Antioxidant potential of chlorogenic acid in Age‐Related eye diseases

Abstract

Oxidative stress is an important mechanism of aging, and in turn, aging can also aggravate oxidative stress, which leads to a vicious cycle. In the process of the brain converting light into visual signals, the eye is stimulated by harmful blue‐light radiation directly. Thus, the eye is especially vulnerable to oxidative stress and becomes one of the organs most seriously involved during the aging process. Cataracts, age‐related macular degeneration (AMD), glaucoma, diabetic retinopathy (DR), and dry eye are inextricably linked to the aging process and oxidative stress. Chlorogenic acid (CGA) has been demonstrated to have antioxidant and anti‐inflammatory activities, and its validity has been established experimentally in numerous fields, including cardiovascular disease, metabolic disorders, cancers, and other chronic diseases. There has previously been evidence of CGA's therapeutic effect in the field of ophthalmopathy. Considering that many ophthalmic drugs lead to systemic side effects, CGA may act as a natural exogenous antioxidant for patients to take regularly, controlling their condition while minimizing side effects. In this paper, in vitro and in vivo studies of CGA in the treatment of age‐related eye diseases are reviewed, and the prospects of CGA's antioxidant application for the eye are discussed. The aim of this review is to summarize the relevant knowledge and provide theoretical support for future research.

Abbreviations

4‐HNE

4‐hydroxynonenal

8‐OHdG

8‐hydroxydeoxyguanosine

A2E

Bis‐retinoid N‐retinylidene‐N‐retinylethanolamine

AMD

Age‐related macular degeneration

AR

Aldose reductase

CAT

Catalase

CGA

Chlorogenic acid

CQA

Caffeoyl quinic acid

DR

Diabetic retinopathy

GPX

Glutathione peroxidase

GSH

Glutathione

HIF‐1α

Hypoxia‐inducible factor 1α

HO1

Heme oxygenase 1

INL

Inner nuclear layer

IOP

Intraocular pressure

IPL

Inner plexiform layer

MDA

Malondialdehyde

NPDR

Non‐proliferative DR

ONC

Optic nerve crush

PDR

Proliferative DR

RGC

Retinal ganglion cell

ROS

Reactive oxygen species

RPE

Retinal pigment epithelial cells

SMEDDS

Self‐microemulsifying drug delivery systems

SOD

Superoxide dismutase

1. INTRODUCTION

The ocular consequences of age‐related eye diseases continue to affect one's physical and mental health as well as quality of life. As the population ages and life expectancy rises, age‐related eye diseases are causing enormous economic burdens to society. ¹ To date, the exact underlying mechanism of aging is not yet clear. Among many theories of aging, the free radical theory is well supported and the most widely accepted. The theory holds that oxidative stress is an important mechanism of aging. The accumulation of reactive oxygen species (ROS), arising from several cellular sources such as mitochondria, NADPH oxidase, xanthine oxidase, cytochrome P450 enzymes, and inflammatory responses, contributes significantly to oxidative stress. Such accumulation leads to damage of cellular components, including proteins, lipids, and DNA, causing cell inflammation and apoptosis. ² This, in turn, can contribute to organismal aging and physical dysfunction, ultimately resulting in a series of age‐related eye diseases. ³ , ⁴ At the same time, aging itself also increases oxidative stress. On the one hand, endogenous antioxidants decrease with increasing age, accompanied by excessive radical and lipid peroxide generation. On the other hand, senescent cells upregulate inflammatory factor expression and disrupt homeostasis within local tissues, leading to the generation and maintenance of elevated oxidative stress status. Thus, increased inflammation and oxidative damage become typical characteristics of aging, and a vicious cycle is formed between oxidative stress and aging. ⁵

Decreased antioxidant defense coupled with long‐term oxidative stress in ocular tissues leads to structural tissue changes or functional deficits. For example, there is increased vascular permeability and neovascularization with age. When these pathological changes occur in the cornea, conjunctiva, blood vessels, and optic nerve, the clinical presentation may be characterized by ocular surface inflammation, lens opacity, elevated intraocular pressure (IOP), and retinal degenerative disorders. ⁶ For ocular redox imbalance, we can improve systemic symptoms associated with the aging process by supplementation with exogenous antioxidants. ⁶ Local or systemic antioxidant therapy in age‐related ophthalmopathy has attracted the attention of many researchers. However, due to the structural particularity of the eye, many drug therapies in the treatment of ophthalmopathy have some limitations and are often accompanied by systemic side effects. ⁵ To pursue long‐term disease control with minimal side effects for patients, there is an increasing call for the prevention and treatment of age‐related eye diseases using natural antioxidants.

