Administration of Chondroitinase ABC Rostral or Caudal to a Spinal Cord Injury Site Promotes Anatomical but Not Functional Plasticity

Abstract

Growth-inhibitory chondroitin sulfate proteoglycans (CSPG) are a primary target for therapeutic strategies after spinal cord injury because of their contribution to the inhibitory nature of glial scar tissue, a major barrier to successful axonal regeneration. Chondroitinase ABC (ChABC) digestion of CSPGs promotes axonal regeneration beyond a lesion site with subsequent functional improvement. ChABC also has been shown to promote sprouting of spared fibers but it is not clear if functional recovery results from such plasticity. Here we sought to better understand the roles rostral or caudal sprouting may play in ChABC-mediated functional improvement. To achieve this, ChABC or vehicle was injected rostral or caudal to a unilateral C5 injury. When injected rostral to a hemisection, ChABC promoted significant sprouting of 5HTþ fibers into dorsal and ventral horns. When ChABC was injected into tissue caudal to a hemisection, no additional sprouting was observed. When injected caudal to a hemicontusion injury, ChABC promoted sprouting of 5HTþ fibers into the ventral horn but not the dorsal horn. None of this sprouting resulted in a change in the synaptic component synapsin, nor did it impact performance in behavioral tests assessing motor function. These data suggest that ChABC-mediated sprouting of spared fibers does not necessarily translate into functional recovery.

Chondroitinase Combined with Rehabilitation Promotes Recovery of Forelimb Function in Rats with Chronic Spinal Cord Injury

“…The beneficial behavioral effects are therefore unlikely to have been caused by long-distance axonal regeneration. The second effect is sprouting of axons above and below the injury (Bradbury et al, 2002;Moon et al, 2002;Barritt et al, 2006;Massey et al, 2006;Cafferty et al, 2008;García-Alías et al, 2009;Tom et al, 2009b). We saw CST sprouting of a similar magnitude to that in acutely treated cord, and also sprouting of serotonergic axons.…”

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

“…A further investigation revealed that chABCmediated, aberrant CGRP-containing primary afferent sprouting caudal to a SCI did not lead to increased innervation of dorsal horn nociceptive neurons or the development of thermal hyperalgesia and mechanical allodynia. Tom et al [79] demonstrated serotonergic axon collateral sprouting throughout gray matter rostral to cervical spinal cord hemisection following a rostral intraspinal ChABC injection. A caudal intraspinal chABC injection did not promote sprouting caudal to the hemisection, but it did caudal to a cervical spinal cord hemi-contusion, a clinically relevant SCI model.…”

Astrocytic and Vascular Remodeling in the Injured Adult Rat Spinal Cord after Chondroitinase ABC Treatment

“…12 Degradation of CSPG through selective removal of glycosaminoglycan (GAG) side chains by the bacterial enzyme chondroitinase ABC (ChABC) renders the scar tissue less inhibitory for axon growth. 4,16,17 In different SCI models, a positive effect of ChABC treatment could be demonstrated, [18][19][20][21][22][23] such as improvement in forelimb performance in rats, 24,25 and recovery of specific locomotor skills in cats. 26 Combining ChABC treatment with peripheral nerve autograft resulted in extensive axon regeneration over rather long distances and greatly enhanced recovery of the functions of the affected forelimb 27 or the diaphragm.…”