts and cataract surgery accounts for approximately $5 billion in Medicare payments. The lens depends on a balanced redox state for maintaining its transparency, and a high content of glutathione (GSH) in the lens is believed to play a key role in doing so. Since depletion of GSH has been implicated in the etiology and pathogenesis of cataracts and other eye disorders, a logical approach to drug development would be the prevention of oxidative damage to the lens by the use of GSH prodrugs. GSH may be increased by supplying esters of GSH, γ-glutamylcysteine, cysteine esters, and N-acetylcysteine (NAC). However, their poor bioavailability and toxicity limit their use as a therapeutic agent. A potential candidate for development as a GSH prodrug is the low molecular weight thiol antioxidant, N-acetylcysteineamide (NACA), which has enhanced ability to penetrate cells giving the drug a greater therapeutic index by lowering the risk of side effects. The development of a useful GSH prodrug therapeutic would be a noninvasive, cost-effective, and safer option for both prevention and treatment of cataracts and would significantly improve patient health and the clinical care of cataracts.

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Abbreviations

ATP:

Adenosine triphosphate

BSO:

l-Buthionine-(S,R)-sulfoximine

CAT:

Catalase

G6PD:

Glucose-6-phosphate dehydrogenase

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GRx:

Glutaredoxin

GS:

Glutamine synthetase

GSH:

Glutathione

GST:

Glutathione-S-transferase

LPO:

Lipid peroxidation

MDA:

Malondialdehyde

Msrs:

Methionine sulfoxide reductases

NAC:

N-acetylcysteine

NACA:

N-acetylcysteineamide

PSSC:

Protein-S-S-cysteine

PSSG:

Protein-S-S-glutathione

PSSP:

Protein-S-S-protein

PUFAs:

Polyunsaturated fatty acids

ROS:

Reactive oxygen species

SOD:

Superoxide dismutase

TR:

Thioredoxin reductase

Trx:

Thioredoxin

TTase:

Thioltransferase

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Authors and Affiliations

  1. Department of Chemistry, Missouri University of Science and Technology, Rolla, MO, USA

    Shakila Tobwala

  2. Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, USA

    Humeyra Karacal

  3. Department of Chemistry, Missouri University of Science and Technology, 236 Schrenk Hall, 400 W. 11th Street, Rolla, MO, 65409-0010, USA

    Nuran Ercal

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  1. Shakila Tobwala
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  3. Nuran Ercal
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Editors and Affiliations

  1. Innovative Vision Products Inc., Moscow, Russia, Innovative Vision Products, Inc.,, County of New Castle, Delaware, USA

    Mark A. Babizhayev

  2. Department of Ophthalmology and Visual Sciences, Truhlsen Eye Institute, College of Medicine, University of Nebraska Medical Center; Key Laboratory of Protein Chemistry and Developmental Biology of Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha, Hunan, China, Omaha, Nebraska, USA

    David Wan-Cheng Li

  3. Department of Pharmaceutical Sciences and Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Anne Kasus-Jacobi

  4. Department of Ophthalmology, University of Pristina, Faculty of Medicine, Kosovska Mitrovica, Serbia

    Lepša Žorić

  5. Ophthalmology, Miguel Hernandez University, Alicante, Spain

    Jorge L. Alió

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Tobwala, S., Karacal, H., Ercal, N. (2015). Antioxidant Defense Network in the Lens and Benefits of Glutathione Prodrugs in Cataracts. In: Babizhayev, M., Li, DC., Kasus-Jacobi, A., Žorić, L., Alió, J. (eds) Studies on the Cornea and Lens. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1935-2_18

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