Neurotrophic factors and CNS regeneration

Abstract

After a traumatic contusion or ischemic injury to the spinal cord many neurons, oligodendrocytes and other cells in the affected region die over the ensuing hours to days through a complex cascade of events. The neurons that contribute to the long projecting tracts generally do not die from such a distant lesion but their axons can be directly interrupted by the spinal cord injury or undergo subsequent degeneration. Ideally, treatments should be aimed at preventing these degenerative events, i.e., rescue local cells and axons from injury-induced death and degeneration. Such a treatment currently consists of infusions of high doses of methylprednisolon within 8 hours after injury which leads to some improvement in motor and sensory recovery (Bracken and Holford, 1993; Young et al., 1994). However, many patients have existing spinal cord injuries and many receive injuries where tissue loss is inevitable. Thus, treatments also have to be developed to replace lost spinal cord tissue and to promote regeneration of long axonal projections. Spontaneous regeneration and recovery of function in the adult mammalian central nervous system (CNS) is very limited, especially in the spinal cord. This is not due to an inherent inability of the CNS neurons to regenerate since they are able to grow into peripheral nerve grafts. Evidently, the adult CNS environment, but not that of the peripheral nervous system (PNS), is restrictive to axonal regeneration. This is also exemplified by the observations that crushed central projections of primary sensory neurons can grow very well in the dorsal roots (PNS) but cannot cross the root-cord interface into the spinal cord (CNS). Similarly, of the CNS axons that grow into and across an implanted peripheral nerve graft, very few reenter the spinal cord tissue and only over very short distances. Recent advances in the understanding about the various elements of spinal cord degeneration and regeneration have been extensively reviewed elsewhere (Schwab and Bartholdi, 1996).