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Y. Kitaoka, Y. Hayashi, H. Fujino, Y. Kitaoka, F. N. Ross-Cisneros, Y. Munemasa, S. Ueno, A. A. Sadun, T. T. Lam; Nicotinamide Mononucleotide Adenylyltransferase1 (Nmnat1) in TNF--Induced Optic Nerve Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2454.
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To examine the involvement of nmnat1 in TNF-α-induced optic nerve degeneration and evaluate the effect of nicotinamide adenine dinucleotide (NAD) on axonal loss and retinal ganglion cell (RGC) loss induced by TNF-α.
Rats were euthanized at 1 day, 2 weeks, or 2 months after PBS or TNF-α (10 ng) intravitreal injection. NAD was injected intravitreally 24 hr before TNF-α injection. Nmnat1 mRNA in the optic nerve and retina was evaluated by quantitative real-time PCR. Fluorogold retrograde labeling of RGCs was performed 5 days before the intravitreal injection. The effects of NAD on TNF-α-induced optic nerve degeneration were determined by transmission electron microscopy (TEM) as well as axon number counting.
Real-time PCR showed that the level of nmnat1 mRNA was significantly decreased (to 45.2 % of control) in the optic nerve of TNF-α-treated eyes compared with that of PBS-treated eyes. However, no significant difference in nmnat1 mRNA level was observed in the retina between TNF-α-treated eyes and PBS-treated eyes. TEM study showed that TNF-α caused disorganization of the microtubules with vacuoles and myelin damage 2 weeks after injection. These TEM findings were blocked with pre-treatment of NAD. Moreover, NAD significantly prevented TNF-α-induced axonal loss evaluated by morphometric analysis. Exogenous NAD did not alter the decrease in mRNA of nmnat1 induced by TNF-α. Fluorogold labeling analysis showed that NAD ameliorated RGC loss 2 months after TNF-α injection.
Axonal nmnat1 decline may be associated with TNF-α induced optic nerve axonal degeneration. Preventing axonal degeneration with NAD may lead to protective effect on delayed loss of RGC bodies.
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