A Review of Pharmacological Agents for Cataract Prevention

Shrushti Darade, Pratik Bhand, Ajay Bhagwat, Ishwari Borhade, Priyanka Narasale, Swapnil Auti,

doi:10.5281/zenodo.17746753

Review Paper | Open Access
Volume 03 | Issue 11 | Article Id IJPS/250311596

A Review of Pharmacological Agents for Cataract Prevention
Shrushti Darade* Pratik Bhand Ajay Bhagwat Ishwari Borhade Priyanka Narasale Swapnil Auti
Samarth College of Pharmacy, Belhe, Pune. Maharashtra. India. 412410.

Abstract

Globally, cataracts continue to be the primary cause of blindness and visual impairment. 180 million people worldwide are thought to be sight-impaired. Of these, 37 million are blind, and with 28,000 new instances reported every day, the figure rises by one to two million per year. Fifty per cent of blindness worldwide is caused by cataracts. The percentage of children who are blind from cataracts varies greatly by location, ranging from 10% to 30%. The global average is believed to be 14%, meaning that 190,000 children are blind as a result of cataracts. The only treatment available at the moment is surgically removing the cataractous lens and replacing it with a synthetic polymer lens. Nevertheless, the prevalence is so high that the surgical facilities that are now available cannot handle the issue. Postoperative problems, including endophthalmitis, posterior capsular opacification, and uncorrected residual refractive error, may also arise. As a result, pharmaceutical interventions that preserve the lens's transparency are being sought. To define the aetiology of cataracts, a great deal of study has been done during the past 20 years. Numerous medicines have been used in an attempt to postpone the start of cataracts and reduce their progression. Regretfully, no single drug has shown clinical utility for this purpose despite significant efforts. This review highlights the various pharmaceutical approaches for preventing cataract formation and the risk factors associated with cataractogenesis.

Keywords

Cataract, Antioxidant, non-enzymatic glycation, Oxidative stress, Polyol pathway

Introduction

1. Factors Involved in Cataract Formation

The pathophysiology of senile cataract has been associated with several risk factors. In addition to age, cataract development is caused by smoking, diabetes, gender, steroids, and nitric oxide. These risk factors have been linked to various cataract morphological types.

Smoking

It is believed that smoking raises the risk of cataracts, at least in part, by increasing the oxidative stress that free radicals produced in the lens cause.^[1-5] In the presence of these free radicals from tobacco smoke, they have the potential to directly harm the lens's Epithelial cell membrane and lens protein ^[6,7] When a person smokes or chews tobacco, a significant amount of cadmium (Cd) is taken into the body. This Cd substitutes bivalent elements like zinc (Zn), copper (Cu), and manganese from superoxide dismutase (SOD), a potent antioxidant.^[8]

- Diabetes

Diabetes can affect the eyes in a number of ways, but cataracts are the most prevalent cause of visual loss. One of the first secondary consequences is cataractogenesis of diabetes mellitus, a severe metabolic condition marked by hyperglycemia.^[2] There are a few theories as to how diabetes mellitus causes cataracts, including elevated free radical generation, aberrant glycosylation of lens proteins, and high tissue sorbitol concentrations. ^[9]

- Female gender

Several epidemiological studies that used cross-sectional data have revealed that women are more likely than men to get cataracts.^[10]The reason behind Although the exact cause of the gender disparities in cataract incidence is unknown, it may be linked to the hormonal differences between men and women. One possible contributing factor is postmenopausal estrogen insufficiency. There is some indication from recent epidemiologic data that estrogen and hormone replacement therapy may help lower the incidence of age-related cataracts.^[11]

- Steroids

It is commonly known that using steroids increases the risk of developing cataracts. There appears to be agreement that the longer the time, the larger the steroid dose of usage, the greater the chance of developing posterior subcapsular cataracts.^[12]Steroids impede the cation pump in the lens capsule, which leads to an electrolyte/water imbalance that causes cataracts.^[13]

- Nitric oxide

Although nitric oxide (NO) is not a very harmful substance by itself, it can combine with other molecules to produce more reactive chemicals. For instance, the interaction with nitric oxide (NO) produces peroxynitrite (ONOO−), which damages cells extensively and may play a significant part in the development of diabetic cataracts.^[14,15]In addition to the risk factors listed above, genetic variables, socioeconomic status, sunshine, ultraviolet (UV), myopia, renal failure, diarrhoea, malnutrition, illiteracy, and hypertension, Cataractogenesis has also been linked to exposure, obesity, chemical burns, glaucoma, and alcohol^[16,17][Fig. 1].