Chlorogenic acid (CGA), formed by the condensation of caffeic acid with quinic acid, is one of the signature polyphenols in many natural plants, including coffee beans, fruits, vegetables, and various herbs. ⁷ Convincing evidence shows potential therapeutic implications of CGA in pathological phenomena such as excessive oxidative stress, ⁸ inflammatory response, ⁸ metabolic disorder, ⁹ neuronal injury, ¹⁰ vascular aging, ¹¹ gastrointestinal disturbance, ¹² and cancers. ¹³ CGA possesses powerful biological activity, yet its oral bioavailability remains low, which has limited its full exploitation for disease prevention and treatment. Particularly in the context of eye diseases, the number of studies exploring CGA's utility is still limited. Fortunately, recent years have seen a surge in research efforts to optimize CGA administration and improve its bioavailability. ¹⁴ , ¹⁵ Thus, given the clinical potential of CGA, we believe that CGA treatment of eye diseases has immense clinical value. By reading the published literature, this article reviews in vitro and in vivo studies of the antioxidant effects of CGA in age‐related eye diseases.

2. ANTIOXIDANT ACTIVITY OF CGA

Commonly used metrics of the body's redox state are the levels of oxidation‐related proteins, which include oxidative stress markers (ROS, NO, etc.) and antioxidants. The antioxidant system comprises exogenous and endogenous antioxidants. Common endogenous antioxidants include superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione (GSH). DNA integrity is another important indicator of the redox state. Reactive oxygen and nitrogen species can directly damage DNA bases or indirectly promote DNA damage by interfering with DNA replication. ¹⁶ In addition, the level of lipid oxidation is also an important index for measuring the oxidation status of the human body. ROS can initiate lipid peroxidation, resulting in the accumulation of lipid peroxidation products such as hydroperoxides and malondialdehyde (MDA). ⁸ Under normal circumstances, oxidative stress and antioxidant activity are in a state of dynamic equilibrium. In contrast, when the balance between the production of ROS and endogenous antioxidative mechanisms fails, cell homeostasis can be disrupted. ¹⁷ Free radicals damage mitochondrial DNA, and ROS act as secondary messengers to further amplify the inflammatory response, leading to early apoptosis of cells and accelerating aging and disease progression in the body. ¹⁸ , ¹⁹

In addition to endogenous cellular antioxidant species, natural food is also an essential source of antioxidants. CGA is highly abundant in many fruits, vegetables, and botanicals and is one of the most powerful polyphenols in human diets. ²⁰ CGA is adopted in a broad range of fields, including medicine, food, and biochemistry, because of its powerful antioxidant activity. Although there are several isomeric forms of CGA in a generalized sense, its name usually specifies the most common isomer, 3‐caffeoyl quinic acid (3‐CQA, renamed 5‐CQA). ²¹ The molecular formula of CGA is C₁₆H₁₈O₉ with a molecular weight of 354.31 g/mol. The chemical structure of CGA is shown in Figure 1. The number of hydroxyl groups on the aromatic ring is considered responsible for the antioxidant properties of phenolic acids. ²² CGA has five hydroxyl groups and one carboxyl group. This special molecular structure is responsible for the strong scavenging activity by donating the hydroxyl group to the free radicals. Hydroxyl radicals are highly reactive and can react with superoxide anions and other radicals they encounter, forming stable intermediate radicals. This process hinders lipid oxidation and contributes to the overall protection of tissues against oxidative damage. ⁸ , ²³

FIGURE 1.

Chemical structure of CGA.

