Neuroplasticity as a basis for therapeutics in spinal cord injuries and diseases.

The concept of neuroplasticity in the adult is now well accepted. Amongst the most striking neuroplastic phenomena are those that systematically follow a lesion in the neural system itself. The work reported in this symposium emphatically illustrates the plasticity of neurons participating in spinal cord networks in various conditions that involve axonal lesions and neuronal degeneration. The purpose of this paper is to evaluate the potential for post-lesion neuroplastic changes to serve as a basis for future therapeutics with specific emphasis on two important pathologies observed in humans: spinal cord injuries and degenerative motoneuronal diseases. Spontaneous attempts at axonal regeneration and growth of axotomized neurons can be seen after a spinal trauma although the number of neurons involved is often low and variable from one population to another. In any case, axons fail to cross the scar tissue, most probably due to specific neurono-glial interactions. Successful recovery of neural systems (and therefore possible functional recovery) that can be expected as a result of these spontaneous attempts at regeneration of axotomized axons is, overall, very poor. Innumerable attempts have been made to provide severed axons in the spinal cord with a suitable substrate. Altogether, the results obtained when regeneration is facilitated in the adult through a series of different ways point to several remarkable conclusions: (i) adult neurons are indeed able to grow an axon; (ii) the failure to grow an axon after axotomy which is normally observed depends, at least in part, on an unsuitable substrate; (iii) growth ability seems to be much more restricted for neurons with large myelinated axons than for neurons with unmyelinated ones. Several therapeutic avenues can be considered that can be grouped in three different endeavors: to fill in the gap, and to change the nature of the gap, to protect fibers that have not been directly injured. An additional possibility is that compensation of lost inputs by transplants of monoaminergic neurons below the level of the lesion can be of therapeutic value. Experimental models of spinal neurodegeneration have been less intensely studied than those of spinal cord injuries. Data suggesting the existence of spontaneous neuronal plasticity in the aftermath of motoneuronal loss are, however, available. Two types of neuronal attempts at regeneration can be considered: sprouting of surviving motoneurons leading to the reoccupation of vacant motor endplates and possible attempts to grow by afferents that have been deprived of their postsynaptic target cells. These attempts may be facilitated experimentally by the use of growth factors and fetal neural transplants. The use of growth factors may be of therapeutic value and preliminary studies are presently in progress. The therapeutic value of neural transplants to replace lost motoneurons in amyotrophic lateral sclerosis or spinal muscular atrophies is not easily determined. It seems excluded that transplanted motoneurons replace lost neurons at all levels of the neuraxis. In contrast, neural transplantation may be interesting to replace a specific set of motoneurons, namely those controlling respiratory muscles.