Figure 1: Major risk factors implicated in cataractogenesis

1. Mechanisms Related to Cataract

Human cataract development is caused by a number of intricate metabolic and physiological processes that work together to alter the refractive index. ^[18] Research on lens proteins shows that chemical processes, including oxidation, glycation, Schiff base formation, proteolysis, transamination, carbamylation, phosphorylation, and increased calcium levels, cause post-translational modifications in the lens proteins during cataractogenesis. ^[17] [Figure 2]. To promote aggregation, disruption of normal lens cell structure, and opacification, the post-translational modifications change the attractive forces between lens proteins. ^[2]

Figure 2: Mechanisms associated with cataractogenesis

This article describes the function of the following pathways in the development of cataracts among the various mechanisms put out for cataractogenesis.

a. non-enzymatic glycation

b. Oxidative stress

c. Polyol pathway

- Non-enzymatic glycation

When blood glucose levels are high, some of the extra glucose reacts non-enzymatically with proteins or other components of tissue or blood, raising the pace of non-enzymatic glycation in the body. ^[19] Long-lived molecules, extracellular matrix, eye lens crystallins, and chromosomal DNA are the main causes of chronic, permanent problems that are not affected by blood glucose correction. Advanced products of non-enzymatic glycation are crucial to the development of sugar cataract because of their distinctive chemical characteristics. As the first stage of the intricate Maillard process, the synthesis of advanced glycation end products (AGEs) starts with the attachment of a glucose carbonyl group to a free amino group of proteins or amino acids to produce a labile Schiff base adduct. The unstable Schiff base levels rise quickly, and equilibrium is reached after a few hours. Schiff base adducts, once created, undergo a gradual chemical rearrangement over several weeks to create an Amadori product that is more stable but still chemically reversible ^[20][Flow chart No. 1].

Flow chart No.1:

Because Amadori products might potentially undergo a wide spectrum of rearrangements, specific chemical identification of AGE proteins has proven challenging. Immunological
and chemical evidence suggests that the gradual build-up of AGEs in the diabetic eye lens accelerates the development of cataracts in both diabetic humans and hyperglycaemic experimental animals. ^{[21, 22]}

- Oxidative stress

The pathogenesis of cataract is significantly influenced by oxidative stress of cataract ^[23]. An imbalance could lead to oxidative stress between the generation of ROS (reactive oxygen species) and the antioxidant defence systems within cells. Within the cells of the ROS may cause a spike in harmful metabolic processes in the eyes. such as severe protein degradation leading to intracellular protein aggregation and peroxidation of membrane lipids, precipitation, which ultimately results in lens opacification. ^{[24, 25]} The redox set point of the single layer of lens epithelial cells rapidly shifts from a strongly reducing to an oxidising environment when the eye is exposed to oxidative stress. Significant damage to the DNA and membrane pump systems occurs almost simultaneously with this alteration. This is followed by the death of epithelial cells through necrotic and apoptotic processes, which results in cataract. ^{[26, 27]}

- Polyol pathway

Diabetic cataracts progress by a different process than senile cataracts. The buildup of polyols inside the lens is the main contributing element. Insulin is not necessary for glucose and other simple carbohydrates to penetrate some bodily tissues, such as the lens of the eye. Sugar can diffuse passively into the lens due to its high concentration in the aqueous humour in diabetics. The lens's enzyme aldose reductase changes glucose into sorbitol or galactose into galactitol [Fig. 4]. These polyols are unable to collect or convert into fructose by diffusing passively out of the lens. An osmotic gradient created by the buildup of polyols promotes the diffusion of fluid from the aqueous humour.

