ReviewInjured mice at the gym: Review, results and considerations for combining chondroitinase and locomotor exercise to enhance recovery after spinal cord injury
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.
Section snippets
Clinical studies
Activity-based strategies seek to promote neuroplasticity and greater recovery than that induced by traditional approaches in which technology or intact body regions compensate for permanent impairments [96]. In recent years, activity-based functional electrical stimulation (FES) and locomotor-based exercise therapies have both been shown to induce measurable improvements in cardiovascular function [43], muscle mass and bone density [110], and improvements in reported quality of life measures
Cellular substrates of plasticity and reorganization mediated by locomotor training
Neural plasticity can be mediated by biochemical changes affecting synaptic efficacy or neural excitability and by structural changes such as axon sprouting or synaptic reorganization. Exercise enhances expression of mRNA and protein levels of growth factors in both the brain and spinal cord, including brain derived growth factor (BDNF), neurotrophin-3, fibroblast growth factor-2 (FGF-2) and insulin-like growth factor (IGF-1) ([64], [116]; reviewed in [112]). Each of these growth factors
Chondroitinase ABC enhances sprouting and recovery after SCI in adult mammals
The adult mammalian central nervous system (CNS) is more restricted in its ability to support sprouting and recovery after injury and to change in response to perturbations in synaptic activity than is the developing nervous system. For example, in primary visual cortex, early monocular deprivation can dramatically alter the formation of ocular dominance columns and disrupt binocular vision [115], while similar deprivation in the adult has little effect on synaptic reorganization. The time
Intraparenchymal injections of ChABC eliminate perineuronal nets and facilitate plasticity
In addition to their role in the local response to injury, CSPGs also participate in the activity-dependent formation and maintenance of ECM structures that surround specific subpopulations of neurons and stabilize synapses. These structures, which are enriched in regions of highly active neurons, are termed perineuronal nets, or PNNs [15], [80], [14], [98], [38]. PNNs are composed of highly crosslinked conjugates of CSPGs, hyaluronan, tenacin-R and link proteins, and they can be identified in
Combining ChABC with rehabilitation in animal models of SCI
Based on the observation that disruption of PNNs in adult cortex, spinal cord and dorsal column nuclei are sufficient to permit functional reorganization of sensory systems, we and others have proposed that a combination of ChABC and functionally appropriate exercise would support repair and recovery where neither therapy alone was sufficient. In a recent such combination study, Garcia-Alias et al. [53] took advantage of the ability of ChABC to digest CSPG–GAGs and perineuronal nets to optimize
Conclusions and future directions
Physical rehabilitation and exercise therapies represent feasible and important components of future strategies to enhance functional recovery after SCI. However, despite the clear presence of intact circuitry for locomotion in the distal segments of the spinal cord, exercise therapy alone has provided only limited improvements for individuals with SCI, and incomplete translation of benefits from the treadmill to overground walking. The addition of enzyme therapy that could be applied directly
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgements
The authors are grateful for technical assistance from Todd Lash, Qin Feng Yin and Lesley Fischer, and editorial comments and discussions from Dr. Ellen Andrews and Ms. Rebekah Richards. ChABC-I was generously provided through a Materials Transfer Agreement with Acorda Therapeutics, Inc., Hawthorne, NY. This work was supported by grants from Spinal Research (STR100) and NINDS (NS043246 and NS045758).
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Treadmill training improves survival and differentiation of transplanted neural precursor cells after cervical spinal cord injury
2020, Stem Cell ResearchCitation Excerpt :Although the lesion affected the dorsal funiculi and roots of the cervical spinal cord as seen in histological injury characterization, our findings in the von Frey filament test suggest that no relevant mechanical allodynia was present in the injured animals 8 weeks after SCI. Treadmill training itself likely has additional positive effects on motor recovery, as it has been shown to preserve the skeletal muscle mass and strength of the limbs after SCI (Peterson et al., 2000) and might also adapt the level of inhibitory transmitters after injury, such as GABA and Glycine (Jakeman et al., 2011). Moreover, hypoxic conditions induced by physical training might enhance the activity-dependent plasticity after injury, which could be represented by electrophysiological changes around graft neurons and might boost the interface of graft and host neurons (Zhu et al., 2018).
Axon regeneration
2020, Cellular Migration and Formation of Axons and Dendrites: Comprehensive Developmental NeuroscienceVeterinary Neurologic Rehabilitation: The Rationale for a Comprehensive Approach
2018, Topics in Companion Animal MedicineChondroitin sulfate proteoglycans: Key modulators in the developing and pathologic central nervous system
2015, Experimental NeurologyCitation Excerpt :Animals which received rehabilitation with ChABC showed enhanced sprouting of CST, increases in the number of PNNs, and improved ladder and beam walking scores (Wang et al., 2011a). Despite these positive findings, other investigations of the combinatorial benefits of ChABC and rehabilitation have shown no beneficial effect (Alluin et al., 2014; Caggiano et al., 2005; Jakeman et al., 2011; Mountney et al., 2013). ChABC injection into the grey matter in the spinal cord lumbar enlargement 1 week following moderate contusion SCI combined with wheel exercise did not show significant improvement in locomotor function (Jakeman et al., 2011).
Restoring function after spinal cord injury: Towards clinical translation of experimental strategies
2014, The Lancet NeurologyCitation Excerpt :A further issue is the optimisation of ChABC delivery. The drug is generally given in multiple doses because its enzymatic activity diminishes over time, and a single injection has little or no effect in the treatment of traumatic injuries.174–176 However, repeated administration increases the invasiveness of the treatment and the risk of infection.
Rolipram promotes functional recovery after contusive thoracic spinal cord injury in rats
2013, Behavioural Brain Research
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