Age-related cataracts and drug therapy: opportunities and challenges for local delivery of antioxidants to the lens
Age-related cataracts and drug therapy: opportunities and challenges for local delivery of antioxidants to the lens
Author
Hamdi Abdelkader, Ryd G. Alani, Barbara Pircionek
As previously published in the Journal of Pharmacy and Pharmacology. — 2015. — Vol. 67. — Issue 4. — P. 537–550.
https://onlinelibrary.wiley.com/doi/10.1111/jphp 12355/full#jphp12355-bib-0015
Objectives
The search for anticataract drugs has been continuing for decades; some treatments no longer exist but antioxidants are still of much interest.
Key findings
The primary function of the human lens, along with the cornea, is to refract light so that it is correctly focused onto the retina for optimum image quality. With age, the human lens undergoes morphological, biochemical, and physical changes leading to opacification. Age‐related or senile cataract is one of the main causes of visual impairment in the elderly; given the lack of access to surgical treatment in many parts of the world, cataract remains a major cause of sight loss. Surgical treatment is the only means of treating cataract; this approach, however, has limitations and complications.
Summary
This review discusses the anatomy and physiology of the lens and the changes that are understood to occur with aging and cataract formation to identify potential areas for effective therapeutic intervention. Experimental techniques and agents used to induce cataract in animal models, the advantages and disadvantages of potential pharmacological treatments specific barriers to delivery of exogenous antioxidants to the lens, and the prospects for future research are discussed.
Lens homeostasis
The lens is bathed by the aqueous humor and posteriorly which compensates for the absence of a blood supply, by providing nutrients, amino acids, and antioxidants (e.g. ascorbic acid) and disposing of waste products such as lactic acid. The lens relies on an effective apparatus of water and ion channels (aquaporins and connexins) to maintain nutrition and homeostasis. These channels are paracellularly and transcellularly located in the lens epithelium and cortex. The other major antioxidant GSH is biosynthesized in the lens cortex and diffuses into the nucleus. There is a paucity of knowledge about the molecular identification of antioxidant transporters and how these transporters are utilized to enhance antioxidant delivery to the lens nucleus. It has, however, been shown that the rates of water and water-soluble transport via the lens epithelium and cortex declines with age. The decrease in antioxidant transport such as ascorbic acid, amino acids, and glutathione precursor cysteine might contribute to the oxidative damage in the lens with age and ultimately to the formation of age‐related cataract and.
Endogenous antioxidants in the lens
Two endogenous antioxidants (e.g. ascorbic acid and glutathione) are dominantly present in the anterior segment of the eye; the cornea, trabecular meshwork, and lens. These tissues are avascular and are susceptible to oxidative damage throughout life. These two antioxidants are fundamentally important for scavenging and correcting any damage due to reactive oxygen and free radical species. The concentration of ascorbic acid (vitamin C) is believed to be highest in the corneal epithelium, while GSH concentration is the highest in the lens.
Humans cannot biosynthesize ascorbic acid de novo due to the lack of L‐gulonolactone oxidase necessary for its synthesis, and hence an exogenous supply is necessary. Ascorbic acid in the lens prevents membrane lipid peroxidation and protects the lens cation pumps. Recent evidence has shown that Aquaporin 0 might be involved in the transport of ascorbic acid to the lens from the aqueous humor.
GSH can be obtained from the diet but is also synthesized de novo from the amino acids cysteine, glutamate, and glycine with the aid of γ‐glutamyl synthetase and GSH synthetase. Glutathione is biosynthesized in the metabolically active lens epithelial cells and then transported to cortical and nuclear lens fibers via gap junction. GSH is an effective antioxidant that acts on sulfhydryl groups (‐SH) to maintain the chemical and physical integrity of the crystallins, protecting them from post‐translational modifications and the onset of cataractogenesis.
Aging of the lens and age‐related cataractogenesis
The lens undergoes some morphological, biochemical, and physical changes with age which are causal for the formation of age‐related nuclear cataract. These changes occur at a very slow rate over the human life span and are not limited to a specific anatomical area but affect different lens layers.