Pharmacological Strategies for Prevention of Cataract: Drugs have been developed that are aimed at interacting at the level of altered lens metabolism and lens pathophysiology. The anticataract agents claimed to be effective in vitro, in vivo and in epidemiological studies may be broadly classified in the following categories:

Aldose reductase inhibitors
Non-steroidal anti-inflammatory drugs
Agents acting on glutathione
Vitamins, minerals, antioxidants and herbal drugs
Miscellaneous agents
- Aldose reductase inhibitors (ARI)

The goal of ARI is to obstruct the glucose metabolic pathways that cause diabetic vascular impairment. Their part in preventing diabetic cataract in animals is now widely recognised. ^{[28, 29]} Aldose reductase has been reported to be inhibited by a wide variety of synthetic and natural substances. By binding to aldose reductase, these so-called ARI prevent the synthesis of polyols. Since the enzyme aldose reductase is very slow with glucose, the justification for employing sorbitol-lowering medications has diminished with time. Moreover, sorbitol does not build up in adult human lenses cultured in high glucose conditions. Several ARI are known to have anticataract potential and to postpone the cataract caused by galactose in several experimental animals. ^[30] Alrestatin, sorbinil, sulindac, naproxen, aspirin, Tolrestat, statin, and bioflavonoids are a few of these.

Figure 4: Polyol pathway

Flavonoids are among the most potent naturally occurring ARI. Various studies of in vitro animal lenses incubated in high-sugar mediums, flavonoids have found to inhibit aldose reductase.^[31,32]In our previous studies, the flavonoids quercetin and myricetin have exhibited signiÞ cant delay in the onset and progression of galactose cataract in rats.^[33]The flavonoids quercetrin and quercetrin-2-acetate, quercetin, rutin, hesperidin, hesperidin chalcone and naringin exhibited AR-inhibiting activity to different extents.^[34]A recent study was carried out to evaluate the potential of AR-inhibiting bioflavonoids extracted from fruits of G. applanatum. ^[35]

A recent study done by Varma et al. showed that administration of pyruvate prevented cataract development by inhibiting the AR in diabetic rats.37 The AR-inhibiting activity in Emblica officinalis was investigated, and it was found to be better than quercetin.^[38]Similarly, vitamin C also has potential as an ARI, with both animal and clinical studies showing that it minimises the levels of sorbitol.^[38,39] Gymnema sylvestre aqueous extract showed potential AR inhibition in sugar-induced cataract and had also protected the lens against osmotic damage.^[40]Table 1 shows some of the most commercially available flavonoids and herbal drugs and their comparative inhibitions. Among the ARI, only sorbinil reached the advanced clinical trial stages in the cataract prevention program. However, due to the manifestation of skin rashes, the trial had to be discontinued. In spite of extensive research input, clinical trials of the sorbitol-lowering agents have not provided convincing evidence of their efficacy.

- Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) have emerged as another group of drugs with anticataract potential. The Þ rst indication regarding the probable use of NSAIDs as prophylactic anticataract agents came from studies on aspirin use in patients with rheumatoid arthritis and diabetes.^[41]

Table 1: Aldose reductase inhibiting activity of some ß avonoids

Flavonoid

Percent inhibition

Quercetrin-2-acetate ^[32]

Quercetrin ^[32]

Quercetin ^[32]

Rutin ^[32]

Hesperidin ^[32]

Hesperidin chalcone ^[32]

Naringin ^[32]

Emblica ofÞ cinalis^[37]

100

82.4

Thereafter, a variety of NSAIDs with different chemical structures have been reported to retard the phenomenon in experimental animals. The NSAIDs extensively such as aspirin, paracetamol, ibuprofen, naproxen, and sulindac. and bendazec.^[42-44]The anticataract activity of these drugs is explained by virtue of their effect on different biochemical pathways. The mechanisms associated with the protective effect of NSAIDs include acetylation, inhibition of glycosylation and carbamylation of lens proteins.

We have earlier shown that naproxen delays the onset and progression of galactose-induced cataract in rats. Moreover, naproxen was also tested for its in vivo effectiveness in rat pups developing cataracts under the oxidative inß uence of sodium selenite.^[46]To explain the mechanism of action of Naproxen as an antioxidant, its effect on light-induced lipid peroxidation in isolated rat lenses was studied, and depletion of lens glutathione and a rise in malondialdehyde levels were observed.^[47]It was also shown that sulindac inhibits lens Polyol to a large extent by its possible inhibiting action on lens AR.^[48]Comparative studies on the anticataract activity of Various NSAIDs demonstrated that though inhibition of lens AR by NSAIDs may be a signi?cant factor-it does not appear to be the sole cause.^[45]The hypothesis of acetylation of lens protein by aspirin does not justify the mechanism of action of other NSAIDs, such as ibuprofen do not have an acetyl group. The Results obtained so far suggest that there are several sites where NSAIDs likely act to impede cataract progression. However, their mechanisms of action need to be elucidated. action in more detail under different culture conditions and in different experimental models.

