Examination of the Combined Effects of Chondroitinase ABC, Growth Factors and Locomotor Training following Compressive Spinal Cord Injury on Neuroanatomical Plasticity and Kinematics

Abstract

While several cellular and pharmacological treatments have been evaluated following spinal cord injury (SCI) in animal models, it is increasingly recognized that approaches to address the glial scar, including the use of chondroitinase ABC (ChABC), can facilitate neuroanatomical plasticity. Moreover, increasing evidence suggests that combinatorial strategies are key to unlocking the plasticity that is enabled by ChABC. Given this, we evaluated the anatomical and functional consequences of ChABC in a combinatorial approach that also included growth factor (EGF, FGF2 and PDGF-AA) treatments and daily treadmill training on the recovery of hindlimb locomotion in rats with mid thoracic clip compression SCI. Using quantitative neuroanatomical and kinematic assessments, we demonstrate that the combined therapy significantly enhanced the neuroanatomical plasticity of major descending spinal tracts such as corticospinal and serotonergic-spinal pathways. Additionally, the pharmacological treatment attenuated chronic astrogliosis and inflammation at and adjacent to the lesion with the modest synergistic effects of treadmill training. We also observed a trend for earlier recovery of locomotion accompanied by an improvement of the overall angular excursions in rats treated with ChABC and growth factors in the first 4 weeks after SCI. At the end of the 7-week recovery period, rats from all groups exhibited an impressive spontaneous recovery of the kinematic parameters during locomotion on treadmill. However, although the combinatorial treatment led to clear chronic neuroanatomical plasticity, these structural changes did not translate to an additional long-term improvement of locomotor parameters studied including hindlimb-forelimb coupling. These findings demonstrate the beneficial effects of combined ChABC, growth factors and locomotor training on the plasticity of the injured spinal cord and the potential to induce earlier neurobehavioral recovery. However, additional approaches such as stem cell therapies or a more adapted treadmill training protocol may be required to optimize this repair strategy in order to induce sustained functional locomotor improvement.

Combined chondroitinase and KLF7 expression reduce net retraction of sensory and CST axons from sites of spinal injury

“…When considering CST regeneration, however, the effects of chondroitinase have been less clear. Indeed, similar to our current results, a number of studies indicate that chondroitinase does not stimulate CST growth beyond complete spinal injuries, including complete transections spanned by transplanted tissue bridges (Fouad et al, 2005; Iseda et al, 2008; Alluin et al, 2014; Kanno et al, 2014). These findings, and the present results, are consistent with the notion that even in the presence of chondroitinase, severe spinal injuries present significant barriers to CST axon extension.…”

“…Although this response has occasionally been described as CST regeneration, it can be difficult in partial injury models to distinguish regeneration from sprouting (Tuszynski and Steward, 2012). Indeed, it is clear from numerous studies that CST axons respond to chondroitinase-mediated degradation of GAGs with increased sprouting of collateral arborization into spinal tissue (Alluin et al, 2014; Barritt et al, 2006; Garcia-Alias et al, 2009; Starkey et al, 2012; Zhao et al, 2011). Similarly, our results in the pyramidotomy injury model show clearly that lenti-chondroitinase promotes collateral sprouting of CST axons into denervated tissue (Figure 7), and it also appeared that in the crush model CST axons treated with Lenti-chase displayed increased collateral sprouting rostral to the injury (Compare Figure 6E,F to 6C,D).…”

Exercise Training Promotes Functional Recovery after Spinal Cord Injury

“…If combined with treadmill exercise training, this effect is more significant [2]. Alluin et al showed that combination therapy of chondroitinase ABC, neurotrophic factors, and exercise training not only enhanced active motor function recovery by enhancing neuroanatomical plasticity of the descending tracts (corticospinal tract and 5-HT pathway) but also significantly reduced the astrocyte proliferation and inflammation around lesions [76]. Transplantation of Schwann cells and olfactory ensheathing cells in the spinal cord of cats combined with chondroitinase ABC treatment significantly improved motor function [77].…”

SDF-1 overexpression by mesenchymal stem cells enhances GAP-43-positive axonal growth following spinal cord injury

“…Unfortunately, SCI-induced disabilities that are observed in humans often are more substantial, which can limit the ability to translate treatments from animal models of SCI to clinically meaningful outcomes (Metz et al, 2000;Somers, 2000). In laboratories across the world, intervention strategies for SCI emphasize four major mechanisms for improving outcomes, including retraining motor abilities, replacing lost tissue, regenerating damaged connections, and/or retaining tissue from necrosis during the propagation of secondary injuries that occur following trauma (Alluin et al, 2014;Taylor, Jones, Tuszynski, & Blesch, 2006;Yasuda et al, 2011;Zendedel et al, 2012). Stem cell therapies show promise as a treatment after SCI in terms of providing trophic support, replacing lost cells, and regenerating functional neuronal architecture.…”