Cataract Management: Bridging The Gap Between Surgical Interventions and Emerging Non- Invasive Treatments

Cataract is the leading cause of avoidable blindness, and is responsible for almost half of cases worldwide [1-2]. This percentage will be doubled in the next two decades if effective measures are not taken in time as per the recent report of World Health Organizations (WHO) [3-4]. Currently, surgery is the sole option for treatment and is accompanied by serious postoperative complications like posterior capsule opacification, dislocation of intraocular lens, inflammation of the eye, macular edema, endophthalmitis and ocular hypertension [5, 6]. Socioeconomic problems, such as illiteracy, poverty, inaccessibility, and exorbitant cost of the treatment, are also significant barriers to successful treatment [7]. Studies show that oxidative stress (OS) is one of the principal triggering factors in the process of cataract [8, 9]. The inadequate defense systems available and non-neutralizing action of the natural antioxidant enzymes (glutathione, glutathione peroxidase, superoxide dismutase and catalase) normally present in the crystalline lens are primarily responsible for the formation of reactive oxygen species (ROS) like hydroxyl radicals, hydrogen peroxide and superoxide anions that ultimately lead to OS. These antioxidant enzymes are crucial for protecting lens proteins and lens fiber cell membranes [10, 11]. Too much ROS counts as denaturation of lens proteins, nucleic acid and lipids which contribute to cataract in development. OS during cataract development significantly reduced the lens's natural antioxidant activity, as research evidence. Thus, the development of antioxidant rich herbal pharmaceutical dosage form would be a savior to this global pandemic. Different plant constituents oppose ROS: At the least, a new ray of hope for them to come out of the cataract prevention woodpile with minimal to no side effects and prevention of cataract delay[12].

PATHOPHYSIOLOGY

Oxidative Stress and Protein Aggregation

Lens is easily damaged by oxidative species, owing to lifelong light exposure and high oxygen demand. Protein structures are destabilized by reactive oxygen species (ROS) and products of lipid peroxidation, resulting in protein misfolding & aggregation/inactivation. High molecular weight aggregates due to oxidation of crystallins (major lens protein), resulting in the lens opacity [13].

Osmotic Stress in Diabetic Cataracts

Osmotic imbalance can be induced by sorbitol (polyol pathway activation) due to the aldose reductase activity and results in lens fiber swelling/damage. This is a primary contributor in diabetic cataracts [14].

Impaired Ion Homeostasis and Calcium Dysregulation

The lens keeps its low intracellular concentration of Ca²? thanks to the function of Ca²? dependent ATPase pumps that provide important regulation on calcium homeostasis and avoid cellular injury. Nevertheless, cataract development is associated with a rise of Ca²? that causes activation of calpain proteases that cleave crystallin proteins holding lens transparency This protein degradation initiates fragmentation and aggregation of lens proteins finally causing clouding. Moreover, the dysfunction of Na?/K? ATPase pump leads to a change in ionic homeostasis maintaining Na? content inside lens fibers. This imbalance," Berson says, "promotes a strong elevation of osmotic pressure, that facilitates more water entering, lens swelling and therefore the loss of transparency which speeds cataract formation [15].

Need for Anti-Cataract Therapies: Importance of Pharmacological and Non-Pharmacological Approaches

Cataract — world's number one cause of blindness with millions infected especially the aged. It is a relentless manifestation of secondary lens opacities—the opacification of lens progresses to a point that vision is lost and, if untreated ultimately leads to blindness.The condition is mostly attributed to aging, but there are many factors (oxidative stress, metabolic disorders UV exposure and genetic predisposition all pretty important to the mix)Cataracts — The only established treatment for cataract is surgical at this time, yet cataract surgery is far from being universally available because of financial issues, distance to a health center and complication in surgery.Henceforth, a demand for efficient pharmacological as well as non-pharmacological methods exists that can either delay, preclude or even revert cataract development.In both cases the proposed approaches could be useful as alternatives (or complementary treatment) especially in resource limited settings[16].

