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Central nervous system (CNS) neurons of mammals regenerate poorly after axonal injury. However, if an injured CNS neuron (rabbit optic nerve) is supplied with appropriate soluble substances ("growth-associated triggering factors") derived from medium conditioned by regenerating fish optic nerve or newborn rabbit optic nerve, it can express regeneration-associated characteristics. Such characteristics include a general increase in protein synthesis, changes in synthesis of specific polypeptides, and sprouting of nerve fibers in culture. The present study of rabbit optic nerves demonstrates that such active substances affect the neuronal environment (i.e., the non-neuronal cells), thereby perhaps causing a shift in the environment from an inhibitory to a regenerative supportive one. Apparently, such an environment is spontaneously achieved in injured CNS nerves of lower vertebrates (e.g., fish optic nerves), which are regenerable. Treatment of injured rabbit optic nerve with soluble factors from medium conditioned by regenerating carp optic nerve resulted in a selective increase in proliferation ([3H]thymidine incorporation) of perineural cells and the appearance of a 12-kDa polypeptide in a homogenate derived from the nerve and its associated cells. This polypeptide may be related to growth, since it comigrates in NaDodSO4/polyacrylamide gel electrophoresis with a 12-kDa polypeptide that is continuously present in a regenerative system. In addition, there were injuryinduced changes in the polypeptides of the nerve that were independent of treatment with conditioned medium and were correlated with nerve maturation. The most prominent changes of this type were in 18-kDa and 25-kDa polypeptides whose levels were reduced after injury and were found to be correlated with the nerve maturation (myelination) state.The loss of function that results from damage to the central nervous system (CNS) of mammals is due to the low regenerative potential of the mammalian CNS. Recent observations have offered new clues as to why the adult CNS fails to regenerate (1-6). It appears that the environment of the injured neuron is involved in determining the ability of the neuron to regenerate after injury. The contribution of the environment (i.e., the non-neuronal cells) to the process of regeneration is possibly in provision of diffusible substances (7, 8) and a proper extracellular matrix needed to induce and support the regenerative cascade (6, 9).Studies carried out in regenerative peripheral (sciatic nerve of rat) and central (optic nerve of fish) nerves have provided evidence that injury causes changes in the type and amount of diffusible molecules originating from non-neuronal cells surrounding the injured nerves. In the peripheral nervous system, a 37-kDa polypeptide was found to be selectively accumulated following injury to the sciatic nerve (10) and was identified recently as a form of apolipoprotein E (11, 12).Studies in our laboratory have demonstrated that, in the regenerating optic nerves of fish, there are alte...

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