The cornea is the transparent avascular anterior part of the eye. Corneal NV is a condition in which excessive blood vessels grow into the cornea and is the leading cause of blindness. This condition is trigged by corneal hypoxia, inflammation, and/or limbal barrier dysfunction. Currently, the treatments for corneal NV include steroids, nonsteroidal anti-inflammatory eye drops, fine needle diathermy, photodynamic therapy, and anti-VEGF therapy (Chang et al., 2001). Though, these therapies ameliorate corneal NV to some extent, the side effects cannot be ignored: steroids may cause corneal thinning, ocular hypertension, and cataracts (Sarchahi et al., 2008); NSAIDs may lead to corneal ulceration and perforation (Guidera et al., 2001); fine needle diathermy and photodynamic therapy may cause an inflammatory response (Shakiba et al., 2009; Koenig et al., 2012); and anti-VEGF therapy complications include corneal thinning, reduced epithelial healing (Kim et al., 2008), and epithelial erosion (Oh et al., 2009). Therefore, a safe and effective therapy for corneal NV is needed.

Vascular endothelial growth factor and basic fibroblast growth factor (bFGF) are supposed to attract and recruit inflammatory cells, leading to corneal NV. Curcumin could inhibit proliferation of primary endothelial cells cultured in vitro, either in the presence or absence of bFGF (Arbiser et al., 1998). It was able to prohibit bFGF-induced mouse corneal NV in vivo (Arbiser et al., 1998). Suturing-induced rabbit corneal NV could also be suppressed by curcumin, in vivo (Kim et al., 2010) via decreasing the VEGF mRNA levels and phosphorylation of NF-κB (Kim et al., 2010). Curcumin NPs might significantly reduce angiogenic sprouting in a dose and time dependent manner in the mouse aortic ring in vitro. Curcumin NPs were also able to inhibit NF-κB in LPS-induced corneal cells in vitro (Pradhan et al., 2015). It may also prohibit corneal angiogenesis in silver nitrate-induced corneal NV in vivo through the mechanism of inhibiting VEGF, inflammatory cytokines [IL-1β, TNF-α], and MMPs (MMP-2 and MMP-9) (Pradhan et al., 2015). Curcuminoids, administered locally or in the diet, could suppress fibroblast growth factor-2 (FGF-2)-induced rabbit corneal NV in vivo, by inhibiting DNA binding activity from transcription factor activator protein-1 (AP-1) and gelatinase B promoter activity (Mohan et al., 2000). The effects and mechanisms of curcumin and curcumin NPs on corneal diseases warrant an effective and safe herbal therapy for preventing corneal NV (Figure 1).

The corneal epithelium provides a strict barrier that is both useful for dependent on tight junctions between adjacent epithelial cells and corneal homeostasis. Barrier function of the corneal epithelium can be undermined by bacterial infection or inflammation, resulting in different conditions of the epithelium and in stromal edema, infection, or melting. Kimura et al. (2008) found that TNF-α or IL-1β could damage the human corneal epithelial cells barrier in vitro by affecting the localization of the tight junctions proteins zonula occludens-1 at tight junctions dependent on NF-κB. Curcumin could inhibit both TNF-α and IL-1β induced subcellular localization of occludens-1 through NF-κB inhibition in vitro, indicating curcumin may prevent corneal epithelial barrier function disruption related with ocular inflammation (Kimura, 2010).

Diabetes increases the risk of corneal diseases, and as high as 50% of diabetic patients suffered from diabetic keratopathy (Zagon et al., 2007), including reduced corneal sensitivity, decreased tear secretion, tear film dysfunction, degeneration of nerve fibers, loss of corneal epithelia, and corneal ulcer (Gao et al., 2015). The current treatments for diabetic keratopathy include artificial tears, antibiotic eye drops, tarsorrhaphy, and bandage contact lens, which helps for corneal wound healing (Abdelkader et al., 2011). However, these measures may not be effective and adequate at accelerating re-epithelialization in diabetes, even if different therapies are used simultaneously. Thus, novel effective methods are required.

Guo et al. reported intranasal nanomicelle curcumin promotes corneal epithelial/nerve wound healing in STZ-induced diabetic mice with corneal epithelium abrasion. The mechanism includes alleviating free radical scavengers, recovering the enhanced accumulation of reactive oxygen species (ROS), decreased mRNA expressions of neurotrophic factors, and increased mRNA expressions of inflammatory cytokines in the cornea. Trigeminal ganglion neurons were also observed in mice with corneal epithelium abrasions. These findings illustrate that intranasal curcumin could effectively promote diabetic corneal epithelial or nerve wound healing. This treatment might be a promising therapy for diabetic keratopathy (Guo et al., 2016).

