Training and anti-CSPG combination therapy for spinal cord injury

Abstract

Combining different therapies is a promising strategy to promote spinal cord repair, by targeting axon plasticity and functional circuit reconnectivity. In particular, digestion of chondroitin sulphate proteoglycans at the site of the injury by the activity of the bacterial enzyme chondrotinase ABC, together with the development of intensive task specific motor rehabilitation has shown synergistic effects to promote behavioural recovery. This review describes the mechanisms by which chondroitinase ABC and motor rehabilitation promote neural plasticity and we discuss their additive and independent effects on promoting behavioural recovery.

Introduction

Several experimental approaches have been shown to promote some degree of functional recovery in animals subjected to experimental spinal cord injury. The initial aim of most of these treatments was to promote regeneration of the long axon tracts. The approaches generally fall into two categories; enhancing the intrinsic regenerative ability of CNS axons, and modification of the injured spinal cord parenchyma to neutralise molecules inhibitory to axon growth. To increase the intrinsic regenerative ability of neurons, the interventions include delivering neurotrophins (Lu and Tuszynski, 2008), injecting cAMP to influence intracellular signalling pathways (Hannila and Filbin, 2008), blocking the protein synthesis inhibitor PTEN (Liu et al., 2010) or blocking the small GTPase RhoA (Ellezam et al., 2002). To decrease inhibition in spinal cord tissue, the treatments have involved blocking or digesting myelin inhibitors (Maier and Schwab, 2006), digesting the extracellular matrix (Kwok et al., 2008) or grafting growth-permissive cells to bridge the spinal cord (Li et al., 1997, Richardson et al., 1980, Tetzlaff et al., 2010).

Recently more attention has been paid to local sprouting and connectivity, the main topic of this review. Damaged and undamaged axons above and below injuries may sprout prolifically, and this process also has the potential to form new functional circuits. In order to obtain efficient functional recovery, it is necessary that those regenerated axons or local sprouts make functional contacts with spinal neurons, creating new circuits to reconnect neurons from above and below the injury. These connections must then be refined, much as the early exuberant connections are refined during development. In this second stage of recovery, activity-dependent approaches, such as physical rehabilitation, may play a key role by enhancing the formation, strength, selection and maintenance of synapses. The expectation is that combinatorial therapies based on promoting structural plasticity (i.e.; axonal sprouting and/or regeneration) and activity-dependent plasticity (i.e.; synaptic plasticity) will be a more effective strategy to promote spinal cord recovery than either regenerative sprouting or activity alone. The assumption is that in a plastic environment new circuits will initially be randomly created and then selected and shaped with rehabilitation. (Fawcett and Curt, 2009).

There have been a few recent studies in which regenerative therapies and rehabilitation have been combined. These experiments suggest that designing how to combine these treatments, and the temporal pattern for their application are not going to be trivial. The various experiments have shown a beneficial combinatorial effect, a deleterious combinatorial effect, no effect at all, or an effect that depends on the relative timing of plasticity treatment and rehabilitation. These experiments are discussed in detail in a later section.