Importance of Pharmacological Approaches

Pharmacological therapies focus on molecular mechanisms of cataractogenesis and include the modalities that prevent or delay lens opacification. Mainly is looking to minimize oxidative stress, prevent protein aggregation and restore lens transparency.

a) Antioxidants and Free Radical Scavengers

Oxidative stress is the major pathogenetic link of cataract formation because overproduction of reactive oxygen species (ROS) has been shown to cause massive lens protein and lipid injury. This oxidative damage cause lenses lose transparency and cataract occurs. The degradative action of these highly reactive molecules is crucial for antioxidants to scavenge them under oxidative stress and prevent lens degeneration in the eye. Various antioxidants (Vitamin C, Vitamin E, Glutathione and Selenium): All can prevent oxidative damage modulating the risk factor for a cataract. Lutein and Zeaxanthin (carotenoids found naturally in the retina) are also part of eye lens protection because they help shield the lens by absorbing UV-light and reducing oxidative stress. Besides protecting lens clarity these compounds have a profound protective effect in halting cataract development, which makes them central to cataract prevention deliberations [17].

b) Aldose Reductase Inhibitors (ARIs) for Diabetic Cataracts

When there is an excess of glucose in the body of diabetic patients it is metabolized using the polyol pathway, which converts glucose into sorbitol through the enzyme aldose reductase. Due to high levels of glucose, sorbitol is formed which causes osmotic stress within the lens of the eye; water is retained within the lens, disrupting the organization of lens fiber cells resulting in visual impairment by making the lens opaque and progressively worsen the condition of diabetic hymse in eye cataracts. ARIs, such as Epalrestat and Quercetin,have proven effective in preventing this process by blocking the enzyme that creates sorbitol. ARIs decrease sorbitol accumulation, and as such facilitate lens protection against osmotic forces and oxidative stresses thus, slowing or preventing cataract by reducing this osmotic risk associated with peripheral anterior synechiae. Several experimental models have confirmed the efficacy of those inhibitors, therefore they are pharmacological strategies to confront diabetes-induced cataractogenesis [18].

c) Anti-Protein Aggregation Compounds

Cataracts often develop due to the misfolding and aggregation of lens crystallins, which disrupts the normal transparency of the lens and leads to opacity. The accumulation of these aggregated proteins impairs vision and is a hallmark of cataract formation. In recent years, several potential therapeutic agents have been discovered, including Lanosterol and 25-hydroxycholesterol, both of which have been shown to prevent the aggregation of faulty proteins in experimental models and successfully restore lens transparency. Furthermore, N-Acetylcarnosine (NAC) eye drops (a prodrug of L-carnosine) have been evaluated in clinical trials that have demonstrated the ability to slow cataract progression, potentially deferring surgical intervention. Our findings suggest that anti-protein aggregation therapies can be a new testable therapeutic strategy for cataract treatment[19].

 Importance of Non-Pharmacological Approaches

a) Dietary and Nutritional Modifications

A nutrient-rich diet helps in reducing oxidative stress in the lens and preventing cataract formation. Antioxidant-rich diets, omega-3 fatty acids, as well as vitamins essential to muscle health protect lens proteins from oxidative stress or environmental damage. Vitamin C and Vitamin E, both essential nutrients are also found in citrus fruits, nuts, and seeds, play a prominent role as powerful antioxidants which protect the lens from UV-induced oxidative damage. It also contains lutein and zeaxanthin which are known for their role in protecting the lens against oxidative damage and ensuring the stability of lens proteins; however, the latter are found in spinach, kale and egg yolk. Similarly, Omega-3 fatty acids which occur naturally in foods such as fish and flaxseeds are highly effective in reducing inflammation while also enhancing the lens fibers structural integrity. Including these nutrients in a daily diet is one of the best prevention strategies for delaying cataract progression and maintaining general eye health[20].

b) Lifestyle Modifications

Because prolonged exposure to UV radiation has been linked to damage to lens protein and lens opacity, protecting the eyes from harmful UV rays is important for helping to prevent cataract formation. All the same, a pair of UV-blocking sunglasses can be an effective deterrent — reducing your risk of direct exposure to these damaging rays. Similarly, quitting smoking is important in cataract prevention, as smoking produces free radicals that induce oxidative stress to lenses and accelerate the formation of cataracts.Just as critical as keeping your blood sugar in a balanced state ( especially for diabetics) since unregulated glucose exposure can cause osmotic stress in lens cells and increases the probability of diabetic cataract is. Implementing these preventive lifestyle changes, people can reduce their risk of developing cataracts to a great extent and keep their lens healthy for longer, clear vision[21].