It is believed that oxidative damage to the eye lens contributes to the development of different kinds of cataracts (Suryanarayana et al., 2005; Manikandan et al., 2010a,b). The primary mechanism for the anti-cataract effect of curcumin is through its antioxidant properties (Manikandan et al., 2009, 2010a, 2011; Radha et al., 2012).

Curcumin may inhibit peroxiredoxin 6 (a pleiotropic oxidative stress-response protein) in cultured human lens epithelial cells (hLECs) in vitro (Chhunchha et al., 2011). Bioactive derivatives of curcumin (salicylidenecurcumin CD1 and benzalidenecurcumin CD2) were reported to inhibit the selenite induced cataract by reversing the activity of antioxidant enzymes, decreasing ROS, and increasing the activities of superoxide dismutase (SOD) (Manikandan et al., 2010a; Radha et al., 2012).

Curcumin was found to have a protective effect against cataract development and/or progression in numerous in vitro and in vivo cataract models (Awasthi et al., 1996; Pandya et al., 2000; Suryanarayana et al., 2003, 2005; Kumar et al., 2005a,b; Raju et al., 2006; Manikandan et al., 2009, 2010a,b, 2011; Grama et al., 2013). It may suppress selenium-induced oxidative stress in rat organ cultured lens and delay the formation of cataracts by inhibiting the non-enzymic antioxidants depletion (Manikandan et al., 2009). Vitamin C is a potent non-enzymic antioxidant, and the level of Vitamin C is high in human lens, suggesting that vitamin C may have a preventive role in cataract progression. The decreased vitamin C levels observed in selenite-induced rat cataracts suggests that weakened non-enzymatic antioxidant defenses may play a role in selenite-induced rat cataracts. Administration of curcumin was found to increase vitamin C levels (Murugan and Pari, 2006). Pretreatment of curcumin may prevent oxidative damage and delay the development of cataracts by increasing superoxidase dismutase and catalase enzyme activity in Wistar rats (Padmaja and Raju, 2004). Curcumin may prevent alterations of protein carbonyls, antioxidant enzymes glutathione peroxidase (GPx), glucose-6-phosphate dehydrogenase (G6PD) and significantly decreased GSH levels, demonstrating curcumin delay the progression of diabetic cataract by preventing hyperglycemia-mediated lenticular oxidative stress in rats (Suryanarayana et al., 2005).

Lipoperoxides is enhanced in selenite-induced rat cataract in vivo (Manikandan et al., 2010b). Hiobarbituric acid-reacting substances (TBARS), commonly measured as a marker of LPO, was also elevated in rat of selenite-induced and STZ-induced cataract in vivo (Suryanarayana et al., 2005; Manikandan et al., 2010b), indicating enhanced lipid peroxidation in cataracts. Curcumin significantly delayed the progression and maturation of cataracts in a dose-dependent manner by decreasing LPO and TBARS (Suryanarayana et al., 2005; Manikandan et al., 2010b). GST is a group of multifunctional proteins that performs tasks ranging from catalyzing the detoxification of electrophilic compounds to protecting against peroxidative damage (Sener et al., 1979). GST is decreased in selenite-induced rat cataracts in vivo, and curcumin increased the activity of GST to near normal level (Manikandan et al., 2010b). 4-hydroxy-2-transnonenal (4-HNE) is a highly electrophilic product of lipid peroxidation. It was reported that curcumin has a protective effect on organ-cultured lens in 4-HNE induced cataract formation. Curcumin treatment caused an induction of the GST isozymer GST8-8 in rat lenticular epithelium. GST8-8 uses 4-HNE as a favorable substrate, suggesting the beneficial effect of curcumin may be regulated by producing this GST isozyme (Suryanarayana et al., 2005; Manikandan et al., 2010b). GSH is believed to prevent the cells from lipid peroxidation. GSH is known as a free radical scavenger, a cofactor for many enzymes and a co-substrate for glutathione peroxidase (GPx) activity (Gregus et al., 1996). Selenite increases lipid peroxidation in rat lens, leading to downregulation of GSH in the lens. Curcumin pretreatment resulted in maintaining normal GSH levels that was detected in tissues and serums in selenite treated lenses in vivo, indicating the protective role of curcumin against oxidative stress (Manikandan et al., 2010b).

Vitamin E, a natural lipid soluble antioxidant, can maintain the integrity of cell membrane and vital membrane functions by inhibiting lipid peroxidation. Vitamin E was reported to have a protective effect in delaying galactose-induced cataract formation and aminothiazole-induced cataract formation in rabbits, inhibiting the lipid photo-peroxidation in lens, limiting radiation related lenticular damage, and preventing diabetic cataract or heat-induced cataract formation (Creighton et al., 1985; Gregus et al., 1996). The level of vitamin E in lens homogenate was decreased in rat treated with selenite alone, and early administration of curcumin produced a protective effect on vitamin E levels (Manikandan et al., 2010b). Curcumin in a 0.01% dose, supplemented with vitamin-E, inhibited galactose-induced rat cataract in vivo by inhibiting lipid peroxidation (Raju et al., 2006).