Anticataract activity of aspirin, sulindac, and naproxen eye drops was also studied, and they were found to delay both onset and progression of cataract in different models of cataractogenesis; moreover, there were no adverse side effects. Even after long-term application 49, subsequent studies further confirmed that aspirin is a potential anti-cataract agent.^[50]Bendazac, a compound similar to indomethacin in its structure, emerged as a potential radical scavenger and anticataract agent. Bendazac protects lens and serum proteinsfrom denaturation in vitro and in vivo.^{[51, 52]}5-hydroxybendazac, a derivative, however, was found to be more effective than the parent compound in protecting lens proteins against cyanate, glucose 6-phosphate and galactose.^[53]Another derivative, bendazac lysine, was found to have better absorption in animal and human studies, and it is reported to delay cataractogenesis.^[54]Bendazac-lysine has undergone clinical trials, but these studies have been small and of short duration.^[55]Bendazac-lysine is already available as an anticataract drug in Italy and in several other European countries, under the trade name of Carbopol. 980NF manufactured by Goodrich Limited.

- Agents that act on glutathione:

The most important function of GSH is to inactivate and render excess free radicals and render them harmless. GSH consists of the amino acids cysteine, glutamic acid, and glycine, and its synthesis within the lens occurs in two ATP-dependent steps [Fig. 5]. There are several ways in which GSH or its depletion can affect the opacity of the lens. A review by researchers on GSH ^[56].

- Mechanisms of cataract prevention are:

1. Maintaining sulfhydryl (SH) groups on proteins in their reduced form, preventing disul de cross-linkage

Protecting SH groups on proteins important for active transport and membrane permeability
Preventing oxidative damage from H2O2

Figure 5: Synthesis of glutathione within the lens

GSH concentration decreases with age in the lens and more markedly in cataract.^[34]GSH has been reported to control calcium inß ux and protect lens protein against damaging e?ects of osmotic and oxidative stress. ^[5,57]. ALarge amount of Research has been done on antioxidants and vitamins, and the role of GSH in preventing cataract has been reported. A recent study shows that vitamin E protects the anti-oxidative defence mechanism indirectly or directly by increasing levels of GSH.^[58]The anticataract effect of melatonin PSI (a scavenger of free radicals) was demonstrated, and the study concluded that the effect is due to its stimulatory effect on GSH production.^[59]Clinical trials on Phaken, a preparation containing three constituents of amino acids GSH plus arginine, inositol, pyridoxine and ascorbic acid, have demonstrated improvements in visual performance. acuity, but due to a high dropout rate, no clear-cut conclusions could be drawn. ^[60]

- Vitamins, minerals, antioxidants and herbal drugs:

It is generally known that vitamins, particularly vitamin C or ascorbic acid, which is crucial to lens biology as a UV filter and antioxidant, may help prevent cataracts. ^[61] Ascorbate concentrations in the lens decreased as a result of vitamin C deficiency in the diet. ^[62] Ascorbate prevents galactose cataract, according to a study conducted on guinea pigs. ^[63] In a similar vein, another study shows that ascorbate consumption raises vitamin C levels in rat lenses. ^[64] Additionally, vitamin E plays a significant role in the antioxidant status of lenticles. Numerous studies have assessed vitamin E's anticataract potential and discovered that it is effective against UV radiation, steroids, and galactose-induced cataract. ^{[58, 65–67]} The precursor to flavin adenine dinucleotide (FAD), a coenzyme for the manufacture of glutathione reductase, is riboflavin. In vitro assessments of surgically excised cataracts have confirmed that glutathione reductase enzyme activity is inactive in a significant majority of the cataracts analysed. ^[68] Additionally, the addition of FAD restored the activity. A study comparing the B vitamin nutritional status of age-matched controls without cataracts (n = 16) and cataract patients (n = 37) revealed that only 12.5% of control subjects and 80% of cataract patients had a riboflavin deficiency. ^[69]

