Targeting NAD+ for retinal ganglion cell protection in experimental glaucoma

Cimaglia, Gloria 2023. Targeting NAD+ for retinal ganglion cell protection in experimental glaucoma. PhD Thesis, Cardiff University. Item availability restricted.

	PDF - Accepted Post-Print Version Restricted to Repository staff only until 28 November 2024 due to copyright restrictions. Download (11MB)
	PDF (Cardiff University Electronic Publication Form) - Supplemental Material Restricted to Repository staff only Download (101kB)

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide. It is characterised by progressive degeneration and loss of retinal ganglion cells (RGCs) and their axons. Despite ocular hypertension (OHT) being the major and only treatable risk factor, increasing evidences suggest that nicotinamide adenine dinucleotide (NAD+) age related decline may exacerbate neuronal vulnerability to glaucomatous damage. NAD+ is an important metabolite, central to neuronal health and energy metabolism. RGCs due to their compartmentalised structure and function are among the most energy consuming neurons of the central nervous system (CNS), and rely on mitochondria to fulfil their energy requirements. Reduced NAD+ bioavailability has an impact on mitochondrial functions, affecting mitochondrial ability to produce ATP, increasing at the same time oxidative stress and inflammatory reactions. This leads to an altered cellular homeostasis which influences RGCs degeneration. Here we show that nicotinamide adenine mononucleotide (NAM) supplementation, a precursor of NAD+, can mitigate RGC dendritic atrophy in ex vivo retinal explants and in vivo following induction of unilateral OHT. NAM enrichment maintained RGCs cellular homeostasis, restoring energy metabolism and cellular antioxidant capacity, which were lost in untreated OHT models. Proof of concept experiments explored whether overexpression of NMNAT2, the rate limiting enzyme of the salvage pathway, could enhance RGCs survival. These findings suggest that supporting energy metabolism can reduce RGCs vulnerability to glaucomatous damage. Preserving RGC integrity is pivotal to visual functions, and considering the ongoing nicotinamide trials, these data further confirm the significant neuroprotection that can be achieved with NAD+-related therapies.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Optometry and Vision Sciences
Subjects:	R Medicine > RE Ophthalmology
Uncontrolled Keywords:	Nicotinamide, Retinal ganglion cells, neuroprotection, experimental glaucoma
Date of First Compliant Deposit:	28 November 2023
Last Modified:	28 Nov 2023 14:02
URI:	https://orca.cardiff.ac.uk/id/eprint/164426

Actions (repository staff only)

Edit Item