Axonal and cell body protection by nicotinamide adenine dinucleotide in tumor necrosis factor-induced optic neuropathy.
Axonal degeneration often leads to the death of neuronal cell bodies. Previous studies have demonstrated the crucial role of nicotinamide adenine dinucleotide (NAD) biosynthesis in axonal protection of motor neurons, but the role of nicotinamide mononucleotide adenylyltransferase 1 and NAD in optic nerve degeneration is unclear. Intravitreal injection of tumor necrosis factor (TNF) induces optic nerve degeneration and subsequent loss of retinal ganglion cells. We found that the levels of nicotinamide mononucleotide adenylyltransferase 1 mRNA and protein and of NAD were significantly decreased in the optic nerve after intravitreal injection of TNF in rats. The concomitant disorganization of microtubules with vacuoles and neurofilament accumulations in the axons were blocked by exogenous NAD treatment. Nicotinamide adenine dinucleotide also prevented TNF-induced axonal loss and delayed retinal ganglion cell loss 2 months after TNF injection. Microglia identified by immunohistochemistry were increased in the optic nerves after TNF injection; this increase was inhibited by NAD treatment. These results suggest that axonal nicotinamide mononucleotide adenylyltransferase 1 and NAD declines are associated with TNF-induced optic nerve axonal degeneration and that axonal protection of NAD may be related to its inhibitory effect on microglial activation.
Kitaoka
Yasushi
Y
Department of Ophthalmology, St Marianna University School of Medicine, Kawasaki, Kanagawa, Japan. kitaoka@marianna-u.ac.jp
Hayashi
Yasuhiro
Y
Kumai
Toshio
T
Takeda
Hiroyuki
H
Munemasa
Yasunari
Y
Fujino
Hiromi
H
Kitaoka
Yuka
Y
Ueno
Satoki
S
Sadun
Alfredo A
AA
Lam
Tim T
TT
D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009243:NAD / Q000235:genetics / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000378:metabolism; D009901:Optic Nerve Diseases / Q000139:chemically induced / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology*; D018709:Statistics, Nonparametric; D013266:Stilbamidines; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha
C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D013266:Stilbamidines; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D009612:Nicotinamide-Nucleotide Adenylyltransferase