Multiple studies have indicated the antioxidant potential of CGA. One study reported that CGA can decrease the levels of ROS, the proinflammatory cytokines IL‐1β and TNF‐α and apoptotic cells in UV‐induced skin fibroblasts. It also increases the expression of live cells and COL‐3 gene expression and thereby plays an anti‐inflammatory and anti‐aging role. ²⁴ Another study found that CGA can effectively reduce the level of ROS and peroxides in alcohol‐induced injury of mouse hepatocytes and decrease the production of 8‐hydroxydeoxyguanosine (8‐OHdG), a marker of DNA damage, and 4‐hydroxynonenal (4‐HNE), a marker of lipid peroxidation, thus inhibiting inflammatory apoptosis and fibrosis and playing a protective role in liver injuries. ²⁵ Apocynum venetum tea extracts can ameliorate hepatocyte edema, reduce the concentration of proinflammatory factors, and increase the expression of anti‐inflammatory factors, of which CGA has been identified and reported as the main active component. ²⁶ Negative regulatory nuclear transcription factor 2 (NRF2) can bind to antioxidant response elements within the cell nucleus, promoting the transcription of various antioxidant genes. ²⁷ Under physiological conditions, NRF2 is present at low concentrations in the cytoplasm. Under oxidative stress conditions, NRF2 translocates into the cell nucleus to maintain redox homeostasis. ²⁸ A study showed that CGA can promote the expression of the antioxidant proteins heme oxygenase 1 (HO1) and NQO‐1 by regulating the NRF2 pathway, increasing SOD activity and the level of GSH, reducing the accumulation of MDA, and inhibiting the expression of apoptosis‐related proteins (cleaved caspase 3 and caspase 9), exerting a neuroprotective effect in rats with cerebral ischemia‐reperfusion injury. ¹⁰ Another study also demonstrated that CGA, through activating the NRF2 pathway, enhances the expression of the downstream antioxidant effectors HO1, NQO1, and GPX1, ameliorating endothelial dysfunction in diabetic mice. ¹¹ , ²⁸ Additionally, CGA can alleviate intestinal barrier disruption in weaned piglets by activating the NRF2/HO1 pathway. ¹² Moreover, CGA can attenuate oxidative stress‐induced inflammation and injury of the intestinal epithelium by coregulating the PI3K/Akt and IκBα/NF‐κB signaling pathways. ²⁹ Accumulating evidence suggests that CGA can combat oxidative damage, with a well‐established research base. CGA inhibits inflammatory cell apoptosis by reducing the level of oxidative stress and mitigating lipid peroxidation and DNA damage (Figure 2).

FIGURE 2.

Antioxidant mechanism of CGA.

3. ANTIOXIDANT ACTIVITY OF CGA IN THE EYE

Oxidative stress can trigger apoptosis through mitochondrial membrane depolarization and the release of proapoptotic factors, resulting in tissue damage. In addition, mitochondria are susceptible to DNA damage. This is why mitochondria play a major role in processes related to aging. ¹⁸ The eye is a relatively independent sensory organ with a complex anatomical structure and specialized physiological characteristics. The eye is directly exposed to sunlight, environmental pollution, and other ROS sources. It converts external light signals into visual information through complex biological processes, and that process is metabolically active and requires a constant supply of blood and oxygen. As such, the eye is extremely vulnerable to oxidative stress. Oxidative stress caused by excess ROS is considered a key factor in some retinal diseases (such as age‐related macular degeneration (AMD), glaucoma, and retinopathy) and ocular surface diseases (including cornea, conjunctiva, lacrimal gland, and meibomian gland dysfunction), and lens opacity. ³⁰ , ³¹ , ³²

