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Abstract: Chondroitin sulfate proteoglycans (CSPGs) are upregulated in the central nervous system following injury. Chondroitin sulfate glycosaminoglycan (CS GAG) side chains substituted on this family of molecules contribute to the limited functional recovery following injury by restricting axonal growth and synaptic plasticity. In the current study, the effects of degrading CS GAGs with Chondroitinase ABC (Ch''ase ABC) in the injured spinal cords of adult cats were assessed. Three groups were evaluated for 5 months following T10 hemisections: lesion-only, lesion+control, and lesion+Ch''ase ABC. Intraspinal control and Ch''ase ABC treatments to the lesion site began immediately after injury and continued every other day, for a total of 15 treatments, using an injectable port system. Delivery and in vivo cleavage were verified anatomically in a subset of cats across the treatment period. Recovery of skilled locomotion (ladder, peg, and beam) was significantly accelerated, on average, by >3 weeks in Ch''ase ABC-treated cats compared to controls. Ch''ase ABC-treated cats also showed greater recovery of specific skilled locomotor features including intralimb movement patterns and significantly greater paw placement onto pegs. Although recovery of basic locomotion (bipedal treadmill and overground) was not accelerated, intralimb movement patterns were more normal in the Ch''ase ABC-treated cats. Qualitative assessment of serotonergic immunoreactivity also suggested that Ch''ase ABC treatment enhanced plasticity. Finally, analyses using fluorophore-assisted carbohydrate electrophoresis (FACE) indicate CS GAG content is similar in cat and human. These findings show, for the first time, that intraspinal cleavage of CS GAGs can enhance recovery of function following spinal cord injury in large animals with sophisticated motor behaviors and axonal growth requirements similar to those encountered in humans. [Copyright &y& Elsevier]

Animal models are necessary to identify pathological changes and help assess therapeutic outcomes following spinal cord injury (SCI). Small animal models offer value in research in terms of their easily managed size, minimal maintenance requirements, lower cost, well-characterized genomes, and ability to power research studies. However, despite these benefits, small animal models have neurologic and anatomical differences that may influence translation of results to humans and thus limiting the success of their use in preclinical studies as a direct pipeline to clinical studies. Large animal models, offer an attractive intermediary translation model that may be more successful in translating to the clinic for SCI research. This is largely due to their greater neurologic and anatomical similarities to humans. The physical characteristics of pig spinal cord, gut microbiome, metabolism, proportions of white to grey matter, bowel anatomy and function, and urinary system are strikingly similar and provide great insight into human SCI conditions. In this review, we address the variety of existing porcine injury models and their translational relevance, benefits, and drawbacks in modeling human systems and functions for neurophysiology, cardiovascular, gastrointestinal and urodynamic functions. [ABSTRACT FROM AUTHOR]

Abstract: A function of the abdominal expiratory muscles is the generation of cough, a critical respiratory defense mechanism that is often disrupted following spinal cord injury. We assessed the effects of a lateral T9/10 hemisection on cough production at 4, 13 and 21 weeks post-injury in cats receiving extensive locomotor training. The magnitudes of esophageal pressure as well as of bilateral rectus abdominis electromyogram activity during cough were not significantly different from pre-injury values at all time points evaluated. The results show that despite considerable interruption of the descending pre-motor drive from the brainstem to the expiratory motoneuron pools, the cough motor system shows a significant function by 4 weeks following incomplete thoracic injury. [Copyright &y& Elsevier]

Abstract: Several lines of reasoning suggest that the phosphorylated axonal form of the neurofilament subunit NF-H is likely to be released from damaged and diseased neurons in significant amounts. Detection of this protein in serum or CSF might therefore provide information about the presence and degree of neuronal loss. We therefore developed a sensitive NF-H ELISA capable of detecting picogram quantities of phosphorylated NF-H (pNF-H). This assay showed that soluble pNF-H immunoreactivity is readily detectable in the sera of adult rats following various types of experimental spinal cord injury (SCI) and traumatic brain injury (TBI), but is undetectable in the sera of normal animals. Here we describe details of the time course and extent of serum pNF-H expression following experimental SCI and TBI. Following SCI, serum pNF-H showed an initial peak of expression at 16h and a second, usually larger, peak at 3 days. Following TBI, lower levels of serum pNF-H were detected with a peak at 2 days post-injury. We also show that the higher levels of pNF-H released from injured spinal cord as compared to brain are in line with the ∼20-fold higher levels of pNF-H present in spinal cord. These findings suggest that serum levels of pNF-H immunoreactivity may be used to conveniently monitor neuronal damage and degeneration in experimental and presumably clinical situations. [Copyright &y& Elsevier]

Aggrecan is a chondroitin sulfate (CS)/keratan sulfate (KS)-substituted proteoglycan (PG) abundant in cartilage which is also present within the mammalian embryonic, adult, and injured adult central nervous system (CNS). Although its role within the CNS is not clear, cell culture studies show that when substituted with CS, aggrecan inhibits neurite extension. To better understand the inhibitory effect of aggrecan on injured adult axons in vivo, we developed a model to independently test intact aggrecan and CS-depleted aggrecan core glycoprotein. Acute rat spinal cord hemisection cavities were filled with a growth-promoting matrix, Matrigel, and severed dorsal rootlets were placed into this matrix. This created an assay in which axons readily grew. The extent of ingrowth in this baseline assay was compared to the ingrowth in Matrigel loaded with intact aggrecan or the purified core glycoprotein of aggrecan. Our results show that both intact aggrecan and equivalent concentrations of the core glycoprotein component significantly inhibit axonal growth in this model system. These results confirm that aggrecan can inhibit the growth of adult axons in vivo and suggest that the inhibitory effects of aggrecan may be mediated, at least in part, by structures located on the core glycoprotein in the absence of the bulk of the CS chains. [Copyright &y& Elsevier]