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

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


Title: Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction
Author: Tribble, James R.
Otmani, Amin
Sun, Shanshan
Ellis, Sevannah A.
Cimaglia, Gloria
Vohra, Rupali
Jöe, Melissa
Lardner, Emma
Venkataraman, Abinaya P.
Domínguez-Vicent, Alberto
... 11 more authors Show all authors
Date: 2021-07
Language: English
Scope: 101988
Department: Faculty of Medicine
Series: Redox Biology; 43()
ISSN: 2213-2317
DOI: https://doi.org/10.1016/j.redox.2021.101988
Subject: Gláka; Hvatberar; Efnaskipti; Sjónhimna; Glaucoma; Metabolism; Metabolomics; Mitochondria; Nicotinamide; Retina; Retinal ganglion cell; Neurodegenerative Diseases; Neuroprotection; Niacinamide; Humans; Retinal Ganglion Cells; Animals; Disease Models, Animal; Clinical Biochemistry; Organic Chemistry
URI: https://hdl.handle.net/20.500.11815/3061

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Citation:

Tribble , J R , Otmani , A , Sun , S , Ellis , S A , Cimaglia , G , Vohra , R , Jöe , M , Lardner , E , Venkataraman , A P , Domínguez-Vicent , A , Kokkali , E , Rho , S , Jóhannesson , G , Burgess , R W , Fuerst , P G , Brautaset , R , Kolko , M , Morgan , J E , Crowston , J G , Votruba , M & Williams , P A 2021 , ' Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction ' , Redox Biology , vol. 43 , 101988 , pp. 101988 . https://doi.org/10.1016/j.redox.2021.101988

Abstract:

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. We assess the effects of nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron in glaucoma) in normal physiological conditions and across a range of glaucoma relevant insults including mitochondrial stress and axon degenerative insults. We demonstrate retinal ganglion cell somal, axonal, and dendritic neuroprotection by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We performed metabolomics enriched for small molecular weight metabolites for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption, including consistent changes to α-ketoglutaric acid, creatine/creatinine, homocysteine, and glycerophosphocholine. This metabolic disruption is prevented by nicotinamide. Nicotinamide provides further neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term nicotinamide treatment as a neuroprotective therapy for human glaucoma.

Description:

Publisher Copyright: © 2021 The Authors Funding Vetenskapsrådet 2018–02124, StratNeuro StartUp grant, Glaucoma Research Foundation Shaffer Grant, Ögonfonden, Stiftelsen Lars Hiertas Minne, Stiftelsen Kronprinsessan Margaretas Arbetsnämnd för synskadade, and Karolinska Institutet Foundation Grants (PAW). Pete Williams is supported by the Karolinska Institutet in the form of a Board of Research Faculty Funded Career Position and by St. Erik Eye Hospital philanthropic donations (PAW). China Scholarship Council 201706100202 (SS). Australian Government Research Training Program Scholarship (SAE). Novo Nordisk Foundation NNF18SA0034956 (RV). Vetenskapsrådet 2019–06076, the Swedish Society for Medical Research, Knut and Alice Wallenberg Foundation, Swedish Research Council, Cronqvist Foundation, and Ögonfonden (GJ). RWB is supported by the National Institutes of Health R37 NS054154, and the generation of the MitoV mice was supported by an ALS Association (RWB). AFA försäkringar, Karolinska Institutet Board of Research senior position support (RB). Velux Foundation 1179261001/2, Fight for Sight Denmark (MK). Fight for Sight UK Studentships 515,905 and 512,264 (JEM). Joan Miller Foundation and Craig and Connie Kimberley Fund (JGC). Marcela Votruba is supported by the School of Vision Sciences, Cardiff University (MV).

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