Aldose reductase, a vital enzyme for polyol pathway, was significantly increased in STZ-induced diabetic rat lens. Curcumin normalized AR activity in vivo, indicating curcumin is effective against osmotic stress caused by hyperglycemia (Suryanarayana et al., 2005; Grama et al., 2013).

Studies have shown that even in the earliest stages of cataract formation, the pattern of lens proteins changed (Manikandan et al., 2010a). Significant decreases were found in β crystallins, gamma (γ)-crystallins, and a high molecular weight (HMW) aggregate peak in STZ-induced diabetic rat lens by High Performance Liquid Chromatography (HPLC). The proportion of cross-linked and aggregated proteins were detected to be increased in the soluble protein in STZ-induced diabetic rat lens, suggesting either aggregation or cross-linking might or any unknown factor might be causing protein modification and degradation in diabetic cataractous lens, leading to the formation of HMW aggregates. The insolubility of otherwise soluble protein and alterations in protein profile can result in lens opacification (Kumar et al., 2005b; Suryanarayana et al., 2005). Curcumin and turmeric remarkable alleviated those protein changes, indicating that curcumin and turmeric has a protective effect against diabetic cataract in rats (Kumar et al., 2005b; Suryanarayana et al., 2005). Heat shock protein 70 (Hsp 70), αA-crystalline, αB-crystallin were the predominant constituent proteins which maintain eye lens transparency, and were increased in cataracts. Curcumin could suppress the expression of Hsp 70, αA-crystalline, and αB-crystallin in STZ or selenite-induced cataracts in rat. (Kumar et al., 2005a; Manikandan et al., 2011).

Although the precise mechanisms of cataracts are not fully elucidated, a plausible mechanism might be that constant oxidative stress causes progressive deterioration of Ca²⁺⁺ homeostasis (Hightower and McCready, 1989). Ca²⁺ is essential for maintenance of lens transparency, and increased Ca²⁺ could activate calpain which can degrade crystallins in lens, leading to cataract formation (Shearer and David, 1982; Thiagarajan and Manikandan, 2013). It was reported that Ca²⁺ ATPase may participate in regulating Ca²⁺ homeostasis in lens (Manikandan et al., 2010a). Curcumin may decrease selenite-induced increase of Ca²⁺ concentration in selenium-induced rat cataract model in vivo by increasing the activities of Ca²⁺ ATPase and thus lowering the Ca²⁺ to an almost normal level (Manikandan et al., 2010a).

Excessive free radical generation (NO, OH^-, O^2-) has been identified as one of the major etiological factors of cataracts (Spector, 1995). An excess of NO, produced by inducible nitric oxide synthases (iNOS), is thought to cause cell injury by nitrosative stress and contribute to cataract formation (Ito et al., 2001; Ornek et al., 2003; Manikandan et al., 2010a). OH^- is also a highly reactive free radical that contributes to lens crystalline modification (Fu et al., 1998). OH^- could react with NO, generating more reactive compounds (Graham et al., 1993). Curcumin has been reported to be able to sequestrate free radicals, and scavenge NO, OH^-, O^2- in isolated rat peritoneal macrophage in vitro (Joe and Lokesh, 1994). Curcumin prevented uncontrolled generation of free radicals by inhibiting the production of iNOS in selenium-stimulated organ cultured lens of rat pups in vitro (Manikandan et al., 2009). Pretreatment of curcumin was found to prevent free radical generation in selenium-induced cataract in rat pups in vivo (Manikandan et al., 2010a).

Lens cell membrane damage is considered as one of the early signs of cataractogenesis, resulting in changes in intraocular metabolism and composition (Vrensen, 1995). Suppressing the proliferation and inducing apoptosis of lens epithelial cells is the primary goal in preventing cataractogenesis. Curcumin could inhibit proliferation of human lens epithelial B3 (HLE-B3) cells cultured in vitro (Hu et al., 2012). It may also induce irreversible apoptosis in bovine lens epithelial cells cultured in vitro, through attenuating mitochondrial transmembrane potential in cytoplasm and decreasing DNA content in nucleus (Huang et al., 2006). Further in vivo experiments are needed to validate curcumin’s effects on proliferation and apoptosis in lens epithelial cells.

Thus, as a viable food-based pharmacologic drug, numerous studies (summarized in Table 1) have demonstrated that curcumin may protect again cataracts and may serve as an effective and low toxic medication for the prevention and treatment of cataract.