The main objective for pharmacological treatment is to delay the lens opacification process, reduce morbidity and the cost of health care. An estimate has been made that one decade delay in the onset of the age‐related cataract will reduce the surgery and associated costs by 50%. Over the past three decades, many anticataract agents have been studied in vivo and with incubated lenses; these drugs showed promising results. However, many of these agents have not yet been evaluated for ocular delivery, long‐term ocular safety, and tolerability. Among these drugs are aspirin/aspirin‐like drugs, protein stabilizers, exogenous antioxidants, and other novel therapeutic strategies that will be discussed below. The table shows the major attributes for some therapeutic groups that could hold promise in delaying/reversing age‐related cataract.
Table. Major attributes of potential anticataract therapeutic agents
Pharmacological group |
Advantages |
Disadvantages |
Aspirin/aspirin-like drugs, for example, aspirin, ibuprofen and paracetamol |
Antidenaturating agents by acetylation of lens proteins Weak antioxidants and plasma sugar lowering properties Effective both systemically and topically |
Major systemic side effects, for example, gastric ulcer and renal impairment Ocular side effects, for example, stinging and corneal disorders Further investigations and clinical trials yet to be done on different cataract models |
Protein stabilisers/protectors, for example, bendazac and hydroxybendazac |
Inhibit protein aggregation and denaturation delay post-translational modifications Effective both systemically and topically |
Long-term safety on ocular tissues are understudied Not supported by large groups clinical trials |
Opioid growth factor antagonist, for example, naltrexone |
Maintaining lens epithelial density Protecting against dry-eye induced cataractogenesis Enhancing transport of endogenous antioxidants and precursors to the lens nucleus |
Over-activation of lens fibres could prompt building up of the diffusion barrier to lens nucleus Lens opacity due to over-expression of ascorbic acid transporters Not supported by research or clinical trials |
Flavonoids, for example, quercetin, diosmin and curcumin |
Antioxidant properties Aldose reductase inhibitors |
Poor water solubility Chemically unstable Not supported by large groups clinical trials |
N-acetyl carnosine |
Antioxidant properties Antiglycating properties reverse cataractous lenses |
Not supported by large groups clinical trials One-centre studies |
Exogenous antioxidants
The role of antioxidants in maintaining the structural and chemical integrity of lens proteins has been highlighted recently. Antioxidants, also known as reducing agents, are molecules capable of inhibiting the oxidation of other more physiologically active molecules by a sacrificing chemical reduction process by accepting two or more electrons from free radicals or reactive oxygen species.
The antioxidants are classified into two main broad groups, depending on whether they are water-soluble (hydrophilic) or insoluble (lipophilic) antioxidants. Notable examples for water-soluble antioxidants, thiol antioxidants, and their chemical derivatives that have been recently highlighted as anticataractogenic agents are GSH, cysteine, cysteine prodrug L‐2‐oxothiazolidine‐4‐carboxylic acid (OTZ), N‐acetyl carnosine, N‐acetylcysteine, and N‐acetylcysteine amide. Selenite-induced cataract in Sprague–Dawley rats was treated by N‐acetylcysteine given intraperitoneally in a dose of 150 μg/g body weight, and the treated rats demonstrated significant protection against cataract (only 14.3% developed dense cataract), compared with 50% cataract for the untreated group. N‐acetylcarnosine drops (1%) have demonstrated promising results for treatment/prevention of senile cataract in humans and showed good ocular tolerability for up to 6 and 9 months. In another study, the topical application of NAC (2% w/w) showed improvement in lens opacity of canine immature cataracts or nuclear sclerosis, whereas marginal reduction was recorded for mature cataract or cataract associated with intraocular inflammation. N‐acetyl carnosine is a prodrug of carnosine that inhibits lipid peroxidation of model membranes. N‐acetyl carnosine was found to have dose‐dependent hydrolysis while passing through the cornea before liberating carnosine in the anterior chamber 15–30 min after instillation onto rabbit eyes.
Problems of antioxidant therapy
The literature contains conflicting conclusions: the benefits of oral antioxidant supplements have been proven, but their long-term use provides limited benefits. Sufficient levels of antioxidants in the intraocular fluid are very important to create a concentration gradient that can direct nutrients to target areas in the lens nucleus; through the cardiovascular system, it is inefficient.
Current research focuses on developing advanced antioxidant delivery systems to the anterior segment of the eye for better ocular bioavailability and, consequently, better therapeutic results by bypassing major anatomical and physiological barriers of the eye, such as precorneal tear film, limiting tight contacts in the lipophilic epithelium channel.
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