Abstract
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.
Highlights
In contrast to the PNS, neurons of the adult CNS do not normally display axon regeneration after nerve injury
We found that IPRG001 induced retinoic acid receptor b (RARb) expression through neural nitric oxide synthase (nNOS)/nitric oxide (NO) signaling in retinal ganglion cells (RGCs)-5 cells [14]
We showed that IPRG001-induced nNOS/NO signaling occurred after the S-nitrosylation of histone deacetylase-2 (HDAC2) leading to increased RARb expression and neuritogenesis in RGC-5 cells [14]
Summary
In contrast to the PNS, neurons of the adult CNS do not normally display axon regeneration after nerve injury. The molecular mechanism of genipin-induced neuroprotective and neurite outgrowth activity was initially believed to be neural nitric oxide synthase (nNOS)/nitric oxide (NO) -dependent because of its structural similarity to tetrahydrobiopterin, which is a cofactor for NOS enzymatic activity [15] Both the neuroprotective and neuritogenic effects of IPRG001 in RGC-5 cells were all nNOS/NO-dependent [13,14]. In the present study, we examined the neuritogenic properties of genipin on optic nerve regeneration in adult rat retinal ganglion cells (RGCs) in vivo after nerve injury. Concomitant with RARb expression, IPRG001 successfully regenerated optic axons from matured rat RGCs in vivo. These findings may be useful for development of novel therapeutic strategies for CNS regeneration
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