Targeting CNS axon regeneration for treating CNS injuries

The optic nerve (ON) is made up of axons of retinal ganglion cells (RGCs).The RGCs axons in adult mammals do not regenerate after damage.However, a peripheral nerve attached to the transected ON provides a goodconduit for damaged retinal axons to regenerate. We conducted a series ofexperiments using this regeneration model, to study the effect of ciliaryneurotrophic factor (CNTF) on the RGC axonal regeneration, and toinvestigate its potential molecular mechanisms. We have found that in theaxotomized retinas of adult hamsters, intravitreal application of humanrecombinant CNTF initiated sprouting of axon-like processes and substan-tially enhances RGC survival. The survival effect is dose-dependent. At lowdosage, it does not promote survival but enhances the regeneration ofdamaged optic axons into a peripheral nerve graft. The magnitude of theregeneration enhancement by CNTF is achieved by a 25-fold increase in thedistal ON axotomy paradigm and by a fourfold increase in the proximal ONaxotomy paradigm. However, bFGF and neurotrophins such as NGF, BDNF,NT-3, and NT-4 do not promote axonal regeneration under the sameexperimental conditions. c-Jun expression in RGCs is up-regulated afterinjury. Proportions and intensity of c-Jun expression are higher in regener-ating than surviving RGCs. CNTF enhances c-Jun expression by increasingthe proportion of c-Jun surviving RGCs. In addition, CNTF can up-regulatethe expression of growth-associated protein-43 (GAP-43) messenger RNA inaxotomized RGCs. Our studies suggest that CNTF may exert its promotingeffect on axonal growth by up-regulating relevant intrinsic genes includingc-Jun and GAP-43.link_to_subscribed_fulltex