Requirement of retinoic acid receptor β for genipin derivative-induced optic nerve regeneration in adult rat retina

PLoS One. 2013 Aug 6;8(8):e71252. doi: 10.1371/journal.pone.0071252. Print 2013.


Like other CNS neurons, mature retinal ganglion cells (RGCs) are unable to regenerate their axons after nerve injury due to a diminished intrinsic regenerative capacity. One of the reasons why they lose the capacity for axon regeneration seems to be associated with a dramatic shift in RGCs' program of gene expression by epigenetic modulation. We recently reported that (1R)-isoPropyloxygenipin (IPRG001), a genipin derivative, has both neuroprotective and neurite outgrowth activities in murine RGC-5 retinal precursor cells. These effects were both mediated by nitric oxide (NO)/S-nitrosylation signaling. Neuritogenic activity was mediated by S-nitrosylation of histone deacetylase-2 (HDAC2), which subsequently induced retinoic acid receptor β (RARβ) expression via chromatin remodeling in vitro. RARβ plays important roles of neural growth and differentiation in development. However, the role of RARβ expression during adult rat optic nerve regeneration is not clear. In the present study, we extended this hypothesis to examine optic nerve regeneration by IPRG001 in adult rat RGCs in vivo. We found a correlation between RARβ expression and neurite outgrowth with age in the developing rat retina. Moreover, we found that IPRG001 significantly induced RARβ expression in adult rat RGCs through the S-nitrosylation of HDAC2 processing mechanism. Concomitant with RARβ expression, adult rat RGCs displayed a regenerative capacity for optic axons in vivo by IPRG001 treatment. These neuritogenic effects of IPRG001 were specifically suppressed by siRNA for RARβ. Thus, the dual neuroprotective and neuritogenic actions of genipin via S-nitrosylation might offer a powerful therapeutic tool for the treatment of RGC degenerative disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Gene Expression / drug effects
  • Iridoids / pharmacology*
  • Male
  • Nerve Regeneration / drug effects*
  • Nerve Regeneration / genetics
  • Nitric Oxide Synthase Type I / genetics
  • Nitric Oxide Synthase Type I / metabolism
  • Optic Nerve / drug effects*
  • Optic Nerve / physiology
  • RNA, Small Interfering / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Retinoic Acid / antagonists & inhibitors
  • Receptors, Retinoic Acid / physiology*
  • Retina / drug effects*
  • Retina / physiology
  • Retinal Ganglion Cells / physiology


  • 1-isopropyloxygenipin
  • Iridoids
  • RNA, Small Interfering
  • Receptors, Retinoic Acid
  • retinoic acid receptor beta
  • genipin
  • Nitric Oxide Synthase Type I

Grants and funding

This work was partly supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Nos 25462753 to YK, 23650163 to SK and 23618006 to KS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.