Role of axon resealing in retrograde neuronal death and regeneration after spinal cord injury

Spinal cord injury leads to persistent behavioral deficits because mammalian central nervous system axons fail to regenerate. A neuron's response to axon injury results from a complex interplay of neuron-intrinsic and environmental factors. The contribution of axotomy to the death of neurons in spinal cord injury is controversial because very remote axotomy is unlikely to result in neuronal death, whereas death of neurons near an injury may reflect environmental factors such as ischemia and inflammation. In lampreys, axotomy due to spinal cord injury results in delayed apoptosis of spinal-projecting neurons in the brain, beyond the extent of these environmental factors. This retrograde apoptosis correlates with delayed resealing of the axon, and can be reversed by inducing rapid membrane resealing with polyethylene glycol. Studies in mammals also suggest that polyethylene glycol may be neuroprotective, although the mechanism(s) remain unclear. This review examines the early, mechanical, responses to axon injury in both mammals and lampreys, and the potential of polyethylene glycol to reduce injury-induced pathology. Identifying the mechanisms underlying a neuron's response to axotomy will potentially reveal new therapeutic targets to enhance regeneration and functional recovery in humans with spinal cord injury.

Heterogeneity in the regenerative abilities of central nervous system axons within species: why do some neurons regenerate better than others?

Some neurons,especially in mammalian peripheral nervous system or in lower vertebrate or in vertebrate central nervous system(CNS)regenerate after axotomy,while most mammalian CNS neurons fail to regenerate.There is an emerging consensus that neurons have different intrinsic regenerative capabilities,which theoretically could be manipulated therapeutically to improve regeneration.Population-based comparisons between"good regenerating"and"bad regenerating"neurons in the CNS and peripheral nervous system of most vertebrates yield results that are inconclusive or difficult to interpret.At least in part,this reflects the great diversity of cells in the mammalian CNS.Using mammalian nervous system imposes several methodical limitations.First,the small sizes and large numbers of neurons in the CNS make it very difficult to distinguish regenerating neurons from non-regenerating ones.Second,the lack of identifiable neurons makes it impossible to correlate biochemical changes in a neuron with axonal damage of the same neuron,and therefore,to dissect the molecular mechanisms of regeneration on the level of single neurons.This review will survey the reported responses to axon injury and the determinants of axon regeneration,emphasizing non-mammalian model organisms,which are often under-utilized,but in which the data are especially easy to interpret.