Journal of neurotrauma
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Journal of neurotrauma · Sep 2019
Melatonin treatment alleviates spinal cord injury-induced gut dysbiosis in mice.
Spinal cord injury (SCI) disturbs the autonomic nervous system and induces dysfunction in multiple organs/tissues, such as the gastrointestinal (GI) system. The neuroprotective effects of melatonin in SCI models have been reported; however, it is unclear whether the beneficial effects of melatonin are associated with alleviation of gut dysbiosis. In this study, we showed that daily intraperitoneal injection with melatonin following spinal cord contusion at thoracic level 10 in mice improved intestinal barrier integrity and GI motility, reduced expression levels of certain proinflammatory cytokines, improved animal weight gain and metabolic profiling, and promoted locomotor recovery. ⋯ Melatonin-treated SCI animals showed decreased relative abundance of Clostridiales and increased relative abundance of Lactobacillales and Lactobacillus, which correlated with alteration of cytokine (monocyte chemotactic protein 1) expression and GI barrier permeability, as well as with locomotor recovery. Experimental induction of gut dysbiosis in mice before SCI (i.e., by oral delivery of broad-spectrum antibiotics) exacerbates neurological impairment after SCI, and melatonin treatment improves locomotor performance and intestinal integrity in antibiotic-treated SCI mice. The results suggest that melatonin treatment restores SCI-induced alteration in gut microbiota composition, which may underlie the ameliorated GI function and behavioral manifestations.
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Journal of neurotrauma · Sep 2019
Key glycolytic metabolites in paralyzed skeletal muscle are altered 7 days after spinal cord injury in mice.
Spinal cord injury (SCI) results in rapid muscle atrophy and an oxidative-to-glycolytic fiber-type shift. Those with chronic SCI are more at risk for developing insulin resistance and reductions in glucose clearance than able-bodied individuals, but how glucose metabolism is affected after SCI is not well known. An untargeted metabolomics approach was utilized to investigate changes in whole-muscle metabolites at an acute (7-day) and subacute (28-day) time frame after a complete T9 spinal cord transection in 20-week-old female C57BL/6 mice. ⋯ These changes were associated with altered expression of proteins associated with glycolysis, as well as monocarboxylate transporter 4 gene expression. Taken together, our data suggest an acute disruption of skeletal muscle glucose uptake at 7 days post-SCI, which leads to reduced pyruvate and lactate levels. These levels recover by 28 days post-SCI, but a reduction in pyruvate dehydrogenase protein expression at 28 days post-SCI implies disruption in downstream oxidation of glucose.
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We previously reported the serendipitous observation that fenbendazole, a benzimidazole anthelmintic, improved functional and pathological outcomes following thoracic spinal cord contusion injury in mice when administered pre-injury. Fenbendazole is widely used in veterinary medicine. However, it is not approved for human use and it was uncertain if only post-injury administration would offer similar benefits. ⋯ Histological analysis of spinal cord sections showed that such treatment with flubendazole also reduced lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing. Flubendazole inhibited the activation of glial fibrillary acidic protein (GFAP); suppressed cyclin B1 expression and Bruton tyrosine kinase activation, markers of B cell activation/proliferation and inflammation; and reduced B cell autoimmune response. Together, these results suggest the use of the benzimidazole anthelmintic flubendazole as a potential therapeutic for SCI.
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Journal of neurotrauma · Sep 2019
Novel speed-controlled automated ladder walking device reveals walking speed as a critical determinant of skilled locomotion after a spinal cord injury in adult rats.
The horizontal ladder task is an established method to assess skilled locomotor recovery after neurological dysfunction. Walking speed is often used as a standardized measure in locomotor assessment of overground walking in human and pre-clinical studies, but the assessment of walking speed is typically ignored during skilled locomotor tasks. Ample empirical evidence indicates that walking speeds on the horizontal ladder are largely non-uniform after central nervous system trauma, suggesting that it could pose a potential source of variability in assessing motor deficits. ⋯ The ADATS allows testing at user-defined speeds, thereby forcing the rats to step consistently. Our results demonstrate that: 1) the ability to walk (or not) at one or multiple speeds on the ADATS serves as a gross measure of motor dysfunction/recovery after a spinal cord injury and 2) skilled motor deficits are more readily detected at lower than higher walking speeds. We conclude that walking speed is an important factor in the analyses of skilled locomotion and testing at multiple speeds is useful in accurately measuring recovery after neurotrauma in rats.
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Journal of neurotrauma · Sep 2019
An accurate method for histological determination of neural tissue loss/sparing following compression-induced spinal cord injury with optimal reproducibility.
In addition to behavioral testing, the efficacy of neuroprotective therapies applied after spinal cord injury (SCI) is commonly evaluated by means of histological quantification of spared neural tissue. The primary insult itself, but mainly the pathological processes of secondary injury are the underlying causes of spinal tissue degeneration, the extent of which depends on the injury severity and post-injury time. ⋯ To overcome the problem, our new quantification approach combines a modified method for predicting the cross-sectional area at the lesion site with semi-automatic measurement of spared neural tissue and cystic cavities, using freely accessible National Institutes of Health (NIH) ImageJ software, with a Java-based image processing program. Based on the histological parameters measured after differing compression-induced SCI and correlated with behavioral outcomes, we can conclude that our new method is relatively fast, accurate, and optimally reproducible.