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
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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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    • "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.
    Experimental Neurology 04/2015; 269. DOI:10.1016/j.expneurol.2015.04.006 · 4.70 Impact Factor
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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.
    Neural Regeneration Research 11/2014; 9(22):1949-1951. DOI:10.4103/1673-5374.145367 · 0.22 Impact Factor
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    • "Microglia and astrocytes near the lesion become activated, proliferate, and release inflammatory cytokines (Bartholdi and Schwab, 1997; Brambilla et al., 2005; Pineau et al., 2010; Popovich et al., 1997). In addition, astrocytes adjacent to the lesion form a matrix-rich glial scar, which limits the extent of hemorrhagic damage and leukocyte migration but also restricts axon plasticity (Alilain et al., 2011; Bradbury et al., 2002; Faulkner et al., 2004; McKeon et al., 1991; Wanner et al., 2013). A novel approach for controlling inflammation might be to manipulate the ECM. "
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    ABSTRACT: Throughout the body, the extracellular matrix (ECM) provides structure and organization to tissues and also helps regulate cell migration and intercellular communication. In the injured spinal cord (or brain), changes in the composition and structure of the ECM undoubtedly contribute to regeneration failure. Less appreciated is how the native and injured ECM influences intraspinal inflammation and, conversely, how neuroinflammation affects the synthesis and deposition of ECM after CNS injury. In all tissues, inflammation can be initiated and propagated by ECM disruption. Molecules of ECM newly liberated by injury or inflammation include hyaluronan fragments, tenascins, and sulfated proteoglycans. These act as “damage-associated molecular patterns” or “alarmins”, i.e., endogenous proteins that trigger and subsequently amplify inflammation. Activated inflammatory cells, in turn, further damage the ECM by releasing degradative enzymes including matrix metalloproteinases (MMPs). After spinal cord injury (SCI), destabilization or alteration of the structural and chemical compositions of the ECM affects migration, communication, and survival of all cells – neural and non-neural – that are critical for spinal cord repair. By stabilizing ECM structure or modifying their ability to trigger the degradative effects of inflammation, it may be possible to create an environment that is more conducive to tissue repair and axon plasticity after SCI.
    Experimental Neurology 08/2014; 258. DOI:10.1016/j.expneurol.2013.11.020 · 4.70 Impact Factor
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