Nicotinamide, iRPE-in-a dish, and age-related macular degeneration therapy development

Bergen, Arthur A. B.

doi:10.21037/sci.2017.09.05

Cited by 4 publications

(6 citation statements)

References 22 publications

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“…This finding is supported strongly by several additional studies such as that by Zhu et al which not only demonstrated the benefit of enhancing NAD + levels in retina/RPE but also further provided insight into the underlying mechanisms to explain this effect: decreased intracellular ROS, inhibition of PARP-1, and upregulated autophagy in 5 Oxidative Medicine and Cellular Longevity RPE cells exposed to prooxidant stimuli [86]. The relevance of NAD + metabolism to AMD is perhaps even more directly demonstrated by a recent report [87], which, using humaninduced pluripotent stem cell-derived RPE (hiPSC-RPE) cells, prepared from donors with and without AMD, showed the benefit of the NAD + precursor, nicotinamide, in limiting the expression of key complement and inflammatory proteins linked directly to drusen development and AMD.…”

Section: Nad + and Aging Retinamentioning

confidence: 73%

Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration

Jadeja

Thounaojam

Bartoli

et al. 2020

Oxidative Medicine and Cellular Longevity

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Nicotinamide adenine dinucleotide (NAD+) plays an important role in various key biological processes including energy metabolism, DNA repair, and gene expression. Accumulating clinical and experimental evidence highlights an age-dependent decline in NAD+ levels and its association with the development and progression of several age-related diseases. This supports the establishment of NAD+ as a critical regulator of aging and longevity and, relatedly, a promising therapeutic target to counter adverse events associated with the normal process of aging and/or the development and progression of age-related disease. Relative to the above, the metabolism of NAD+ has been the subject of numerous investigations in various cells, tissues, and organ systems; however, interestingly, studies of NAD+ metabolism in the retina and its relevance to the regulation of visual health and function are comparatively few. This is surprising given the critical causative impact of mitochondrial oxidative damage and bioenergetic crises on the development and progression of degenerative disease of the retina. Hence, the role of NAD+ in this tissue, normally and aging and/or disease, should not be ignored. Herein, we discuss important findings in the field of NAD+ metabolism, with particular emphasis on the importance of the NAD+ biosynthesizing enzyme NAMPT, the related metabolism of NAD+ in the retina, and the consequences of NAMPT and NAD+ deficiency or depletion in this tissue in aging and disease. We discuss also the implications of potential therapeutic strategies that augment NAD+ levels on the preservation of retinal health and function in the above conditions. The overarching goal of this review is to emphasize the importance of NAD+ metabolism in normal, aging, and/or diseased retina and, by so doing, highlight the necessity of additional clinical studies dedicated to evaluating the therapeutic utility of strategies that enhance NAD+ levels in improving vision.

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Section: Nad + and Aging Retinamentioning

confidence: 73%

Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration

Jadeja

Thounaojam

Bartoli

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…The multifactorial nature of AMD complicates modeling its phenotype considerably [ 17 , 63 ]. Consequently, this lack of representative models severely hampers studies into the etiology and effective treatment modalities of the disease [ 17 , 44 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

“…In the eye, the first known retinal cell layer to be affected by SI is the RPE. The RPE is extremely important for the normal function of the retina, as indicated by its role in many retinal degenerative diseases [ 7 , 43 , 44 , 82 , 83 , 84 , 85 ]. Severe damage to the RPE layer disrupts the blood-retina barrier and leads to impaired RPE-specific function.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, animal disease models of AMD have been reduced to more or less representing the critical disease symptoms. Therapeutic research into AMD has been hampered by the lack of suitable experimental models, both in vivo and in vitro [ 44 ]. Recently, a partial AMD cellular phenotype was replicated in vitro using an induced pluripotent stem cell-derived RPE culture harboring disease-associated CFH variants [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

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Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

Koster

Hurk

Brink

et al. 2022

IJMS

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Purpose: The lack of suitable animal models for (dry) age-related macular degeneration (AMD) has hampered therapeutic research into the disease, so far. In this study, pigmented rats and mice were systematically injected with various doses of sodium iodate (SI). After injection, the retinal structure and visual function were non-invasively characterized over time to obtain in-depth data on the suitability of these models for studying experimental therapies for retinal degenerative diseases, such as dry AMD. Methods: SI was injected into the tail vein (i.v.) using a series of doses (0–70 mg/kg) in adolescent C57BL/6J mice and Brown Norway rats. The retinal structure and function were assessed non-invasively at baseline (day 1) and at several time points (1–3, 5, and 10-weeks) post-injection by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and electroretinography (ERG). Results: After the SI injection, retinal degeneration in mice and rats yielded similar results. The lowest dose (10 mg/kg) resulted in non-detectable structural or functional effects. An injection with 20 mg/kg SI did not result in an evident retinal degeneration as judged from the OCT data. In contrast, the ERG responses were temporarily decreased but returned to baseline within two-weeks. Higher doses (30, 40, 50, and 70 mg/kg) resulted in moderate to severe structural RPE and retinal injury and decreased the ERG amplitudes, indicating visual impairment in both mice and rat strains. Conclusions: After the SI injections, we observed dose-dependent structural and functional pathological effects on the retinal pigment epithelium (RPE) and retina in the pigmented mouse and rat strains that were used in this study. Similar effects were observed in both species. In particular, a dose of 30 mg/kg seems to be suitable for future studies on developing experimental therapies. These relatively easily induced non-inherited models may serve as useful tools for evaluating novel therapies for RPE-related retinal degenerations, such as AMD.

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“…Rodent experiments with light-induced retinal damage and ex vivo retinas explant cultures of AMD mouse models have demonstrated that restoring normal NAD + either prevents RPE-induced light insult or reduces the propagation of retinal damage [ 82 , 83 , 84 ]. Moreover, restoring NAD + levels in AMD retinas decreased ROS RPE damage and significantly reduced the expression of proinflammatory molecules that are responsible for drusen formation [ 85 , 86 ]. Supporting this, experiments blocking NMNAT enzymatic activity promoted RPE detriment and induced a pathologic state that affected photoreceptors, outer and inner nuclear layer, and the plexiform layer [ 87 , 88 ].…”

Section: Nicotinamide Adenine Dinucleotidementioning

confidence: 99%

Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration

et al. 2020

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Glaucoma and age-related macular degeneration are leading causes of irreversible blindness worldwide with significant health and societal burdens. To date, no clinical cures are available and treatments target only the manageable symptoms and risk factors (but do not remediate the underlying pathology of the disease). Both diseases are neurodegenerative in their pathology of the retina and as such many of the events that trigger cell dysfunction, degeneration, and eventual loss are due to mitochondrial dysfunction, inflammation, and oxidative stress. Here, we critically review how a decreased bioavailability of nicotinamide adenine dinucleotide (NAD; a crucial metabolite in healthy and disease states) may underpin many of these aberrant mechanisms. We propose how exogenous sources of NAD may become a therapeutic standard for the treatment of these conditions.

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Nicotinamide, iRPE-in-a dish, and age-related macular degeneration therapy development

Cited by 4 publications

References 22 publications

Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration

Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration

Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration

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Nicotinamide, iRPE-in-a dish, and age-related macular degeneration therapy development

Cited by 4 publications

References 22 publications

Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration

Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration

Sodium-Iodate Injection Can Replicate Retinal Degenerative Disease Stages in Pigmented Mice and Rats: Non-Invasive Follow-Up Using OCT and ERG

Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration

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Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration

Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration