NAD+ maintenance attenuates light induced photoreceptor degeneration

Abstract

Light-induced retinal damage (LD) occurs after surgery or sun exposure. We previously showed that zinc (Zn2+) accumulated in photoreceptors and RPE cells after LD but prior to cell death, and pyruvate or nicotinamide attenuated the resultant death perhaps by restoring nicotinamide adenine dinucleotide (NAD+) levels. We first examined the levels of NAD+ and the efficacy of pyruvate or nicotinamide in oxidative toxicities using primary retinal cultures. We next manipulated NAD+ levels in vivo and tested the affect on LD to photoreceptors and RPE. NAD+ levels cycle with a 24-h rhythm in mammals, which is affected by the feeding schedule. Therefore, we tested the affect of increasing NAD+ levels on LD by giving nicotinamide, inverting the feeding schedule, or using transgenic mice which overexpress cytoplasmic nicotinamide mononucleotide adenyl-transferase-1 (cytNMNAT1), an NAD+ synthetic enzyme. Zn2+ accumulation was also assessed in culture and in retinal sections. Retinas of light damaged animals were examined by OCT and plastic sectioning, and retinal NAD levels were measured. Day fed, or nicotinamide treated rats showed less NAD+ loss, and LD compared to night fed rats or untreated rats without changing the Zn2+ staining pattern. CytNMNAT1 showed less Zn2+ staining, NAD+ loss, and cell death after LD. In conclusion, intense light, Zn2+ and oxidative toxicities caused an increase in Zn2+, NAD+ loss, and cell death which were attenuated by NAD+ restoration. Therefore, NAD+ levels play a protective role in LD-induced death of photoreceptors and RPE cells.

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

“…Moreover, the retinal dysfunction associated with light-induced degeneration can be partially rescued with NMN. These findings offer powerful therapeutic avenues for degenerative diseases of the eye and are supported by past studies exploring the therapeutic applications of NAD + supplementation in light-induced degeneration (Bai and Sheline, 2013), noise-induced hearing loss (Brown et al, 2014), and high-fat diet- and age-induced metabolic complications (Canto et al, 2012; Ramsey et al, 2008; Stein and Imai, 2014; Yoshino et al, 2011). …”

Exogenous NAD+ decreases oxidative stress and protects H2O2-treated RPE cells against necrotic death through the up-regulation of autophagy

“…Exogenous NAD + supplement has been reported to protect cell from death induced by oxidative stress 17 23 . Besides, study on the light-induced retinal damage shows that NAD + treatment attenuates photoreceptor degeneration and RPE cell death triggered by zinc toxicity, a result from pathologic light exposure 24 25 . All these studies suggest that NAD + might be a novel cytoprotective agent against oxidative stress or zinc toxicity.…”

“…A number of studies have shown that oxidative stress or zinc toxicity can induce DNA damage and cell death by causing intracellular NAD + depletion or ATP depletion 24 25 26 27 . In the present study, neither NAD + depletion by measurement of intracellular NAD + levels and NAD + /NADH ratios nor inhibition of NAD + synthesis by measurement of gene expression of seven enzymes involved in NAD + biosynthesis was detected in the RPE cells treated with 300 μM H 2 O 2 ( Fig.…”

Sublethal treatment with plasma-activated medium induces senescence-like growth arrest of A549 cells: involvement of intracellular mobile zinc

“…Hydrogen peroxide and nitric oxide have been reported to promote Zn 2+ release from intracellular Zn 2+ stores in several cell types. (12,(25)(26)(27) Knoch et al (28) demonstrated that peroxynitrite triggers Zn 2+ liberation, leading to Zn 2+ -dependent neuronal cell death. NTAPP irradiation generates ROS/RNS to produce peroxynitrite, which reacts with protein and causes protein nitration.…”