A large amount of evidence suggests that CGA can negatively regulate oxidative stress and the inflammatory response. ⁸ Although there are significant inter‐individual differences in the absorption, utilization, and metabolism of CGA, it is currently known that it undergoes varying degrees of metabolism in the gastrointestinal tract, liver, and kidneys, with distribution throughout the systemic circulation. ⁷ Various in vivo and in vitro studies have demonstrated its broad biological effects and numerous health benefits on nervous system, cardiovascular system, digestive system, urinary system, and even muscle. ²⁰ Its antioxidant and anti‐inflammatory activities have been studied and applied to various fields, including ophthalmology. ³³ , ³⁴ Research has proven that after oral administration to rats, CGA can be transported to eye tissues to exert its local effects, improving the survival rate of retinal ganglion cells (RGCs) in the retina. This research also demonstrated that CGA can upregulate antiapoptotic proteins such as Bcl‐2 and Bcl‐X_L and downregulate proapoptotic proteins such as Bad and cleaved caspase 3, thus significantly reducing RGC apoptosis induced by hypoxia and optic nerve crush (ONC) and thus preventing retinal degeneration. ³⁰ Oral administration of Peucedanum japonicum extract, of which CGA is identified as one of the main ingredients, enhances the expression of endogenous antioxidant genes such as CAT, HO1, and GPX1, inhibiting corneal inflammatory cell infiltration and enhancing re‐epithelialization. ³⁵ Moreover, not only intraperitoneal injection of blueberry leaf decoction containing CGA but also oral administration of CGA can reduce the occurrence of cataracts in rats by alleviating oxidative damage to the lens. ³⁶ , ³⁷ Multiple in vitro and in vivo experiments have also documented that CGA can help the cornea, lens, and even retinal tissues counteract oxidative damage. ³⁵ , ³⁶ , ³⁸

In summary, as an antioxidant supplement, CGA can enter ocular structures to play a role, rendering CGA an attractive compound for ocular antiaging interventions. The literature indicates that CGA not only achieves an antiaging effect by protecting cellular antioxidant proteins and inhibiting lipid peroxidation but also by combating inflammation and suppressing apoptosis. We summarize the in vitro and in vivo studies on the antiaging activity of CGA in the eye. Specifically, we divide the review into several subsections, each discussing a certain disease type. The main mechanisms by which CGA acts as an antioxidant in age‐related eye diseases are presented in Figure 3. In addition, Table 1 gives a summary of the different biological activities of CGA against ocular aging based on the studies. Among these, studies that used CGA as the only intervention component were selected for further review, collecting basic research information (see Table 2).

FIGURE 3.

Main mechanisms of CGA's antioxidant effect in age‐related eye diseases.

TABLE 1.

Evidence of CGA activity against age‐related eye diseases.

Ocular disease	Antioxidant activity	Anti‐inflammatory activity	Anti‐Apoptotic activity	Anti‐lipid peroxidation activity
Cataract	36, 42, 46, 47		42	36
AMD	54, 55	54	54	54
Glaucoma	30, 34, 38, 60		30, 34, 38	60
DR	67	67
Dry eye	35	35	35

TABLE 2.

Antioxidant effects of CGA on the eye in vivo and in vitro.

Model	Outcome Measure	Intervention	Results compared to the control groups	References
In vitro experiments
Human HLE‐B3 lens epithelial cell + H2O2	ROS, cell viability, cell apoptosis	pretreatment with 10–50 μM of CGA for 2 h	↓ROS ↑cell viability ↓cell apoptosis	42
RGC‐5 + SNAP(S‐nitroso‐N‐acetyl D,L‐penicillamine) and hypoxia	cell viability, cell apoptosis	pretreatment with 10–100 μM of CGA for 1 h	↑cell viability ↓cell apoptosis	30
		pretreatment with 25–100 μM of CGA		38
RGC‐5 + H2O2	ROS, cell viability, cell apoptosis	Pretreatment with 25–100 μM of CGA for 6 h	↓ROS ↑cell viability ↓cell apoptosis	34
HRECs/ARPE19 cell + TNFα	ROS, cell inflammation	Pretreatment with 0.625–2.5 μM of CGA for 6 h	↓ROS ↓Cell inflammation	67
In vivo experiments
Optic nerve crush rat model	RGC survival	Intravitreal injections with 0.1–10 μM of CGA 1 day before and 1 h after the procedure	↑RGC survival	30
Optic nerve crush mouse model	IPL thickness, cell apoptosis, RGC survival, NO	Orally administered at 10–30 mg/kg daily for 2 weeks	↑IPL thickness ↓Cell apoptosis ↑RGC survival ↓NO	38
Ocular hypertension ischemia‐reperfusion mouse model	NRF2 IPL thickness	Intragastrically administered at 10–30 mg/kg daily for 2 weeks	↑NRF2 ↑IPL thickness	34
Mouse model of oxygen‐induced retinopathy	Retinal neovascularization, VEGF	Administered intraperitoneally at 25–50 mg/kg for 5 days	↓Retinal neovascularization ↓VEGF	55
Streptozotocin‐induced diabetic mouse model	ROS, cell inflammation, thickness of INL and ONL	Orally given at 1 mg/kg for 1 consecutive month	↓ROS ↓Cell inflammation ↑Thickness of INL and ONL	67

