Injured mice at the gym: Review, results and considerations for combining chondroitinase and locomotor exercise to enhance recovery after spinal cord injury

Abstract

Exercise provides a number of important benefits after spinal cord injury in clinical studies and animal models. However, the amount of functional improvement in overground locomotion obtained with exercise alone has been limited thus far, for reasons that are still poorly understood. One hypothesis is that the complex network of endogenous extracellular matrix components, including chondroitin sulfate proteoglycans (CSPGs), can inhibit exercise-induced remodeling and limit plasticity of spared circuitry in the adult central nervous system. Recent animal studies have shown that chondroitinase ABC (ChABC) can enhance plasticity in the adult nervous system by cleaving glycosaminoglycan sidechains from CSPGs. In this article we review the current literature on plasticity observed with locomotor training and following degradation of CSPGs with ChABC and then present a rationale for the use of exercise combined with ChABC to promote functional recovery after spinal cord injury. We also present results of a preliminary study that tested the simplest approach for combining these treatments; use of a single intraparenchymal injection of ChABC administered to the lumbar enlargement of mice with voluntary wheel running exercise after a mid-thoracic spinal contusion injury. The results are negative, yet serve to highlight limitations in our understanding of the most effective protocols for combining these approaches. Further work is directed to identify the timing, type, and quantity of exercise and pharmacological interventions that can be used to maximize functional improvements by strengthening appropriate synaptic connections.

Chondroitinase ABC Promotes Recovery of Adaptive Limb Movements and Enhances Axonal Growth Caudal to a Spinal Hemisection

“…The current results are consistent with prior studies indicating that Ch’ase ABC can enhance plasticity by disrupting the growth inhibitory CS GAGs (reviewed in (Silver and Miller, 2004; Bradbury and Carter, 2010; Jakeman et al, 2010; Bradbury and Carter 2010) and decrease axonal retraction post-SCI (Busch et al, 2009). They also provide new information regarding the effects of Ch’ase ABC on adaptive features of locomotion including limb trajectories, placement accuracy, interlimb coordination and how these changes combine with non-Ch’ase ABC-mediated plasticity seen in controls.…”

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

“…The locomotion and sensory recovery of injured mice housed afterwards with running wheels was similar to those treated with chABC, without wheels and injured mice housed with or without wheels. These studies point out that CSPGs in the injured cervical spinal cord limit the effects of task-specific and general rehabilitation on some forelimb functions recovery [57,126]. Moreover, CSPGs here may be important for the effect of general rehabilitation of some forelimb functional recovery.…”

“…Moreover, CSPGs here may be important for the effect of general rehabilitation of some forelimb functional recovery. It is possible that the ineffectiveness of chABC in the study of Jakeman et al [126] may have been due to the week delay between the SCI and treatment, the use of a single injection, and also that the axon growth may not have occurred. Acute then repeated chABC treatments that led to axon sprouting had positive effects on some forelimb functions recovery, but not others [57].…”

“…Corticospinal tract and serotonergic axon sprouting occurred in rats treated with chABC, however, this was not improved by task-specific or general rehabilitation. Jakeman et al [126] performed thoracic spinal cord contusions in mice. They injected chABC once into the lumbar enlargement gray matter.…”

Translational spinal cord injury research

“…Studies, however, have been conducted primarily using partial transection models in rats and many assess anatomical changes only. Although outcomes associated with ChABC application in these models are promising and consistent, few studies use contusion-type lesions and the results from those reports are mixed (Caggiano et al, 2005; Iseda et al, 2008; Harris et al, 2010; Jakeman et al, 2011). Confounding interpretation of discrepancies in the literature relate to several factors, including dosing and the delivery route of ChABC.…”