REGENERATION OF LESIONED RAT OPTIC-NERVE FIBERS IS IMPROVED AFTER NEUTRALIZATION OF MYELIN-ASSOCIATED NEURITE GROWTH-INHIBITORS

Optic nerve axons do not regenerate after lesions in postnatal mammals, except if peripheral nerve transplants are offered as a substrate [20,36,42]. In the present study, regeneration was assessed after intracranial freeze-crush lesions of the optic nerve, which completely interrupted air axons. In rats lesioned at the age of 8-9 days and surviving for additional 5-6 days, regenerating retinal fibers were seen to enter and partially cross the lesion site, reaching a maximum distance of 0.8 mm ((x) over bar+/-S.E.M.=0.62+/- 0.07 mm) in the presence of brain-derived neurotrophic factor (BDNF). Without BDNF, almost all the axons were lost due to axonal die-back. This regeneration distance could be significantly enhanced, up to 1.9 mm, by application of a monoclonal antibody (mAB IN-1 [6]) directed against oligodendrocyte- and myelin-associated neurite growth inhibitory proteins. Similar results were obtained in rats lesioned at 16-18 days and surviving for 2 weeks: whereas fibroblast growth factor (FGF) stimulated sprouting did not exceed distances of 0.5 mm ((x) over bar=0.38+/-0.07 mm), FGF and IN-1 antibody treated rats showed regenerations up to 2.3 mm ((x) over bar=1.53+/-0.15 mm). The specificity of this effect was confirmed by lesions of myelin- and oligodendrocyte-free optic nerves: optic nerves were locally X-irradiated at birth, day 2, 4 and 6, a procedure which kills the dividing oligodendrocyte precursor cells [12,30]. When these myelin-free nerves were lesioned at 3 weeks of age, regeneration distances between 2.5 and 3.2 mm were observed 3 weeks later. Our results demonstrate the ability of postnatal rat optic nerve fibers to regenerate within the CNS microenvironment under two conditions: axonal die-back has to be prevented with appropriate neurotrophic factors, and neurite growth inhibitory components, in particular those associated with CNS oligodendrocytes and myelin, have to be inactivated.