4. CGA IN AGE‐RELATED EYE DISEASES

4.1. Cataract

Cataracts can develop as a result of a complex interplay of external and internal factors, with advancing age being the most critical risk factor. ³⁹ Senile cataract is a prominent cause of global vision impairment. ⁴⁰ This age‐related eye condition involves degenerative alterations in lens cells, and the underlying mechanisms are the aggregation and modification of lens proteins induced by cumulative oxidative stress, lipid peroxidation, and DNA damage. ⁴¹ Lens transparency relies on the function of lens epithelial cells. Oxidative stress has both direct and indirect effects on the survival, differentiation, and proliferation of these cells. A report showed that CGA can significantly reduce ROS levels and inhibit human lens epithelial cell apoptosis by decreasing the ratio of BAX/BCL‐2, thus effectively ameliorating H₂O₂‐induced lens opacity. ⁴² According to another report, CGA‐rich blueberry leaf extract can increase the activities of SOD, CAT, GPX, and GSH in cells, protect rat lenses from oxidative damage caused by selenite, prevent proteolytic activity, and preserve the integrity of lens crystallins. ³⁶ Another driving factor of cataracts is diabetes, which is generally considered strongly related to aging. The lens in diabetic conditions has a decreased antioxidant capacity, causing increased susceptibility to oxidative stress, consequently leading to lens opacity. ³² , ⁴³ According to the hyperosmolar theory of diabetic cataract etiology, aldose reductase (AR) contributes to sorbitol accumulation, leading to lens fiber degeneration and increased lens opacity. ⁴⁴ Both in vitro and in vivo studies have demonstrated that CGA can alleviate diabetes‐induced lens opacity by AR inhibition. ³⁷ , ⁴⁵ Moreover, studies have documented that several natural plant extracts with CGA as their main active ingredient (such as Artichoke leaf, Maackia amurensis, Smilax China L. Stems, etc.) can reduce cellular ROS expression, inhibit AR activity and effectively suppress sorbitol accumulation in the diabetic lens. ⁴⁶ , ⁴⁷ , ⁴⁸ Taken together, these results suggest the potential of CGA in the prevention and treatment of cataracts. Its therapeutic effect can be achieved by the upregulation of antioxidant enzymes, modulation of apoptosis‐related proteins, and direct inhibition of AR.

4.2. Age‐related macular degeneration (AMD)

AMD stands as the leading cause of vision impairment in individuals aged over 55, ⁴⁹ with the incidence rate sharply increasing in the population over 70 years old. ⁵⁰ The serum levels of MDA and advanced oxidation protein products are significantly increased in AMD patients, and their SOD activity is considerably lower than normal. ⁵¹ The cumulative damage of daily oxidative stress to the retina is considered the main source of risk for AMD. On the other hand, atrophy of retinal pigment epithelial cells (RPE) and loss of their normal physiological functions are thought to be the direct etiology of AMD. ⁵² AMD is subdivided into two types: dry AMD and wet AMD. The pathological changes in dry AMD include the accumulation of lipofuscin in RPE cells, deposits of proteins and lipids in the macula, and atrophy of the RPE at later stages. However, the pathological characteristic of wet AMD is the formation of choroidal neovascularization. Lipofuscin is a product of free radical‐induced lipid peroxidation. An essential component of lipofuscin is bis‐retinoid N‐retinylidene‐N‐retinylethanolamine (A2E), which can be photooxidized by blue light to produce ROS. ⁵³ Solanum melongena L., with CGA as its active component, is able to remove A2E in RPE cells, reduce the level of ROS, repress NFκB signaling and proinflammatory gene (CXCL8 and IL1B) transcription, and decrease apoptosis induced by blue light, therefore, effectively restraining the degeneration of the retina and decreasing the thickness of the outer nuclear layer (ONL) in mouse models. ⁵⁴ Furthermore, in a study utilizing a mouse model of wet AMD, the therapeutic potential of Aster koraiensis extract in reducing VEGF‐mediated retinal neovascularization was confirmed. CGA is considered the primary compound responsible for this activity. ⁵⁵ Another study also showed that CGA can suppress laser‐induced choroidal neovascularization in a rat model and may be useful as an inhibitor in the treatment or prevention of neovascular AMD. ⁵⁶ Taken together, these results demonstrate that CGA might be a promising candidate for AMD treatment. The therapeutic effect may be achieved by preventing the formation of lipofuscin, attenuating inflammatory cell apoptosis and inhibiting retinal neoangiogenesis.