- Minerals:

The excessive free radical attack implicated in the development of cataract can be prevented by dietary intake of micronutrients such as zinc, copper and manganese. Copper and zinc are required for the catalytic activity of metal proteins and SOD.^[70]Plasma levels of zinc and copper were found to be significantly low in cataract patients.^[69]Selenium is an integral part of the enzyme glutathione peroxidase. A decrease in glutathione peroxidase activity has been found in the lenses of selenium-deficient rats.^[71]

- Antioxidants:

It is commonly acknowledged that oxidative stress plays a significant role in the development of cataracts. ^[72–74] Because superoxide is transformed into the harmful chemical hydrogen peroxide, oxidative stress is linked to an increase in reactive oxygen species and is known to hasten the development of cataracts. Antioxidant enzymes like glutathione peroxidase, superoxide dismutase, and catalase stop this process. One important preventive measure against oxidation-related cataractogenesis is the use of antioxidants. The impact of dietary antioxidant supplements on cataract incidence has been the subject of numerous epidemiological and interventional investigations. • Carotenoids are natural lipid-soluble antioxidants. It is reported that persons with a high intake of carotene reduce the risk of cataract^[75]and the relationship between nuclear cataract and intakes of α-carotene, β-carotene, lutein, lycopene and cryptoxanthin stratifying by gender and by regular multivitamin use.^[76] All carotenoids, including lycopene antioxidative activity and exert a protective effect against various diseases.^[77]In previous studies, we found that lycopene protects against oxidative stress-induced experimental cataract^[74] and prevents sugar-induced diabetic cataract.^[57]• Turmeric’s key ingredient, curcumin, has been demonstrated to have antioxidant properties both in vitro and in vivo. ^[78] Curcumin’s effect on cataracts has also been demonstrated. Curcumin postponed the development of diabetic cataracts caused by streptozotocin and galactose ^[79]. ^[80] Curcumin also stopped cataract development brought on by oxidative stress. ^[81]

A new synthetic pyridoindole called stobadine has been shown in numerous experiments to be an effective antioxidant ^[82] and to shield bovine serum albumin from glycol oxidative harm. It has been demonstrated that stobadine can postpone the onset of diabetic cataract. ^[84]

- Herbal drugs:

Investigating the potential of utilising our natural resources to postpone the start and progression of cataracts has received a lot of attention in recent years. It has been observed that medicinal herbs and their preparations have antioxidant qualities and provide cataract protection. The aqueous extract of Ocimum sanctum has been demonstrated by Gupta et al. to have promising anticataract action against oxidative stress-induced experimental cataractogenesis. Restoring the antioxidant defence system increased the protective effect. ^[85] The aqueous extracts of Pterocarpus marsupium and Trigonella foenum-graceum, two well-known herbal antidiabetic medications, have a positive anticataract effect. ^[86]

Proanthocyanidin extract from grape seeds effectively inhibited the development of cataracts in rats, according to a recent study. ^[87] Emilia sonchifolia's flavonoids alter the lens's opacity and oxidative stress in cataracts caused by selenium. ^[88] Dregea volubilis is a medicinal plant that has long been used to cure a variety of eye conditions. Its potential anticataract effect has now been scientifically demonstrated, and it has also been discovered that the effect is caused by the triterpenoid aglycone drevogenin D. ^[89]Bilberry, also known as Vaccinium myritillus, has long been used to treat a variety of eye disorders. ^[34]A combination of bilberry and vitamin E prevented the progression of cataracts up to 96% in a clinical trial report of 50 individuals with senile cataracts. ^[90]

