Oligodendrocyte- and myelin-associated inhibitors of neurite outgrowth: their involvement in the lack of CNS regeneration.

Until now central nervous system (CNS) neurites have been thought to have little capacity for regeneration following a lesion. When allowed to grow into peripheral nervous system (PNS) grafts, however, lesioned CNS axons are known to regenerate. Recently, an inhibitory substrate effect of CNS myelin and oligodendrocytes has been discovered which could be directly involved in the lack of regeneration. In culture, neurite growth cones were shown to specifically arrest their movement when contacting oligodendrocyte processes. The inhibitory components were characterized as two proteins of 35 and 250 kDa. A specific monoclonal antibody was generated (IN-1) that could neutralize these inhibitory effects. The role of the inhibitors in CNS regeneration was investigated in young rats receiving lesions of the corticospinal tract and implanted with a source of IN-1 mAB or control mAB. Results showed clear regeneration to over 10 mm in 2-5 weeks in IN-1 mAB-treated animals, while no fibers were detected further than 1 mm caudal to the lesion in controls. A similar, highly significant enhancement of regeneration was also found for the cholinergic septohippocampal pathway and for the optic nerve. These results show that lesioned CNS neurons can regenerate in CNS tissue when specific myelin components are neutralized, thus demonstrating that these inhibitory components play a crucial role in the lack of CNS regeneration.