4.3. Glaucoma

Glaucoma is a chronic progressive neurodegenerative disease characterized by progressive damage to RGCs and their axons. Its prevalence is strongly associated with increasing age. ⁵⁷ Elevated IOP is a leading risk factor for glaucoma, whereas optic nerve degeneration is the main cause of visual impairment and visual field loss in glaucoma patients. Hence, optic nerve injury and visual function decline can occur even if the IOP is well controlled in patients with glaucoma. Therefore, neuroprotection and neuroregeneration are considered the main therapeutic goals of glaucoma prevention and treatment. Oxidative stress is an important aspect in the pathogenesis of glaucoma, in which inflammation, excitotoxicity, retinal ischemia and hypoxia, and axonal transport dysfunction are common pathological changes. ⁵⁸ Traumatic optic nerve injury can induce axonal degeneration and apoptosis of RGCs through inflammation and oxidative stress in the ONC mouse model. ⁵⁹ In a comprehensive study, researchers found that CGA not only downregulates the expression of apoptosis‐related proteins, such as Bad and cleaved caspase 3, in a dose‐dependent manner, but also increases the expression of the anti‐apoptotic protein Bcl‐X_L. This dual action serves to enhance the viability of RGCs subjected to oxidative stress. Furthermore, CGA has been shown to elevate the survival rate of RGCs in an in vivo ONC rat model. ³⁰ There is also an in vitro study showing that CGA significantly reduces the apoptosis of RGCs induced by hypoxia, which may be mediated by scavenging NO. At the same time, it was found in vivo that CGA can repress cell death by preventing the downregulation of Thy‐1, an early sign of RGC loss, and it is also able to help maintain the normal thickness of the inner plexiform layer (IPL) in the ONC mouse model, thus showing strong neuroprotective function. ³⁸ In another major study, CGA showed promoting effects on lncRNA TUG1 expression, nuclear NRF2 protein levels and IPL thickness in a glaucoma mouse model. Furthermore, it also decreases the apoptosis rate and ROS production, protecting RGCs from oxidative damage. ³⁴ Moreover, as a major component of propolis extract, CGA can reduce cell lipid peroxidation and protect against glutamate‐induced RGC death. ⁶⁰ In summary, CGA displayed neuroprotective function and is promising as an adjuvant therapy for glaucoma.

4.4. Diabetic retinopathy (DR)

Oxidative stress and inflammation can lead to the loss or impairment of pancreatic islet β‐cells and accelerate insulin resistance. ⁶¹ Additionally, chronic exposure to hyperglycemia can cause mild inflammation, increase the production of ROS, further disrupt oxidation‐reduction equilibrium, and induce diabetes‐related complications. ⁶² Mitochondrial dysfunction and Müller cell injury occurring with aging make the retina more susceptible to oxidative stress, ⁶³ which results in the increasing prevalence of DR in elderly individuals. As a common complication of diabetes, DR is characterized by retinal microvascular degeneration with progressive optic nerve damage, which may lead to an irreversible impairment of visual function. CGA has proven to prevent or delay the onset of diabetes per se, which is essential for the prevention and treatment of its related complications. Evidence shows that CGA can improve insulin sensitivity and reduce insulin resistance. ⁶⁴ Moreover, a study found that CGA can increase the activity of a series of antioxidants in the blood of diabetic model rats. ⁶⁵ Another study also demonstrated that CGA can reduce ROS production and cellular morphological changes induced by streptozocin, promote insulin secretion, increase GSH and GPX activity in pancreatic INS‐1E β‐cells, and therefore play a role in protecting pancreatic islet β‐cells. ⁶⁶ Clinically, DR is classified into two major stages, nonproliferative DR (NPDR) and proliferative DR (PDR). Pathological changes in DR mainly include basement membrane thickening, increased leukocyte‐endothelial adhesion, RGC and pericyte loss and blood‐retinal barrier disruption in NPDR and neovascularization in PDR. ⁶⁷ The results showed that CGA not only reverses the process of endothelial‐mesenchymal transition and ameliorates blood‐retinal barrier dysfunction by reducing oxidative stress and retinal inflammatory signals in the early NPDR stage ⁶⁷ but also inhibits retinal neovascularization by suppressing the transcriptional activation of hypoxia‐inducible factor 1α (HIF‐1α) and blocking the expression of microglial VEGF paracrine signaling produced by microglial sources in the advanced PDR stage. ⁶⁸ Another study showed that He‐Ying‐Qing‐Re formula, in which CGA was identified as a vital component, can alleviate RGC death and retinal microvascular degeneration induced by diabetes through antioxidation and antiapoptotic effects. This formula was noted to be able to reverse the thinning of the RGC layer, inner nuclear layer (INL), and IPL. ⁶⁹ These findings indicate that CGA may help to delay the progression of DR by alleviating ocular pathological changes in diabetic conditions and by treating diabetes itself.

