ReviewTraining and anti-CSPG combination therapy for spinal cord injury
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.
Section snippets
Overcoming inhibition by chondroitin sulphate proteoglycans
Chondroitin sulphate proteoglycans (CSPGs) are a diverse group of extracellular proteoglycans, composed by a central core protein which has covalently linked sulphated glycosaminoglycan (GAG) side chains. In biology as a whole they are generally used for barrier formation, relying on the ability of CSPGs to inhibit cell migration, axon growth and probably also bacterial invasion. In the CNS, CSPGs are principal constituents of neuronal and glial extracellular matrix, and can be attached to the
Digestion of CSPGs in the glial scar promotes axonal regrowth
The glial scar is dense meshwork of microglial, macroglial cells and fibroblasts which proliferate and migrate to the site of injury, isolating the preserved spinal tissue from the non-neural environment (Fawcett and Asher, 1999, Silver and Miller, 2004). The hypertrophied astrocytes of the glial scar perform important functions in wound healing, blood–brain barrier repair, inflammation restriction and neuroprotection (Bush et al., 1999, Faulkner et al., 2004). Together with oligodendrocyte
Chondroitin sulphate proteoglycans, conduction and neuronal preservation
Following spinal cord injury, individuals may appear to have undamaged axons passing through the injury site apparently providing a connection between brain and cord, yet the lesion is functionally complete, implying that the preserved axons do not conduct. A reason why apparently undamaged axons may fail to conduct has recently come to light. Arvanian and colleagues examined axonal conduction of undamaged ventrolateral fasciculus axons contralateral to a lateral hemisection of the cord finding
Digestion of CSPGs promotes plasticity
In several spinal injury repair experiments functional recovery has been faster than would be expected if it were due to axon regeneration, and greater than expected from the relatively modest number of regenerating axons. This led to a hypothesis that chABC promotes plasticity as well as regeneration. The first demonstration of this was in the visual system, where young rodents show ocular dominance plasticity after monocular deprivation, but adult rats do not. Digestion with chABC reactivated
CSPGs and memory
Memory is a form of plasticity, so Gogolla and colleagues asked whether chABC treatment would influence it. The model they used was fear conditioning, a one-shot learning and memory paradigm that depends on the amygdala. Normally rats remember to associate the conditioned stimulus with fear indefinitely, but erasure by frequent exposure without the aversive stimulus is a form of reverse learning. Young rats are able to erase fear memories when exposed to an extinction protocol, whilst adult
CSPGs in perineuronal nets are the controllers of plasticity in the adult CNS
Perineuronal nets (PNNs) are dense, reticular extracellular matrix (ECM) structures that envelop many neuronal cell bodies and proximal dendrites late in development (Hockfield et al., 1990, Bruckner et al., 1996, Murakami and Ohtsuka, 2003). Interest focused on these structures because they contain several CSPGs, because they are digested by ChABC, and because they appear throughout the nervous system at the same time as critical periods for plasticity close. PNNs are mainly composed of CSPGs,
Conclusion
Combination therapies based on enhancing axonal plasticity and activity-dependent mechanisms are promising as a method of promoting functional recovery after CNS damage. CSPG digestion, by means of chABC delivery, together with voluntary task specific rehabilitation is one combination treatment that has been effective, probably because the mechanisms of functional improvement from chABC and rehabilitation are synergistic but non-interfering. However, rendering the nervous system plastic may
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