Functional regeneration of respiratory pathways after spinal cord injury

Department of Neurosciences, Case Western Reserve University School of Medicine, 2109 Adelbert Road, Cleveland, Ohio 44106, USA.
Nature (Impact Factor: 41.46). 07/2011; 475(7355):196-200. DOI: 10.1038/nature10199
Source: PubMed


Spinal cord injuries often occur at the cervical level above the phrenic motor pools, which innervate the diaphragm. The effects of impaired breathing are a leading cause of death from spinal cord injuries, underscoring the importance of developing strategies to restore respiratory activity. Here we show that, after cervical spinal cord injury, the expression of chondroitin sulphate proteoglycans (CSPGs) associated with the perineuronal net (PNN) is upregulated around the phrenic motor neurons. Digestion of these potently inhibitory extracellular matrix molecules with chondroitinase ABC (denoted ChABC) could, by itself, promote the plasticity of tracts that were spared and restore limited activity to the paralysed diaphragm. However, when combined with a peripheral nerve autograft, ChABC treatment resulted in lengthy regeneration of serotonin-containing axons and other bulbospinal fibres and remarkable recovery of diaphragmatic function. After recovery and initial transection of the graft bridge, there was an unusual, overall increase in tonic electromyographic activity of the diaphragm, suggesting that considerable remodelling of the spinal cord circuitry occurs after regeneration. This increase was followed by complete elimination of the restored activity, proving that regeneration is crucial for the return of function. Overall, these experiments present a way to markedly restore the function of a single muscle after debilitating trauma to the central nervous system, through both promoting the plasticity of spared tracts and regenerating essential pathways.

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    • "However, it is also important to note that in the intact adult mice some types of axons are non-myelinated, such as the brainstem-derived serotonergic axons in the spinal cord. Indeed, neutralizing inhibitory activities in the environments after spinal cord injury have been shown to promote the regrowth of serotonergic axons with subsequent functional recovery (Alilain et al., 2011;Hellal et al., 2011;Lang et al., 2015;Ruschel et al., 2015). Similarly, terminals of corticospinal tract (CST) axons are not myelinated (Zukor et al., 2013), and stimulating sprouting of CST axons in the gray matter of the spinal cord leads to partial recovery of forelimb function (Cafferty and Strittmatter, 2006;García-Alías et al., 2009;Wahl et al., 2014). "
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    ABSTRACT: Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian CNS, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC) but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after retinal axon injury.
    Full-text · Article · Jan 2016 · Cell
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    • "ChABC treatment alone has been shown to promote plasticity of spared tracts and restore limited activity to the paralyzed diaphragm (Alilain et al., 2011). Combined with peripheral nerve autograft, ChABC treatment results in lengthy regeneration of serotonergic axons and other bulbospinal fibers with significant improvements in diaphragm function (Alilain et al., 2011). CSPGs also induce progressive axonal dieback and atrophy following SCI and ChABC treatment has been shown to be attenuate this process (Carter et al., 2008, 2011; Karimi-Abdolrezaee et al., 2010). "
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    ABSTRACT: Chondroitin Sulfate Proteoglycans (CSPGs) are a major component of the extracellular matrix in the central nervous system (CNS) and play critical role in the development and pathophysiology of the brain and spinal cord. Developmentally, CSPGs provide guidance cues for growth cones and contribute to the formation of neuronal boundaries in the developing CNS. Their presence in perineuronal nets plays a crucial role in the maturation of synapses and closure of critical periods by limiting synaptic plasticity. Following injury to the CNS, CSPGs are dramatically upregulated by reactive glia which form a glial scar around the lesion site. Increased level of CSPGs is a hallmark of all CNS injuries and has been shown to limit axonal plasticity, regeneration, remyelination, and conduction after injury. Additionally, CSPGs create a non-permissive milieu for cell replacement activities by limiting cell migration, survival and differentiation. Mounting evidence is currently shedding light on the potential benefits of manipulating CSPGs in combination with other therapeutic strategies to promote spinal cord repair and regeneration. Moreover, the recent discovery of multiple receptors for CSPGs provides new therapeutic targets for targeted interventions in blocking the inhibitory properties of CSPGs following injury. Here, we will provide an in depth discussion on the impact of CSPGs in normal and pathological CNS. We will also review the recent preclinical therapies that have been developed to target CSPGs in the injured CNS. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Experimental Neurology
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    • "Recently, this C 2 SCI rodent model has also been used to study respiratory and hindlimb impairment and the subsequent spontaneous recovery and induced recovery following a non-invasive strategy (Intermittent hypoxias ), and a successful translational application has been conducted in spinal injured patients (Lovett-Barr et al., 2012). But the most impressive result obtained with this model is a total functional restoration of the respiratory activity by grafting a peripheral nerve into the spinal cord to bypass the injury site, combined with chondroitinase ABC treatment to further ameliorate nerve insertion and axonal regrowth (Alilain et al., 2011). However, despite the extensive results published in the literature and the growing community of scientists using this model, some limitations must be discussed in this perspective article. "
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    ABSTRACT: Traumatic cervical spinal cord injury (SCI), with an annual incidence of 12,000 new cases in USA (NSCISC 2013), caus-es devastating locomotor and respiratory paralysis and un-fortunately compromises the human patient's lifespan. The severity of the injury depends on the degree and the extent of the initial trauma. In fact, respiratory failure is the leading cause of mortality following upper cervical SCI. However, 80% of the injuries are incomplete, allowing some modest spontaneous recovery. To date, no effective treatment is available in order to restore the loss of function. The only existing therapy is to place the patient under ventilatory as-sistance. Few patients can be weaned off the ventilatory as-sistance, mostly due to spontaneous recovery which occurs with post-lesional delay. Thus, enhancing spontaneous plas-ticity may be of great importance, or at least of a more im-mediate goal, than regeneration of spinal tracts since the majority of spinal injuries are incomplete. The necessity of having a preclinical model that combines respiratory insuffi-ciency with spared non-functional respiratory pathways is crucial in order for scientists to study putative therapeutics.
    Full-text · Article · Nov 2014 · Neural Regeneration Research
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