As the RPE is a major source of angiogenic and antiangiogenic factors, dysregulation of the balance between them can contribute to the development of choroidal neovascularization of the retina [192].

In summary, oxidative stress induced by lipofuscin, and certain components of lipofuscin in particular, may contribute to eliciting proinflammatory and angiogenic responses. It is particularly important because AMD is related to chronic low-level inflammation characterized by the presence of inflammatory markers (C-reactive proteins) and—in its so-called wet form—with choroidal neovascularization of the retina [155, 192, 194].

APPROACHES TO DIMINISH LIPOFUSCIN ACCUMULATION OR LIPOFUSCIN-INDUCED DAMAGE

Accumulated lipofuscin can be viewed as a proof that RPE cells were exposed to oxidative stress, and once accumulated, lipofuscin can further propagate oxidative damage, in particular when it is excited with short-wavelength visible light. Lipofuscin in the RPE may induce damage to the retina not only directly but also indirectly by inducing proinflammatory and angiogenic signaling, leading to retinal degeneration. Therefore, it is essential to minimize lipofuscin formation and to prevent damage induced by lipofuscin already present.

To achieve this, the key element is to minimize ATR accumulation in POS disks and to provide adequate antioxidant protection. ATR accumulation and subsequent lipofuscin accumulation can be successfully diminished by diminishing the exposure to light, by diminishing stores of retinoids in the RPE by depletion of vitamin A, or by pharmacological inhibition of enzymes involved in conversion of all-trans retinyl esters into 11-cis retinal.

Depletion of vitamin A, achieved either by dietary depletion or by HPR treatment, needs to be carefully monitored to avoid undesirable effects related to deficiency of its metabolite all-trans retinoic acid—a vital regulator of gene expression and essential factor for maintaining the integrity of the skin and mucous membranes as well as a regulatory factor in the immune system [195]. HRP at concentrations tested in numerous cancer trials induces delayed dark adaptation but otherwise is safe and well tolerated [110].

As mentioned, 13-cis retinoic acid, TDT, and TDH are effective inhibitors of the retinoid cycle and subsequent lipofuscin accumulation. However, as 13-cis retinoic acid acts as a competitive inhibitor, it needs to be present in a high concentration, which can cause teratogenicity and systemic toxicity. The long-term effects of TDT and TDH are unknown. Other inhibitors of isomerization of all-trans retinyl esters are all-trans retinylamine and its isomers and derivatives [196–198]. In addition to direct inhibition of isomerization, all-trans retinylamine is a substrate for LRAT and undergoes reversible acylation to form N-retinylamides [197]. As a result, all-trans retinylamine is a more potent inhibitor of 11-cis retinal synthesis than HPR or 13-cis retinoic acid, when compared at the same doses, and its action is sustained over a period of several days after a single injection. Treatment with all-trans retinylamine effectively prevents light-induced damage to the retina [198]. Therefore, it may be expected that all-trans retinylamine will be effective in prevention of lipofuscin accumulation.

N-Retinylamine may be metabolized through retinol and retinal into retinoic acid [198]. Importantly, when compared with retinol treatment, only a trace elevation of potentially toxic all-trans retinoic acid is detected. Moreover, N-retinylamine interacts only at micromolar concentrations with retinoic acid receptor and does not activate retinoid X receptor [196]. Yet, treatment with N-retinylamine results in massive changes in gene expression in the liver and retina, similar to those induced by HPR, albeit less dramatic than those induced by 13-cis retinoic acid. Therefore, a thorough study of potential toxicity is required before recommendation of N-retinylamine as a potential prophylactic treatment.

Also, there are potential risks related to chronic inhibition of isomerization. The minor drawback of inhibition of 11-cis retinal synthesis is delayed dark adaptation. More important, dysfunction of proteins involved in synthesis of 11-cis retinal, such as RPE65, RDH5, RPE65, LRAT, and CRALBP, results in early-onset photoreceptor degenerations and mild-to-severe loss of vision [103].

It seems that avoiding exposures of the retina to bright short-wavelength light is the simplest preventive measure against ATR accumulation and subsequent oxidative damage mediated by ATR and lipofuscin. Inserting yellow intraocular lenses after cataract surgery can mimic protection offered by the natural lens in the elderly patients [199]. Alternatively, yellow or amber sunglasses may offer the same or even better protection against overexposure to blue light.

However, it needs to be remembered that blue light photoactivates melanopsin (maximum at 480 nm) in ganglion cells, which plays an important role in pupillary responses to changing light levels and in setting circadian rhythms [200]. Therefore, chronic filtering out all blue light may have undesirable systemic effects. Certainly, filtering out infrared and short-wavelength light in ophthalmic instruments can decrease the risk of retinal damage during ocular surgery or ophthalmic examination [201, 202], and transient inhibition of the synthesis of 11-cis retinal may offer further protection.

