Abstract
In 1928, Ramon y Cajal stated in his “Degeneration and Regeneration of the Nervous System” that the central adult nervous system (CNS) was “fixed and immutable” and that neurons in the adult mammalian spinal cord were incapable of anything more than very limited or abortive growth. Due to this limited capability of axons to regenerate, injuries to the adult spinal cord are particularly traumatic
and lead to permanent functional impairments. Two decades of research have shed new light on the mechanisms involved in degeneration and tissue destruction, and new biological concepts and mechanisms were found that can account for the failure of CNS neurons to successfully regenerate their
axons after injury. Over the last few years promising experimental interventions to overcome this regenerative failure have been reported. Chapter 1 summarizes crucial characteristics of mammalian spinal cord development and injury, current observations concerning limited axonal regrowth as well as promising experimental therapeutic approaches to overcome neurite growth inhibitory conditions.
Today Ramon y Cajal’s old dogma of a ‘fixed’ neuronal set-up in the CNS is no longer tenable.
Spontaneous, injury induced structural rearrangements of spared descending fibers and adaptations at the spinal level have been reported and contribute to spontaneous behavioral recovery observed after small lesions. Much recent work has focused on the identification and neutralization of factors in the adult CNS that restrict this spontaneous plasticity. Blocking Nogo-A, a myelin associated inhibitor of neurite growth, by monoclonal antibodies induces compensatory growth of descending motor tracts and almost full recovery of sensory as well as motor functions in animal models of spinal cord injury.
Feasibility and effectiveness of anti-Nogo-A antibodies in human patients are currently investigated in a clinical trial. Rehabilitative treadmill training is the only widely established and routinely used therapy for human spinal cord injury but only a few laboratories use elaborate animal models to assess the effect of specific training paradigms or analyze the underlying mechanisms. In Chapter 2 we show that forced forelimb use (constraint induced movement therapy, CIMT) in adult rats after unilateral corticospinal tract injury led to behavioral recovery of the impaired forelimb on a skilled forelimb task, paralleled by increased growth and synapse formation of midline crossing fibers originating from the intact,
contralateral CST. We used DNA microarrays to identify key molecules in the denervated spinal cord that might play an important role in activity dependent plasticity.
Over the last 20 years of research it has become clear that no single therapeutic intervention will be sufficient to promote structural repair and functional recovery in the acutely and chronically injured spinal cord. Spatially and temporally specific interventions are required in order to induce regeneration and guide regrowing fibers to appropriate targets. In Chapter 3 we combined anti-Nogo-A antibody treatment with forced limb use after unilateral corticospinal tract injury. Both treatments independently
led to behavioral recovery of skilled forelimb function back to pre-injury levels but a synergistic effect of
the combined treatment could not be observed.
In Chapter 4 we combined anti-Nogo-A antibody treatment and extensive treadmill training after a severe but incomplete lesion at the thoracic level. Both treatments alone improved functional recovery due to different specific modifications in stepping behavior suggesting that the plastic mechanisms underlying functional recovery associated with each treatment alone were different. The synchronous combination of both treatments did not show a synergistic but rather a detrimental effect, whereas
delaying the start of training resulted in improved locomotor behavior.
A short summarizing discussion in Chapter 5 leads to a final conclusion and outlook.
Maier, I C