Certain herbal drugs, especially Ginkgo biloba extract, have been found to possess potential therapeutic effects in radiation-induced cataract.^[91]Most of the studies conducted focus on green tea, Camellia sinensis. and the explained antioxidative potential is the major mechanism in the prevention of cataractogenesis. Gupta et al. have demonstrated that green tea protects against selenite-induced cataract and acts mainly by preserving the antioxidant defence. system.^[92]It was also presented that the oxidative potential of green tea retards the progress of cataractogenesis. ^[93] Recently, both green tea and black tea have been shown to delay the development of diabetic cataract, also by hypoglycemic effect.^[94]The recent study reveals that E. officinalis, also known as amla, used against diabetes, is also effective in delaying the progression from diabetic cataract.^[95]The herbal formulation Diabecon is used for diabetics, contains 25 herbal drugs. inhibited the sugar-induced lens opacity in organ culture and also showed that the effect is mainly due to Gymnema sylvestre, which is one of its constituents.^[40]A study by our laboratory on polyherbal preparation, Chyavanprash, containing about 35 natural herbs. including amla), found it to be protective against steroid-induced opacities in the lens of the chick embryo.^[96](Table 2) summarises potential vitamins, antioxidants and herbal drugs for the prevention and treatment of cataract.

- Miscellaneous Agents:

Different materials with different chemical structures and It has been discovered that some characteristics have a protective effect against cataract in different experimental models. A study was conducted with pyruvate, a compound of metabolic origin and having an alpha-keto-carboxyl group. It was discovered effective in preventing the development of cataracts in diabetics^[97]as well as in selenite ^[98]models of experimental cataracts. A study was also carried out using alpha-ketoglutarate and discovered an extremely strong anticataratogenic effect in selenite-induced cataract ^[98]ACE inhibitors have been shown to provide defence against free radical damage under a variety of experimental circumstances ^[99] Lisinopril and enalapril's anticataract efficacy was recently assessed in vitro using glucose-induced cataract and found to Significant protection. A decrease in malondialdehyde in the treated lens led the study to conclude that the effect might be due to the antioxidant and free radical scavenging activity. ^[100] Age-related cataracts can be effectively prevented and treated using N-acetylcarnosine, which is marketed as the ophthalmic medication Can-C. In recent clinical research, it was demonstrated to provide an effective, safe, and long-lasting improvement in vision while shielding the crystalline lens from oxidative stress. N-acetylcarnosine acts as a time-release prodrug form of L-carnosine that is resistant to hydrolysis with carnosinase when Can-C is applied topically.

N-acetylcarnosine has the capacity to function as a universal antioxidant in vivo due to its
capacity to defend against oxidative damage in the lipid phase of biological cellular membranes and in the aqueous environment by a gradual intraocular turnover into L-carnosine. The clinical
Effects of a topical solution of Can-C on lens opacities were studied in elderly dogs and individuals with cataracts associated cataracts. These findings demonstrated that N-acetylcarnosine.

It is successful in treating age-related cataract reversal. and prevention in both canine and human eyes ^[101]. There have long been reports of the protective effects of alpha lipoic acid ^[102], pantethine ^[103], DL-penicillamine ^[104], and deferoxamine ^[105], but sadly, none of these medications have proven clinically assessed. Many anticataract medications, such as Itone (a blend of 19 herbal remedies, including triphala and tulsi),^[106-109] as well as a few other herbal remedies, are accessible in India without any evidence of their effectiveness; therefore, thorough scientific research is needed to determine the effectiveness of these herbal remedies.

Numerous areas of research on anticataract medications are progressing, and some medications have advanced to the point of clinical testing. Additionally, several organisations are attempting to look at the anticataract effects of both synthetic and natural medications.^[110-117] Our initial research on the usage of a unique combination of a few antioxidants and herbal medications has shown promising results. It appears likely that some of these substances will be demonstrated to be effective in postponing or decreasing the onset of cataracts in the future.

CONCLUSION

Numerous studies on the prevention and treatment of vitamins, minerals, herbal medications, and nutritional supplements have been conducted in vitro, in vivo, and epidemiologically of cataracts. The majority of research is still in its early stages, despite the fact that a number of medications may be able to treat cataracts. However, more extensive and prospective clinical research is required about the use of herbal medications and nutrients to treat cataracts. Similarly, therapeutic intervention is limited by the potential for toxicity linked to prolonged exposure to most medications. Positive reports exist regarding the topical application of these medications with negligible or no adverse effects. Preventing or delaying cataract blindness in humans through such an application will prove to be a significant accomplishment.

Conflicts Of Interest

There are no conflicts of interest or disclosures regarding the manuscript.

ACKNOWLEDGMENT

The authors sincerely thank Samarth College of Pharmacy, Belhe, University Libraries, and all other sources for their cooperation and advice in writing this review.

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