4.5. Dry eye

The etiology of dry eye varies and includes hyperosmolarity and instability of the tear film, ocular surface damage, inflammation and neuropathic paresthesia. The factors mentioned above are believed to increase the potential for oxidative stress and ocular surface inflammation. ⁷⁰ Aging is a major risk factor for dry eye. The aging process can lead to acinar atrophy of lacrimal and meibomian glands and inflammatory cell infiltration. Furthermore, aging can also lead to corneal and conjunctival degeneration, thereby disrupting the integrity of the tear film. These changes make the ocular surface microenvironment more irritable, with increases in a series of oxidative stress markers, such as 8‐OHdG, nitrotyrosine, 4‐HNE and lipofuscin‐like inclusions. ⁷¹ The data showed that the accumulation of lipofuscin‐like material in lacrimal acini and corneal epithelial metaplasia are higher among aged rats, accompanied by a decrease in the level of the antioxidant marker vitamin E. ⁷² Under conditions of desiccating stress, additional oxidative stress is produced, which is accompanied by a decrease in the antioxidant capacity of the corneal epithelium. ³¹ Hence, maintaining the cellular redox balance on the ocular surface could serve as a strategic approach for dry eye prevention and treatment. An investigation revealed elevated levels of inflammation, oxidative stress, and apoptosis in a rat model of corneal abrasion exposed to urban particulate matter. However, oral administration of an extract from P. japonicum, rich in CGA as its primary component, enhanced the migration activity of corneal epithelial cells and upregulated the expression of antioxidant genes, including CAT, HO1, and GPX1. This resulted in re‐epithelialization without altering corneal thickness, effectively supporting the recovery from corneal abrasion. ³⁵ Notably, there is a lack of research on CGA treatment of age‐related dry eye. Nevertheless, given the pivotal roles of inflammation and oxidative stress in the pathogenesis of dry eye, along with the antioxidant and anti‐inflammatory properties demonstrated by CGA in the study of ocular surface injury, CGA is a promising candidate for potential clinical applications in dry eye treatment. Further experimental studies are eagerly anticipated to validate the efficacy of CGA as a therapeutic option for dry eye.

5. KEY QUESTIONS TO BE SOLVED

Free CGA can be rapidly cleared under physiological conditions, contributing to its low stability. Only a small portion of given CGA can be bioactive in the appropriate tissue, which consequently limits its therapeutic efficacy in clinical applications. Hence, it is necessary to optimize the mode of administration of CGA and improve its bioavailability to develop it as an ocular antioxidant supplement. Currently, considerable attention is being given to CGA and its antiaging properties. Even so, many current studies do not mention the unavoidable limitations of its oral administration, which might lead to underestimation and inefficient utilization of CGA's biological activity. On the other hand, although there is a large body of previous experimental research that preliminarily proved the antioxidant effect of CGA, there is still a lack of outcome data from clinical studies. Thus, the clinical efficacy of CGA has yet to be fully explored. To better utilize its powerful and wide pharmacological activities in the field of age‐related eye diseases, continuous research is needed, and novel drug delivery methods should be explored. Additionally, investigations in both preclinical models and human studies are needed to improve the possibility of CGA becoming a drug candidate for age‐related eye diseases.