New Approaches and Directions

Liposome and nanoparticle-based delivery system for anti-cataract therapy in the nanotechnology

A dawn of nanotechnology based drug delivery systems in ophthalmology has been foreseen with cataract treatment lagging the ranking as one of the major causes of blindness worldwide and Nanomedicine will provide non-invasive, targeted & efficient drug delivery alternatives to traditional cataract treatments. Liposomes/nanoparticle are one of the effective routes to to deliver anticalattic agents for improving bio availability as well as retention time and in generally ingression into the lens. As biocompatible and specifically capable of forming liposomes including hydrophobic/ hydrophilic drug carriers, liposomal delivery systems have long been a hope. Nanoparticles (solid lipid nanoparticles, SLNs; polymeric nanoparticles; nanomicelle) have shown increased drug stability and targeted delivery with reduced systemic exposure[22].

Stem cell regenerative solution for an artificial lens

Regeneration of artificial lens using stem cell-based strategyHow stem cells enable artificial lens to be developed lie in the utilization of endogenous stem cells or exogenous them on restoring vision, especially for emerging diagnoses such as cataract. Hope is not lost though; In one of these strategies, most compellingly reviewed in Criado & Charles[1], say lens epithelial stem/progenitor cells (LECs) can be coaxed to re-grow a lens post-surgery. Studies indicated that activation of endogenous LECs by growth factor activation or gene editing may also lead to lens regeneration in prenatally cataracty infants (17). Alternatively, pure pluripotent stem cells (iPSCs and ESCs) can be guided to differentiate into lens-like cells in vitro and then transplanted into the eye. This is an alternative to the current approach of intraocular tissues (IOLs) that usually destroys natural accommodation and transparency. However, issues such as immune reactions, efficiency of integration and safety dilemmas are by far the most major bottlenecks to practical functional use[23].

Cataract Diagnosis using AI & Machine Learning | Drug Discovery with AI

Artificial intelligence (AI) and machine learning (ML) are rapidly changing cataract diagnosis as well as drug discovery through early detection, auto classification and faster therapeutic development. Deep learning models (classification meta such as CNNs and vision transformers) have proven very accurate at classifying cataracts in ophthalmic images thus driving the pace of any diagnosis, thus minimizing both overall error and human error. Besides, results of prior studies suggest that state-of-the-art architectures such as ResNet-18 and transformer based models can successfully separate cataracts from other ophthalmologic conditions in the field of precision medicine. In addition AI is also automating the discovery of existing drugs to find potential cataract treatments via molecular docking, virtual screening and predictive analytics to reduce the time and expenditure of conventional drug discovery. The time and technology associated with such advancements if envisioned into ophthalmic healthcare, the integration of these technologies into cataract management holds potential in enhancing patient care as well revolutionising outcome[24].

