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.

Introduction

The current prognosis for improvement in functional sensory and motor recovery after sustaining a spinal cord injury (SCI) remains relatively poor, despite recent marked advances in medical care and rehabilitation [44]. A wide range of promising therapies directed at preventing secondary injury and repairing the spinal cord at the site of injury have been shown to exert improvements in neuroprotection, regeneration, and/or recovery of function in animal models of SCI (reviewed in [95], [13], [79], [93], [62]). These include single therapies, such as cell transplantation [58], [26], [103], [92], neurotrophic factor infusion or overexpression [56], [63], [74], anti-inflammatory therapies [17], [91], [106], [102], [119], [47], [57] or administration of anti-growth inhibitory antibodies [49], [120], [19]. More dramatic improvements are observed with approaches combining two or more of these treatments [76], [20], [22], [88], [87], indicating that multiple mechanisms contribute to the lack of endogenous regeneration and subsequent failure of complete functional recovery. To date, however, none of these interventions or combinations has proven to be so robust and reproducible across laboratories, injury models, and animal species to provide a compelling consensus for uncontested translation to the clinical setting [101], [100], [118], [71], [105], [72]. Thus, the SCI research community continues to search for effective and feasible therapeutic strategies that can be advanced to promote improved recovery of the injured adult spinal cord.

In addition to the strategies referred to above that seek to prevent secondary injury or repair the spinal cord at the site of injury, considerable recent research has been directed at understanding how the circuitry in the uninjured or “spared” segments of the spinal cord can be activated to permit reorganization or plasticity that might drive meaningful functional recovery [13], [50], [25], [36]. Exercise, including locomotor training, can stimulate neural activity in appropriate muscle groups and neurological centers and can easily be included with other repair strategies to improve prognosis following SCI. However, the limited efficacy of exercise therapy alone in translation to overground walking after severe contusion injury suggests that characteristics of the mature central nervous system (CNS) contribute to an environment that is refractory to activity directed plasticity. Interventions that combine enhanced activity of appropriate circuitry with treatments that can modify the structure and efficacy of the synapses in the injured CNS show great promise for optimizing the extent and nature of functional recovery after injury. In the following pages, we describe the evidence implicating a combination of locomotor training and chondroitinase enzymatic treatment for improving functional outcomes after SCI. A review of the evidence supporting this combination and preliminary work from our lab show that further investigation is needed to define the timing, type, and amount of exercise training and pharmacological interventions that could interact or synergize to enhance useful functional recovery.