Axonal Protection by Nicotinamide Riboside via SIRT1-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration

Mol Neurobiol. 2020 Dec;57(12):4952-4960. doi: 10.1007/s12035-020-02063-5. Epub 2020 Aug 20.


Nicotinamide adenine dinucleotide (NAD+) synthesis pathway has been involved in many biological functions. Nicotinamide riboside (NR) is widely used as an NAD+ precursor and known to increase NAD+ level in several tissues. The present study aimed to examine the effect of NR on tumor necrosis factor (TNF)-induced optic nerve degeneration and to investigate whether it alters SIRT1 expression and autophagic status in optic nerve. We also examined the localization of nicotinamide riboside kinase 1 (NRK1), which is a downstream enzyme for NR biosynthesis pathway in retina and optic nerve. Intravitreal injection of TNF or TNF plus NR was performed on rats. The p62 and LC3-II protein levels were examined to evaluate autophagic flux in optic nerve. Immunohistochemical analysis was performed to localize NRK1 expression. Morphometric analysis showed substantial axonal protection by NR against TNF-induced axon loss. TNF-induced increment of p62 protein level was significantly inhibited by NR administration. NR administration alone significantly increased the LC3-II levels and reduced p62 levels compared with the basal levels, and upregulated SIRT1 levels in optic nerve. Immunohistochemical analysis showed that NRK1 exists in retinal ganglion cells (RGCs) and nerve fibers in retina and optic nerve. NR administration apparently upregulated NRK1 levels in the TNF-treated eyes as well as the control eyes. Pre-injection of an SIRT1 inhibitor resulted in a significant increase of p62 levels in the NR plus TNF treatment group, implicating that SIRT1 regulates autophagy status. In conclusion, NRK1 exists in RGCs and optic nerve axons. NR exerted protection against axon loss induced by TNF with possible involvement of upregulated NRK1 and SIRT1-autophagy pathway.

Keywords: Autophagy; NRK1; Nicotinamide riboside; SIRT1; p62.

MeSH terms

  • Animals
  • Autophagy* / drug effects
  • Axons / drug effects
  • Axons / pathology*
  • Male
  • Microtubule-Associated Proteins / metabolism
  • Nerve Degeneration / pathology*
  • Neuroprotection* / drug effects
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Optic Nerve / drug effects
  • Optic Nerve / pathology*
  • Phosphotransferases (Alcohol Group Acceptor)
  • Pyridinium Compounds / pharmacology*
  • Rats, Wistar
  • Retina / drug effects
  • Retina / metabolism
  • Sequestosome-1 Protein / metabolism
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / metabolism*
  • Tumor Necrosis Factor-alpha


  • LC3 protein, rat
  • Microtubule-Associated Proteins
  • Pyridinium Compounds
  • Sequestosome-1 Protein
  • Tumor Necrosis Factor-alpha
  • nicotinamide-beta-riboside
  • Niacinamide
  • Phosphotransferases (Alcohol Group Acceptor)
  • Sirtuin 1

Grant support