Effect of Metformin on Locomotor Function Recovery in Rat Spinal Cord Injury Model: A Meta-analysis

Background. Disorder of locomotor function is universal in patients with spinal cord injury (SCI) and has a severe impairment on their quality of life. Metformin, the first-line antidiabetic drug, has been used to improve locomotor function in SCI rats through antioxidative mechanisms recently. Methods. A search strategy was conducted from databases, including PubMed, Web of Science, MEDLINE, and Scopus database until April 2021. The methodological quality of the animal experimental studies was assessed according to the Systematic Review Centre for Laboratory animal Experimentation’s Risk of Bias tool. The weighted mean difference was calculated with the random-effects model. Results. Seven eligible studies on SCI and metformin were reviewed. The meta-analysis indicated that SCI rats receiving metformin therapy showed a significant locomotor function recovery. Limitations and no obvious publication bias were presented in the studies. Conclusion. Metformin can promote the recovery of the locomotor function of SCI rats. However, the use of this meta-analysis was influenced due to the not high quality of studies. Consequently, more high-quality studies are necessary for preclinical studies of SCI in the future.

Silencing long ascending propriospinal neurons after spinal cord injury improves hindlimb stepping in the adult rat

Long ascending propriospinal neurons (LAPNs) are a subpopulation of spinal cord interneurons that directly connect the lumbar and cervical enlargements. Previously we showed, in uninjured animals, that conditionally silencing LAPNs disrupted left-right coordination of the hindlimbs and forelimbs in a context-dependent manner, demonstrating that LAPNs secure alternation of the fore- and hindlimb pairs during overground stepping. Given the ventrolateral location of LAPN axons in the spinal cord white matter, many likely remain intact following incomplete, contusive, thoracic spinal cord injury (SCI), suggesting a potential role in the recovery of stepping. Thus, we hypothesized that silencing LAPNs after SCI would disrupt recovered locomotion. Instead, we found that silencing spared LAPNs post-SCI improved locomotor function, including paw placement order and timing, and a decrease in the number of dorsal steps. Silencing also restored left-right hindlimb coordination and normalized spatiotemporal features of gait such as stance and swing time. However, hindlimb-forelimb coordination was not restored. These data indicate that the temporal information carried between the spinal enlargements by the spared LAPNs post-SCI is detrimental to recovered hindlimb locomotor function. These findings are an illustration of a post-SCI neuroanatomical-functional paradox and have implications for the development of neuronal- and axonal-protective therapeutic strategies and the clinical study/implementation of neuromodulation strategies.

Attenuation of Activated eIF2α Signaling by ISRIB Treatment After Spinal Cord Injury Improves Locomotor Function

Following spinal cord injury (SCI), multiple signaling cascades are activated instantaneously in the injured segments of the spinal cord to create a complex and pathogenic microenvironment, making it difficult to treat SCI. Nevertheless, the significance of the integrated stress response (ISR) to the series of physiological and pathological changes that occur after SCI remains unclear. Through western blotting (WB), we determined that the autophosphorylation of stress receptors (GCN2, PERK, PKR, and HRI) was enhanced after SCI, leading to increased phosphorylation of eIF2α at Ser51. Strikingly, we found that eIF2α was highly phosphorylated at 1 day post injury (dpi) and that this hypophosphorylation was maintained thereafter in the spinal cord, especially in neurons, which suggests that intervening with eIF2α phosphorylation may be a treatment strategy for SCI. Therefore, we employed the small molecule ISRIB, which inhibits eIF2α phosphorylation when the ISR is activated at moderate or low levels but not when the ISR is highly activated. Daily intraperitoneal injection of ISRIB significantly inhibited ISR signaling after SCI, reduced the cytosolic localization of RNA-binding proteins, and decreased neuronal apoptosis. Histological and functional experiments further demonstrated that treatment with ISRIB after SCI effectively curbed morphological deterioration and promoted the recovery of locomotor function. In summary, the ISR plays an important role in SCI, and ISRIB is a promising drug for the treatment of SCI.