6. CURRENT AND EMERGING CGA DELIVERY METHODS

In recent years, scientists have been exploring the optimization of CGA delivery, such as liposomal delivery, micelle delivery, or nanoparticle delivery. Liposomes, because of their excellent encapsulating capacity, biocompatibility, and biosafety, are often utilized to improve the stability of CGA in vivo, to prolong its blood circulation time, and thus to reduce the dosing frequency. ¹⁴ CGA liposomes are capable of improving the oral bioavailability of CGA and increasing its antioxidant activity in vivo. ⁷³ In addition, self‐microemulsifying drug delivery systems (SMEDDS) have also proven to be quite efficient in diverse CGA delivery applications. Studies have demonstrated that the SMEDDS of CGA can enhance drug permeation through intestinal epithelial cells and promote drug accumulation in mesenteric lymph nodes via the lymphatic transport pathway. ¹⁵ CGA‐loaded water‐in‐oil‐in‐water double emulsions prepared with Span 80 and lecithin proved stable properties and strong antioxidant capacity. ⁷⁴ The results also suggest that the SMEDDS of CGA has a high self‐emulsifying rate and exhibits good stability in dissolution media, and when compared with the water suspension of CGA, the SMEDDS of CGA is more orally bioavailable in mice and shows better tissue‐targeting properties. ⁷⁵ Furthermore, the phospholipid complex of CGA was proven to increase CGA skin permeation and achieve a sustained‐release effect, which can be used for the protection of skin from the toxic effect of longwave ultraviolet light for a long duration. ⁷⁶ In addition, many studies have explored the potential use of nanocarriers for CGA. However, graphene oxide and polyethylene glycol nanocarriers are able to exert a sustained release effect and enhance CGA's pharmacological effect with good stability and safety. ⁷⁷ , ⁷⁸ Nanotechnology is expected to provide greater permeability to CGA at the cellular level and to precisely control its release, thereby overcoming the obstacles in its absorption, specificity, and bioavailability. ⁷⁹ Overall, the enhancement of CGA bioavailability has interested scientists for a long time.

7. CONCLUSIONS AND FUTURE PERSPECTIVES

Numerous in vitro and in vivo studies have demonstrated the excellent antioxidative properties of CGA that enable its utility in treating age‐related ophthalmopathy, including cataracts, AMD, glaucoma, DR, and dry eye. However, the poor stability, low bioavailability, and insufficient clinical trials of CGA limit its further development and exploitation. Fortunately, an increasing number of research results are available. Innovations in CGA delivery include local skin administration and oral targeted therapies, which make it possible to administer CGA locally and orally for eye diseases and lay a solid theoretical and practical foundation for subsequent experiments on the ophthalmic applications of CGA. In this section, we call for more evidence of the optimal means of CGA administration by researchers. In the meantime, we also strongly appeal to more extensive clinical investigations of CGA to maximize its benefit to human health. Given the progress in our understanding of natural antioxidants and the emerging strategies of CGA delivery, we have good reasons to be hopeful for its further clinical applications in preventing or delaying age‐related eye diseases.

NOMENCLATURE OF TARGETS AND LIGANDS

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander et al., 2019).

AUTHOR CONTRIBUTIONS

Yu Tang and Chi Fang: conceptualization, original draft preparation, review, and editing; Jian Shi: conceptualization, review and editing, resources, and supervision; Huimei Chen: original draft preparation, review, and editing; Xiong Chen: resources, review and editing; Xiaolei Yao: conceptualization, funding acquisition, project administration, supervision, resources, review, and editing. Yu Tang and Chi Fang are contributed equally to this work.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Not applicable.

Tang Y, Fang C, Shi J, Chen H, Chen X, Yao X. Antioxidant potential of chlorogenic acid in Age‐Related eye diseases. Pharmacol Res Perspect. 2024;12:e1162. doi: 10.1002/prp2.1162

DATA AVAILABILITY STATEMENT

All data used in this review are available from the referenced original sources.