Regeneration of immature mammalian spinal cord after injury

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Abstract

In this review we describe the growth of regenerating fibres through lesions in immature mammalian spinal cord. In newborn opossums and foetal rats, repair occurs rapidly and reliably without antibodies, implants or bridges of undamaged spinal cord. In the neonatal opossum one can compare recovery from lesions made to the CNS at various stages of development in the animal and in culture. As the CNS matures, the capacity for regeneration ceases abruptly. In particular, the extracellular matrix and molecules associated with glia have been shown to play a role in promoting and inhibiting regeneration. Major problems concern the precision with which regenerating axons become reconnected to their targets, and the specificity needed for recovery of function. Trends Neurosci. (1996) 19, 229–234

Section snippets

Repair of lesions with grafts from peripheral nerve or foetal CNS

A key step in defining problems of CNS regeneration was the use of peripheral nerve grafts to bridge distant parts of the CNS, for example from the retina to the superior colliculus or from the thalamus to the spinal cord. Such experiments have demonstrated that: (1) adult CNS neurones still possess intrinsic mechanisms for axonal growth over long distances if they are provided with an appropriate environment; and (2) adult CNS tissue is unfavorable for growth. Thus, axons that leave the graft

Molecules that inhibit neurite outgrowth

In a systematic and elegant series of experiments, growth-inhibitory molecules associated with myelin from the CNS have been isolated and characterized. Known as NI-35250 (NI standing for ‘neurite inhibitor’ and 35250 for the molecular weights), these molecules block the outgrowth of neurites in culture17, 18. Moreover, growth cones that make contact with oligodendrocytes or myelin from the CNS collapse[19]. These inhibitory effects are in turn blocked by a monoclonal antibody (IN-1), in the

Regeneration of CNS in neonatal marsupials

Marsupials have certain advantages for studying regeneration in immature mammalian CNS and for determining the stage of development at which it stops. Newborn opossums are born at a highly immature stage, particularly with respect to their CNS and limb development. In many respects they correspond to E13–E14 rat embryos29, 30. Thus, the cortex consists of two layers of cells (neuroependyma and marginal zone). The cerebellum is still rudimentary. There is a more pronounced rostrocaudal gradient

Regeneration or growth of new fibres?

There is an inherent interpretation problem with experiments examining the response to injury in immature spinal cord. At the time when lesions are made, major spinal-cord tracts have not developed, so some fibres might not have arrived at the site of injury. When axons subsequently grow across the lesion, it is important to know whether they are regenerating from injured cells or are new, uninjured fibres that had not reached the site of injury at the time when it was made. Several groups have

Regeneration of immature mammalian CNS in culture

Certain advantages for the study of spinal-cord repair accrue from CNS preparations that can be maintained in culture. As in the chick, fibre outgrowth can be observed in living preparations, and drugs as well as antibodies can be applied directly to the preparation via the culture medium. The CNS of neonatal M. domestica aged 1–18 days can be removed in its entirety and maintained for periods of seven days or more in suitable medium42, 43, 44. Under these conditions reflexes persist, fine

Prospects for spinal-cord repair in patients

What can the neuroscientist working in the laboratory with experimental animals tell victims of spinal-cord injury today about the chances for effective new treatments? At present, the only possible answer is that no new therapy is yet at the stage where clinical trials could be contemplated.

The problems are immense. They include the heterogeneous types of lesions, ranging from compression to transection, with variable degrees of haemorrhage, tissue destruction, and variable delays between

Concluding remarks

A major recent advance is that pieces of the puzzle are becoming available even though their place in the picture as a whole is not yet known. Thus, adult CNS neurones can indeed grow for long distances and make connections if they are provided with an appropriate environment; and the spinal cord in an immature mammal can repair as effectively as that in a frog or a fish. Particularly encouraging for future research is the abrupt transition that occurs in just a few days in early life. One can

Acknowledgements

We are grateful to our colleagues, W. Adams, the late S. Erulkar, J. Fernandez, G. Knott, M. Schwab and Z. Varga who collaborated in the experiments reported here. We also wish to thank P. Bättig for photography. We thank the Swiss National Funds and the International Research Institute for Paraplegia for grants to JGN, and the Australian Research Council for grants to NRS.

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