Article

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

ABSTRACT

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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    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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    • "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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