Biomarker Potential for Early Diagnosis

Cataract, one of the major causes of visual impairment in the world is characterized by the opacification of the eye lens due to oxidative stress, metabolic imbalance and aggregates of proteins [1. Oxidative stress, metabolic derangements, and protein aggregation lead to cataractogenesis-it is a systemic pathophysiological process affecting the majority of population. Identifying specific and reliable biomarker for the early diagnosis is the key to overcome clinical difficulty in early cataract detection. Evidence from recent studies has also shown that oxidative stress markers like malondialdehyde (MDA), advanced glycation end products (AGEs) and glutathione are important in cataractogenesis [4]. MDA and AGEs levels are increased as well as decreased GSH concentrations showing oxidative lens damage, protein modification, lens clouding. Furthermore, other cytokines (eg, tumor necrosis factor-alpha [TNF-alpha], IL-6 and IL-1 beta) have been implicated in lens epithelial cell dysfunction suggesting its potential as an early marker too; indeed lens-specific crystallins especially α-, β- and γ-crystallins display posttranslational modifications at early onset stage during cataract formation as promising diagnostic biomarker. Alterations in specific metabolite profiles (proteomic and metabolomic studies, respectively) also showed alterations as in the case with sorbitol and ascorbic acid or other amino acids indicating metabolic derangement of cataractogenesis. Therewith, integrating these molecular biomarkers with state-of-the-art imaging, and artificial intelligence-based diagnosis will enable rapid early detection of cataracts while implementing patient-centric management strategies to further enhance clinical outcome[25].

Challenges and Limitations

Side effects of anti-cataract drugs

Anti-cataract drugs, primarily aimed at preventing or slowing cataract formation, often work through antioxidant, anti-inflammatory, or metabolic regulation pathways. While some promising compounds have been identified, side effects remain a significant concern. The most commonly reported adverse effects include ocular irritation, allergic reactions, corneal damage, dry eyes, and systemic toxicity depending on the drug formulation and delivery method[26].

Experimental & Clinical Studies on Anti-Cataract Activity

In Vivo Studies:  Animal models play a crucial role in evaluating the anti-cataract potential of test compounds by mimicking cataract formation under controlled conditions. Among these, the galactose-induced cataract model in rats or mice is widely used, as excessive galactose intake leads to osmotic stress and oxidative damage in the lens. Similarly, the sodium selenite-induced cataract model in neonatal rats is useful for studying oxidative stress-related cataracts, as selenite exposure leads to crystallin protein aggregation and lens opacity. The STZ-induced diabetic cataract model mimics cataract formation in diabetic patients due to chronic hyperglycemia and oxidative damage. Additionally, UV-induced cataract models in rabbits or rats help assess the protective effects of compounds against radiation-induced protein denaturation in the lens. These in vivo models provide insights into disease progression, therapeutic efficacy, and pharmacokinetics of anti-cataract agents[27].

In Vitro Studies: In vitro assays are essential for assessing the anti-cataract activity of potential compounds at a cellular and biochemical level. Lens organ culture models involve incubating excised lenses in media with cataract-inducing agents like galactose or selenite, allowing real-time monitoring of lens opacity and drug effects. Protein aggregation assays measure the ability of test compounds to prevent the aggregation of crystallin proteins, a hallmark of cataractogenesis, often assessed using turbidity measurements via spectrophotometry. Oxidative stress marker assays evaluate changes in antioxidant enzyme levels such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), along with lipid peroxidation markers like malondialdehyde (MDA), indicating oxidative damage in lens cells. Additionally, aldose reductase inhibition assays are crucial in diabetic cataract research, as they determine whether test compounds inhibit aldose reductase, an enzyme responsible for sorbitol accumulation and osmotic stress in the lens. These assays help screen potential anti-cataract agents and elucidate their mechanisms at a molecular level[28].

Computational Molecular Docking: Molecular docking is an important application in preclinical cataract research that assists in prediction of virtual compounds interactions with any of the cataract related molecular targets. Aldose reductase docking studies are designed to find structural inhibitors owing to sorbitol buildup alleviation and thereby protecting diabetic cataracts from osmotic stress. The docking studies on calpain inhibition aim at determining small molecules that can target calpain and therefore block cataract by preventing lens protein degradation. Furthermore, antioxidant enzyme docking deals with interacting important test compounds to protective enzymes (SOD or CAT and GPx) that upregulate these docking interactions to boost antioxidant capacity against oxidative injury. Using docking simulations, growth inhibitors with potentially many of the desirable features of lead compounds can be identified and their structures optimized for the final identity of best candidates to undergo in vitro or in vivo validation; thereby expediting the process of finding new drugs for cataract treatment[29].