Cardiorespiratory performance and locomotor function of patients with anorectal malformations

The aim of this study was to assess whether adolescents following anorectal malformation repair have a decreased cardiorespiratory performance capacity and impaired motor skills. All eligible children treated for ARMs between 2000 and 2014 were invited to participate in a prospective study consisting of a clinical examination, evaluation of Bowel function and Quality of Life, spirometry, spiroergometry and assessment of the motor activity. The results were compared to a healthy age- and sex-matched control group. There was no statistically significant difference in height, weight, BMI, muscle mass or body fat percentage between the study and the control group. Nine out of 18 patients (50%) had an excellent functional outcome with a normal Bowel Function Score. Spirometry revealed no significant differences between ARM patients and controls, four patients showed a ventilation disorder. Spiroergometry revealed a significantly lower relative performance capacity and the overall rating of the motor activity test showed significantly decreased grades in ARM patients. ARM patients were affected by an impaired cardiopulmonary function and decreased motor abilities. Long-term examinations consisting of routine locomotor function evaluation and spiroergometry are advisable to detect impaired cardiopulmonary function and to prevent a progression of associated complications and related impaired quality of life.

Protective effect of Boldine against neuroinflammation in spinal cord injury in rats

The successful clinical management of spinal cord injury (SCI) is still a unmet medical need. Despite advances in novel therapeutics, the multifactorial etiology of SCI still poses significant challenge to the mankind. Thus, in the present study, we intend to scrutinize the protective effect of Boldine (BOL), an alkaloid obtained from the boldo tree against experimental spinal cord injury. The effect of BOL was investigated on locomotor function of rats with various biomarkers of oxidative stress (MDA, SOD and GSH), inflammation (TNF-α, IL-1β and IL-6), and apoptosis. Results suggest that BOL showed improvement in locomotor function (on BBB scale) of rats with does-dependent reduction in oxidative stress and inflammation. It also reduces neuronal apoptosis in flow cytometry experiment. The study successfully demonstrated the possible clinical utility of BOL against SCI.

Contralateral Axon Sprouting but Not Ipsilateral Regeneration Is Responsible for Spontaneous Locomotor Recovery Post Spinal Cord Hemisection

Spinal cord injury (SCI) usually results in permanent functional impairment and is considered a worldwide medical problem. However, both motor and sensory functions can spontaneously recover to varying extents in humans and animals with incomplete SCI. This study observed a significant spontaneous hindlimb locomotor recovery in Sprague-Dawley rats at four weeks after post-right-side spinal cord hemisection at thoracic 8 (T8). To verify whether the above spontaneous recovery derives from the ipsilateral axonal or neuronal regeneration to reconnect the lesion site, we resected either the scar tissue or right side T7 spinal cord at five weeks post-T8 hemisected injury. The results showed that the spontaneously achieved right hindlimb locomotor function had little change after resection. Furthermore, when T7 left hemisection was performed five weeks after the initial injury, the spontaneously achieved right hindlimb locomotor function was dramatically abolished. A similar result could also be observed when T7 transection was performed after the initial hemisection. The results indicated that it might be the contralateral axonal remolding rather than the ipsilateral axonal or neuronal regeneration beyond the lesion site responsible for the spontaneous hindlimb locomotor recovery. The immunostaining analyses and corticospinal tracts (CSTs) tracing results confirmed this hypothesis. We detected no substantial neuronal and CST regeneration throughout the lesion site; however, significantly more CST fibers were observed to sprout from the contralateral side at the lumbar 4 (L4) spinal cord in the hemisection model rats than in intact ones. In conclusion, this study verified that contralateral CST sprouting, but not ipsilateral CST or neuronal regeneration, is primarily responsible for the spontaneous locomotor recovery in hemisection SCI rats.