Protection of human retinal pigment epithelial cells from oxidative damage using cysteine prodrugs

Kularatne, Ruvanthi N.; Bulumulla, Chandima; Catchpole, Timothy; Takacs, Alison; Christie, Abigail; Stefan, Mihaela C.; Csaky, Karl G.

doi:10.1016/j.freeradbiomed.2020.03.024

Cited by 19 publications

(18 citation statements)

References 33 publications

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“…Analogs and prodrugs are employed for the delivery of GSH because of its poor stability and poor bioavailability [ 114 ]. For example, N-acetyl-L-cysteine (a prodrug of L-cysteine) significantly increased GSH levels in RPE in vitro [ 59 ]. It would be of interest to study whether this prodrug will be applicable to prevent retinal degeneration in animal models, specifically those that exhibit elevated oxidative stress in the RPE monolayer (for example, in Sod2 knockout mice [ 115 ]).…”

Section: Future Directionsmentioning

confidence: 99%

Glutathione Metabolism and the Novel Role of Mitochondrial GSH in Retinal Degeneration

2021

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Glutathione (GSH) is present ubiquitously, and its role as a crucial cellular antioxidant in tissues, including the retina, is well established. GSH’s antioxidant function arises from its ability to scavenge reactive oxygen species or to serve as an essential cofactor for GSH S-transferases and peroxidases. This review summarizes the general functions, retinal distribution, disorders linked to GSH deficiency, and the emerging role for mitochondrial GSH (mGSH) in retinal function. Though synthesized only in the cytosol, the presence of GSH in multiple cell organelles suggests the requirement for its active transport across organellar membranes. The localization and distribution of 2-oxoglutarate carrier (OGC) and dicarboxylate carrier (DIC), two recently characterized mitochondrial carrier proteins in RPE and retina, show that these transporters are highly expressed in human retinal pigment epithelium (RPE) cells and retinal layers, and their expression increases with RPE polarity in cultured cells. Depletion of mGSH levels via inhibition of the two transporters resulted in reduced mitochondrial bioenergetic parameters (basal respiration, ATP production, maximal respiration, and spare respiratory capacity) and increased RPE cell death. These results begin to reveal a critical role for mGSH in maintaining RPE bioenergetics and cell health. Thus, augmentation of mGSH pool under GSH-deficient conditions may be a valuable tool in treating retinal disorders, such as age-related macular degeneration and optic neuropathies, whose pathologies have been associated with mitochondrial dysfunction.

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Section: Future Directionsmentioning

confidence: 99%

Glutathione Metabolism and the Novel Role of Mitochondrial GSH in Retinal Degeneration

2021

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“…In this context, NAC ester prodrugs, such as NACET, with their increased lipophilicity can be very interesting drug candidates. It is worth noting that while this manuscript was in preparation, Kularatne and colleagues described how four ester derivatives of NAC, including NACET, were able to protect RPE cells against oxidative damage induced by treatment with hydroquinone (HQ), a component of cigarette smoke [21]. Moreover, following HQ treatment, N-acetylcysteine butyl ester (NACBE) protected RPE cells from cell-cell junction disruption and, in general, ester derivatives of NAC prevented mitochondrial oxidative damage, measured as mitochondrial depolarization, even better than MitoQ, a well-known mitochondrial-targeted antioxidant.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, another important observation of our study was the increase in GSH in the eyes of animals that orally received NACET, when NAC failed. Hence, the lipophilicity of NACET, and in general of ester derivatives of NAC, not only has the advantage of promoting their entry into cells and mitochondria, where they produce NAC and cysteine [13,21], but also of remarkably enhancing their tissue absorption and of crossing various blood barriers [13].…”

Section: Discussionmentioning

confidence: 99%

Superior Properties of N-Acetylcysteine Ethyl Ester over N-Acetyl Cysteine to Prevent Retinal Pigment Epithelial Cells Oxidative Damage

Tosi

Giustarini

Franci

et al. 2021

IJMS

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Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats’ eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.

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“…Under conditions of oxidative stress, cellular GSH concentrations are markedly reduced due to a combination of enhanced degradation and decreased synthesis (Wu et al 2004). Supplementation of GSH precursors protects RPE from oxidative damage (Kularatne et al 2020;Terluk et al 2019). The deficiency of Nrf2, a transcription factor in the GSH system, results in drusen-like deposits similar to AMD in mice.…”

Section: Proline Metabolism In Amdmentioning

confidence: 99%

Proline metabolism and transport in retinal health and disease

Zhu

Lim

et al. 2021

Amino Acids

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The retina is one of the most energy-demanding tissues in the human body. Photoreceptors in the outer retina rely on nutrient support from the neighboring retinal pigment epithelium (RPE), a monolayer of epithelial cells that separate the retina and choroidal blood supply. RPE dysfunction or cell death can result in photoreceptor degeneration, leading to blindness in retinal degenerative diseases including some inherited retinal degenerations and age-related macular degeneration (AMD). In addition to having ready access to rich nutrients from blood, the RPE is also supplied with lactate from adjacent photoreceptors. Moreover, RPE can phagocytose lipid-rich outer segments for degradation and recycling on a daily basis. Recent studies show RPE cells prefer proline as a major metabolic substrate, and they are highly enriched for the proline transporter, SLC6A20. In contrast, dysfunctional or poorly differentiated RPE fails to utilize proline. RPE uses proline to fuel mitochondrial metabolism, synthesize amino acids, build the extracellular matrix, fight against oxidative stress, and sustain differentiation. Remarkably, the neural retina rarely imports proline directly, but it uptakes and utilizes intermediates and amino acids derived from proline catabolism in the RPE. Mutations of genes in proline metabolism are associated with retinal degenerative diseases, and proline supplementation is reported to improve RPE-initiated vision loss. This review will cover proline metabolism in RPE and highlight the importance of proline transport and utilization in maintaining retinal metabolism and health.

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Protection of human retinal pigment epithelial cells from oxidative damage using cysteine prodrugs

Cited by 19 publications

References 33 publications

Glutathione Metabolism and the Novel Role of Mitochondrial GSH in Retinal Degeneration

Glutathione Metabolism and the Novel Role of Mitochondrial GSH in Retinal Degeneration

Superior Properties of N-Acetylcysteine Ethyl Ester over N-Acetyl Cysteine to Prevent Retinal Pigment Epithelial Cells Oxidative Damage

Proline metabolism and transport in retinal health and disease

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