Harnessing the eye’s natural defenses, scientists explore innovative ways to boost antioxidants and reduce oxidative stress in the lens, offering new hope for cataract prevention and delayed surgery.
Review: Minimizing Oxidative Stress in the Lens: Alternative Measures for Elevating Glutathione in the Lens to Protect against Cataract. Image Credit: ARZTSAMUI / Shutterstock
In a review article published in the journal Antioxidants, researchers at the University of Auckland, New Zealand, have discussed potential cataract treatment strategies that utilize endogenous molecular machinery of the eye lens to increase the level of antioxidant glutathione in different lens regions.
Background
Cataract is a leading cause of visual impairment and a potential cause of blindness worldwide. The major risk factors for cataract onset include advancing age, diabetes, and having vitrectomy surgery.
Cataract surgery is highly effective in treating the condition and restoring vision. It is the most commonly performed surgical procedure worldwide. However, such high demand often creates significant pressure on the healthcare system, resulting in lengthy waiting times for surgery. This highlights the need for developing alternative strategies to prevent or delay the onset of cataracts.
Oxidative stress contributes significantly to the development of cataracts. Several antioxidant therapies have been found to delay cataract progression. Glutathione (GSH) is the primary antioxidant in the eye lens. Glutathione supplementation in the lens is believed to be a promising strategy to prevent or delay cataract formation.
However, the limited bioavailability of glutathione due to rapid degradation hinders its delivery to the lens. The journal article elaborates that anatomical barriers in the anterior eye and intracellular barriers within the lens contribute to the challenge of delivering glutathione to various lens regions. Other potential challenges include anatomical barriers of the anterior eye that limit glutathione delivery to the lens and intracellular barriers within the lens that limit glutathione delivery to different lens regions.
Three strategies that utilize the endogenous molecular machinery of the lens have shown promising results in terms of increasing glutathione levels in the lens and preventing cataracts. These strategies are based on leveraging existing molecular pathways, thereby avoiding some of the pitfalls of supplementing the lens with exogenous antioxidants, which have shown mixed results. In this review article, the authors have provided a detailed overview of these strategies.
Leveraging nuclear factor erythroid 2-related factor 2 (Nrf2) pathway
Nrf2 is a ubiquitously expressed transcription factor that regulates the expression of around 20 antioxidant genes to provide protection against oxidative stress. Some of these genes are associated with the synthesis and regeneration of glutathione.
The Nrf2 activity remains suppressed under physiological conditions due to its degradation via ubiquitination and proteasomal pathways. However, oxidative stress-mediated changes in cellular machinery allow Nrf2 to escape the degradation pathways and translocate to the nucleus. In the nucleus, Nrf2 promotes glutathione synthesis and regeneration by binding to antioxidant response elements on DNA and subsequently activating the transcription of antioxidant enzymes.
Considering the connection between Nrf2 and glutathione, researchers have investigated the role of Nrf2 in preventing cataract formation in animal and human lenses.
The review explains that studies on Nrf2 knockout mice have shown disruptions in lens cell architecture, leading to faster cataract development compared to wild-type mice. Additionally, histological changes in these animals were observed, such as ectopic nuclei in deeper lens regions, further supporting the protective role of Nrf2 in lens health. Studies conducted on Nrf2 knockout mice have shown certain changes in the lens, including disruptions in cortical cell architecture, abnormal presence of nuclei in deeper lens regions, and ectopic nuclei in the posterior region. These changes are associated with faster development of cataracts in knockout mice compared to wild-type mice.
Studies utilizing animal models of cataracts have shown that administering antioxidants, such as trimetazidine and ferulic acid, delays cataract formation by increasing Nrf2 expression. These animal models, though promising, may not fully replicate the slow, age-related progression of cataracts seen in humans, emphasizing the need for further research. An increased nuclear translocation of Nrf2, an induction of glutathione levels, and subsequent prevention of histological changes in the lens epithelial cells have been observed in rats treated with ferulic acid before and after ionizing radiation exposure.
