Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction

Tribble, James R.; Otmani, Amin; Sun, Shanshan; Ellis, Sevannah A.; Cimaglia, Gloria; Vohra, Rupali; Jöe, Melissa; Lardner, Emma; Venkataraman, Abinaya Priya; Domínguez‐Vicent, Alberto; Kokkali, Eirini; Rho, Seungsoo; Jóhannesson, Gauti; Burgess, Robert W.; Fuerst, Peter G.; Brautaset, Rune; Kolko, Miriam; Morgan, James E.; Crowston, Jonathan G; Votruba, Marcela; Williams, Pete A.

doi:10.1016/j.redox.2021.101988

Cited by 99 publications

(88 citation statements)

References 86 publications

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“…The explant model of the mouse eye and optic nerve enables the image analysis of the living optic nerve head, showing that the percentage of mitochondria in motion significantly decreases with an acute and chronic IOP elevation (Kimball et al, 2017(Kimball et al, , 2018. Nicotinamide, which protects the RGCs of DBA/2J mice, increases mitochondrial size and motility in primary RGC cultures (Tribble et al, 2021).…”

Section: Defect Of Mitochondrial Biogenesis Motility Dynamics and Mitophagy In Glaucomamentioning

confidence: 99%

“…Numerous studies have demonstrated mitochondrial abnormalities occurring in the neurodegeneration accompanying glaucoma in patients and animal ocular hypertension (OHT) models ( Ju et al, 2008 ; Williams et al, 2017 ; Hass and Barnstable, 2019 ; Tribble et al, 2019 , 2021 ). Previous studies have demonstrated that mitochondrial dysfunction is an early driver of neuronal dysfunction preceding clinically observable neurodegeneration ( Williams et al, 2017 ).…”

Section: Mitochondria Of Rgcs: Critical Target Of Metal Ionsmentioning

confidence: 99%

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Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Tang

Zhuo

2021

Front. Cell Dev. Biol.

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Glaucoma is the most substantial cause of irreversible blinding, which is accompanied by progressive retinal ganglion cell damage. Retinal ganglion cells are energy-intensive neurons that connect the brain and retina, and depend on mitochondrial homeostasis to transduce visual information through the brain. As cofactors that regulate many metabolic signals, iron and zinc have attracted increasing attention in studies on neurons and neurodegenerative diseases. Here, we summarize the research connecting iron, zinc, neuronal mitochondria, and glaucomatous injury, with the aim of updating and expanding the current view of how retinal ganglion cells degenerate in glaucoma, which can reveal novel potential targets for neuroprotection.

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Section: Defect Of Mitochondrial Biogenesis Motility Dynamics and Mitophagy In Glaucomamentioning

confidence: 99%

Section: Mitochondria Of Rgcs: Critical Target Of Metal Ionsmentioning

confidence: 99%

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Tang

Zhuo

2021

Front. Cell Dev. Biol.

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“…Animal models show that nicotinamide prevents RGC death during IOP elevation. Improvement of mitochondrial function also protects RGCs ( 85 , 86 ). A clinical trial is currently underway to show whether nicotinamide is beneficial in humans for visual field-testing performance [NCT03797469].…”

Section: Discussionmentioning

confidence: 99%

Glaucoma Clinical Research: Trends in Treatment Strategies and Drug Development

et al. 2021

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Purpose: To investigate the trends and progresses in glaucoma research by searching two major clinical trial registries; clinicaltrials.gov, and Australianclinicaltrials.gov.au.Methods: All clinical trials with glaucoma covered by Clinicaltrials.gov, and Australianclinicaltrials.gov.au starting the study before 1 January 2021 were included. Trials evaluating glaucoma treatment were separated from non-treatment trials and divided into three major categories: “laser treatment,” “surgical treatment,” and “medical treatment.” In the category of “medical treatment,” new compounds and their individual targets were identified and subcategorized according to treatment strategy; intraocular pressure (IOP)-lowering, neuroprotective or vascular. The phase transition success rates were calculated.Results: One-thousand five hundred and thirty-seven trials were identified. Sixty-three percent (n = 971) evaluated glaucoma treatment, of which medical treatment accounted for the largest proportion (53%). The majority of medical trials evaluated IOP-lowering compounds, while trials with neuroprotective or vascular compounds accounted for only 5 and 3%, respectively. Eighty-eight new compounds were identified. Phase I, II, and III transition success rates were 63, 26, and 47%, respectively.Conclusion: The number of clinical trials in glaucoma research has increased significantly over the last 30 years. Among the most recently evaluated compounds, all three main treatment strategies were represented, but clinical trials in neuroprotection and vascular modalities are still sparse. In addition to traditional medicines, dietary supplements and growth factors are assessed for a potential anti-glaucomatous effect. Phase II and III success rates were below previously reported success rates for all diseases and ophthalmology in general. A stricter phenotyping of patients can improve the success rates in glaucoma and ophthalmological research and gain a better understanding of responders and non-responders.

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“…The Pete Williams lab has done extensive research into bioenergetic insufficiency driving neurodegeneration and novel therapeutic approaches to address this. They have examined NAD's effect in rodent models with induced, isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults [186]. The use of nicotinamide supplementation in this study provided neuroprotective effects by increasing oxidative phosphorylation and mitochondrial size and motility, as well as by buffering and preventing metabolic stress [186].…”

Section: Nad/nadhmentioning

confidence: 96%

Metformin and Glaucoma—Review of Anti-Fibrotic Processes and Bioenergetics

Hurley

Irnaten

O’Brien

2021

Cells

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Glaucoma is the leading cause of irreversible blindness globally. With an aging population, disease incidence will rise with an enormous societal and economic burden. The treatment strategy revolves around targeting intraocular pressure, the principle modifiable risk factor, to slow progression of disease. However, there is a clear unmet clinical need to find a novel therapeutic approach that targets and halts the retinal ganglion cell (RGC) degeneration that occurs with fibrosis. RGCs are highly sensitive to metabolic fluctuations as a result of multiple stressors and thus their viability depends on healthy mitochondrial functioning. Metformin, known for its use in type 2 diabetes, has come to the forefront of medical research in multiple organ systems. Its use was recently associated with a 25% reduced risk of glaucoma in a large population study. Here, we discuss its application to glaucoma therapy, highlighting its effect on fibrotic signalling pathways, mitochondrial bioenergetics and NAD oxidation.

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Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction

Cited by 99 publications

References 86 publications

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Effects of Iron and Zinc on Mitochondria: Potential Mechanisms of Glaucomatous Injury

Glaucoma Clinical Research: Trends in Treatment Strategies and Drug Development

Metformin and Glaucoma—Review of Anti-Fibrotic Processes and Bioenergetics

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