Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction
James R. Tribble,
Amin Otmani,
Shanshan Sun,
Sevannah A. Ellis,
Gloria Cimaglia,
Rupali Vohra,
Melissa Jöe,
Emma Lardner,
Abinaya P. Venkataraman,
Alberto Domínguez-Vicent,
Eirini Kokkali,
Seungsoo Rho,
Gauti Jóhannesson,
Robert W. Burgess,
Peter G. Fuerst,
Rune Brautaset,
Miriam Kolko,
James E. Morgan,
Jonathan G. Crowston,
Marcela Votruba,
Pete A. Williams
Affiliations
James R. Tribble
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
Amin Otmani
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
Shanshan Sun
School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK
Sevannah A. Ellis
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
Gloria Cimaglia
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden; School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK
Rupali Vohra
Department of Veterinary and Animal Sciences, Pathobiological Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Drug Design and Pharmacology, Eye Translational Research Unit, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
Melissa Jöe
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
Emma Lardner
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
Abinaya P. Venkataraman
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
Alberto Domínguez-Vicent
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
Eirini Kokkali
School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK
Seungsoo Rho
School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK; Department of Ophthalmology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
Gauti Jóhannesson
Department of Clinical Sciences, Ophthalmology, Umeå University, Umeå, Sweden; Wallenberg Centre of Molecular Medicine, Umeå University, Umeå, Sweden
Robert W. Burgess
The Jackson Laboratory, Bar Harbor, ME, USA
Peter G. Fuerst
WWAMI Medical Education Program, University of Idaho, Moscow, ID, USA
Rune Brautaset
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden
Miriam Kolko
Department of Drug Design and Pharmacology, Eye Translational Research Unit, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Ophthalmology, Copenhagen University Hospital, Rigshospitalet-Glostrup, Glostrup, Denmark
James E. Morgan
School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK; Cardiff Eye Unit, University Hospital Wales, Cardiff, UK; School of Medicine, Cardiff University, Cardiff, UK
Jonathan G. Crowston
Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore, Singapore; Centre for Vision Research, Neuroscience and Behavioural Disorders, Duke-NUS, Singapore, Singapore
Marcela Votruba
School of Optometry and Vision Sciences, Cardiff University, Cardiff, UK; Cardiff Eye Unit, University Hospital Wales, Cardiff, UK
Pete A. Williams
Department of Clinical Neuroscience, Division of Eye and Vision, St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden; Corresponding author.
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.