In human studies, Nrf2 suppression has been linked to cataract formation in lenses collected from diabetic and older patients, with the upregulation of Keap1 (an Nrf2 suppressor) found in these individuals. Nrf2 activators, such as sulforaphane, have shown potential in preventing cataract formation in human lens epithelial cells under oxidative stress conditions. A reduced expression of Nrf2 has also been observed in human lens epithelial cells collected from donors of varying ages as well as diabetic patients. Various suppressors of Nrf2 have also been found to mimic the features of cataracts in these cells.
In contrast, Nrf2 activators, such as sulforaphane, have been found to prevent homocysteine- or hydrogen peroxide-induced cataract formation in human lens epithelial cells by increasing nuclear translocation of Nrf2 and expressions of cellular antioxidants, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione.
Both animal and human study findings highlight the significance of Nrf2 in increasing antioxidant status and reducing oxidative stress in the lens epithelial and cortical fiber cells. However, because Nrf2 activation primarily affects the lens epithelium and cortex, alternative strategies are required to replenish glutathione in the lens nucleus. More studies are required to develop alternative strategies to alleviate oxidative stress and replenish glutathione levels in the lens center.
Leveraging Cysteine Analogues
Cysteine is the rate-limiting amino acid required for glutathione synthesis. It has strong antioxidant properties. Cysteine is synthesized via the transsulfuration pathway, in which homocysteine is first converted to cystathionine by cystathionine-beta-synthase (CBS) and subsequently to cysteine.
An upregulated expression of CBS has been observed in hydrogen peroxide-exposed human and porcine lenses, indicating that oxidative stress can upregulate the transsulfuration pathway to trigger the conversion of homocysteine to cysteine for glutathione production.
In the review, researchers describe two cysteine-based analogs, N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA), that have been studied extensively for their role in treating cataracts. NAC, though widely used, has relatively low bioavailability, while NACA, due to its greater membrane permeability, can be used in lower concentrations and shows greater antioxidant potential. Lipid-permeable analogs of cysteine, such as N-acetylcysteine (NAC) and N-acetylcysteine amide (NACA), have been studied widely to treat cataracts in different animal models. Topical or intraperitoneal application of NAC has been found to delay cataract formation in rats by increasing glutathione synthesis and suppressing oxidative stress.
NACA is a derivative of NAC with higher lipophilicity and membrane permeability. Intraperitoneal and topical application of NACA has been found to reduce the severity of cataracts in rats by enhancing glutathione levels and inhibiting malondialdehyde formation.
Additionally, the immediate precursor of NACA, diNACA, has also been explored in the context of cataract treatment. DiNACA may function not by increasing glutathione synthesis but by forming mixed disulfides that protect lens proteins from oxidative damage. In rats treated with an inhibitor of glutathione synthesis, NACA has been found to prevent cataract formation and replenish glutathione levels. An immediate precursor of NACA called diNACA has recently gained attention for cataract treatment. Both in vitro and in vivo studies have shown that diNACA prevents cataract formation by regulating mixed disulfide formation but not by increasing glutathione synthesis.
Upregulation of microcirculation system of lens
The microcirculation system of the lens provides a promising platform for improving nutrient and antioxidant delivery specifically to the lens nucleus. According to the journal article, recent advances in imaging techniques, such as MRI and imaging mass spectrometry, have confirmed that the lens's microcirculation system can deliver solutes to the nucleus faster than passive diffusion alone. This opens the door for potential pharmacological manipulation to enhance antioxidant delivery. Magnetic resonance imaging has shown that the lens microcirculation system can deliver solutes to the lens nucleus faster than is predicted to occur via passive diffusion alone.
A strong hydrostatic pressure gradient is generated during the outflow of water through lens-gap junctions. This pressure gradient is highly regulated by a dual feedback system, which can be manipulated pharmacologically to upregulate water transport through the lens and subsequently increase the delivery of antioxidants to the core region of the lens to prevent age-related nuclear cataracts.