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Glaucoma as a Metabolic Optic Neuropathy: Making the Case for Nicotinamide Treatment in Glaucoma
Open accessAbstract
Mitochondrial dysfunction may be an important, if not essential, component of human glaucoma. Using transcriptomics followed by molecular and neurobiological techniques, we have recently demonstrated that mitochondrial dysfunction within retinal ganglion cells is an early feature in the DBA/2J mouse model of inherited glaucoma. Guided by these findings, we discovered that the retinal level of nicotinamide adenine dinucleotide (NAD, a key molecule for mitochondrial health) declines in an age-dependent manner. We hypothesized that this decline in NAD renders retinal ganglion cells susceptible to damage during periods of elevated intraocular pressure. To replete NAD levels in this glaucoma, we administered nicotinamide (the amide of vitamin B 3). At the lowest dose tested, nicotinamide robustly protected from glaucoma (~70% of eyes had no detectable glaucomatous neurodegeneration). At this dose, nicotinamide had no influence on intraocular pressure and so its effect was neuroprotective. At the highest dose tested, 93% of eyes had no detectable glaucoma. This represents a ~10-fold decrease in the risk of developing glaucoma. At this dose, intraocular pressure still became elevated but there was a reduction in the degree of elevation showing an additional benefit. Thus, nicotinamide is unexpectedly potent at preventing this glaucoma and is an attractive option for glaucoma therapeutics. Our findings demonstrate the promise for both preventing and treating glaucoma by interventions that bolster metabolism during increasing age and during periods of elevated intraocular pressure. Nicotinamide prevents age-related declines in NAD (a decline that occurs in different genetic contexts and species). NAD precursors are reported to protect from a variety of neurodegenerative conditions. Thus, nicotinamide may provide a much needed neuroprotective treatment against human glaucoma. This manuscript summarizes human data implicating mitochondria in glaucoma, and argues for studies to further assess the safety and efficacy of nicotinamide in human glaucoma care.
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“Recent work has strongly implicated energy deficits in glaucoma [18–23], and reduced AMPK correlates with anti-inflammatory responses and RGC protection [24].”
From AMPK hyperactivation promotes dendrite retraction, synaptic loss, and neuronal dysfunction in glaucoma (2021) · cites this paper as [22]
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Cites
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Tribble, J. R., Otmani, A., Sun, S., Ellis, S. A., Cimaglia, G., Vohra, R., Jöe, M., Lardner, E., Venkataraman, A. P., Domínguez‐Vicent, A., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101988 · Cited by 236
Self-citationHui, F., Tang, J., Williams, P. A., McGuinness, M. B., Hadoux, X., Casson, R. J., Coote, M., Trounce, I. A., Martin, K. R., van Wijngaarden, P., et al. (2020) · Clinical & Experimental Ophthalmology · doi:10.1111/ceo.13818 · Cited by 226
Self-citationNicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma
Moraes, C. G. D., John, S. W. M., Williams, P. A., Blumberg, D. M., Cioffi, G. A., & Liebmann, J. M. (2021) · JAMA Ophthalmology · doi:10.1001/jamaophthalmol.2021.4576 · Cited by 166
Self-citationPossible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment
Hwang, E., & Song, S. (2020) · Biomolecules · doi:10.3390/biom10050687 · Cited by 144
Retinal energy metabolism in health and glaucoma
Casson, R. J., Chidlow, G., Crowston, J. G., Williams, P. A., & Wood, J. P. M. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100881 · Cited by 132
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Metadata
- Authors
- Williams, P. A., Harder, J. M., & John, S. W. M.
- Affiliations
- Howard Hughes Medical Institute (US)
- Tufts University (US)
- Corresponding author
- Williams, Pete A.
- Harder, Jeffrey M.
- John, Simon W.M.
- Venue
- Journal of Glaucoma
- Published
- 2017-12
- Volume
- 26
- Issue
- 12
- Pages
- 1161-1168
- ISSN
- 1057-0829 (ISSN-L)
- PMC
- PMC5854489
- OpenAlex
- W2753388315
- Cited by
- 102
- References
- 108
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 8 · 2023: 17 · 2022: 12 · 2021: 19 · 2020: 13 · 2019: 5 · 2018: 4
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Glaucoma (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Eye Institute (R01EY011721)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007065)
- Topics
- Health Sciences › Medicine › Ophthalmology › Glaucoma and retinal disorders
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
- Keywords
- glaucoma, nicotinamide, NAD+, mitochondrial dysfunction, retinal ganglion cells, intraocular pressure, neuroprotection, NAD+ precursors, glaucoma prevention
- MeSH terms
- Animals, Glaucoma, Humans, Intraocular Pressure, Niacinamide, Optic Nerve Diseases, Vitamin B Complex
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