As mentioned, the retina is equipped with effective defense mechanisms that, despite harsh conditions putting it at risk of oxidative damage, allow the retina to perform well its function in most cases throughout lifetime. Also, long-term adaptation to the environmental light levels plays an important role in modulating the susceptibility to photooxidative damage and includes decreased concentration of rhodopsin, changes in lipid composition of POSs, and increased concentration of low-molecular antioxidants. To enable this protective mechanism to operate, an adequate dietary intake of antioxidant vitamins and micronutrients is necessary.

However, it needs to be pointed out that experiments on animals demonstrated that lifelong exposure to light causes retinal degeneration, with its severity correlating with the intensity of light at which the animals are reared [203]. Moreover, rats reared even at dim cyclic light ( 20–30 lux) exhibit an increasing susceptibility to retinal photodamage with aging, while rats reared in the dark are equally susceptible to light-induced damage at different ages. This suggests that chronic exposure to light results in a gradual decline of efficiency of the defense mechanisms.

The retina contains abundant antioxidants that scavenge reactive oxygen species or quench excited states of photosensitizers and singlet oxygen. The retinal antioxidants include low molecular weight antioxidants synthesized endogenously, such as lipoic

acid and ubiquinone, and of dietary origin (vitamin E, vitamin C, lutein, and zeaxanthin). The retina expresses a number of antioxidant enzymes. Some of the enzymes are directly responsible for decomposition of reactive oxygen species, such as superoxide dismutase, catalase, and glutathione peroxidase, which decompose superoxide, hydrogen peroxide, and lipid hydroperoxides. Other enzymes are responsible for detoxification and removal of toxic products or repair of damaged proteins. For instance, glutathione transferase conjugates secondary products of lipid peroxidation to glutathione, and these adducts can be subsequently excreted from the cell [204].

Several studies in vivo and in vitro have demonstrated that antioxidant protection of the retina can be further improved via antioxidant supplementation or upregulation of antioxidant enzymes [128, 205–209]. For example, loss of photoreceptor RDH activity in the rat retina on exposure to intensive green light may be prevented with a synthetic antioxidant, 1,3-dimethylthiourea [128].

A powerful way to increase the retinal resistance to oxidative stress is exposure to phytochemicals, such as common dietary components (resveratrol, sulforaphane, catechins, flavonoids, allium, and curcumin), which activate cell survival signaling and transcription pathways and inhibit proinflammatory signaling [210, 211]. In particular, sulforaphane, highly abundant in broccoli sprouts, stimulates NRF2-dependent expression of antioxidant and detoxification enzymes such as glutathione, thoredoxin, and NAD(P)H:quinone oxidoreductase and effectively protects RPE cells in vitro and the retina in vivo against photooxidative damage [208, 212, 213].

Last but not least, the retina contains a large concentration of DHA that can, itself or after enzymatic oxidation, effectively inhibit or counteract proapoptotic and inflammatory signaling [214–216].

CONCLUSIONS

Phototransduction is necessary for visual perception, but it is inherently related to a release of ATR. There is a great deal of evidence implicating ATR released from opsin as a mediator of acute photodamage to the retina as well as accumulation of lipofuscin in the RPE. Once formed, lipofuscin has the potential to impose further threats to the RPE, which include lipofuscin-mediated oxidative damage, and initiation of signaling pathways, potentially leading to the activation of complement and angiogenesis and therefore contributing to the development of atrophic and neovascular forms of AMD. Therefore, to avoid the risk of oxidative stress and lipofuscin formation, preventive measures against ATR accumulation should be taken, including avoiding overexposure of the retina to bright light and, if necessary, pharmacological intervention inhibiting 11-cis retinal synthesis. As ATR accumulation may be particularly damaging during exposure to light, understanding the signaling pathways responsible for mobilization of all-trans retinyl esters under light adaptation may provide a powerful strategy for prophylactic treatment. With age, the transmission of the short-wavelength light to the retina decreases. However, as both the lipofuscin concentration in the RPE and the photoreactivity of the lipofuscin granule increase with age, the risk of photooxidative damage mediated by lipofuscin remains. To counteract the oxidative stress, minimization of exposure to short-wavelength light and upregulation of antioxidant and detoxifying

pathways are needed. Recent advances in understanding the molecular pathways leading to elevation of cellular resistance to oxidative damage offer hope that they can be utilized for the benefit of the retina.

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