Epidural oscillating field stimulation increases axonal regenerative capacity and myelination after spinal cord trauma

Oscillating field stimulation(OFS)with regular alterations in the polarity of electric current is a unique,experimental approach to stimulate,support,and potentially guide the outgrowth of both sensory and motor nerve fibers after spinal cord injury(SCI).In previous experiments,we demonstrated the beneficial effects of OFS in a 4-week survival period after SCI.In this study,we observed the major behavioral,morphological,and protein changes in rats after 15 minutes of T9 spinal compression with a 40 g force,followed by long-lasting OFS(50μA),over a 8-week survival period.Three groups of rats were analyzed:rats after T9 spinal compression(SCI group);SCI rats subjected to implantation of active oscillating field stimulator(OFS+SCI group);and SCI rats subjected to nonfunctional OFS(nOFS+SCI group).Histopathological analysis of spinal tissue indicated a strong impact of epidural OFS on the reduction of tissue and myelin loss after SCI in the segments adjacent to the lesion site.Quantitative fluorescent analysis of the most affected areas of spinal cord tissue revealed a higher number of spared axons and oligodendrocytes of rats in the OFS+SCI group,compared with rats in the SCI and nOFS+SCI groups.The protein levels of neurofilaments(NF-l),growth-associated protein-43(marker for newly sprouted axons),and myelin basic protein in rats were signifiantly increased in the OFS+SCI group than in the nOFS+SCI and SCI groups.This suggests a supporting role of the OFS in axonal and myelin regeneration after SCI.Moreover,rats in the OFS+SCI group showed great improvements in sensory and motor functions than did rats in the nOFS+SCI and SCI groups.All these findings suggest that long-lasting OFS applied immediately after SCI can provide a good microenviroment for recovery of damaged spinal tissue by triggering regenreative processes in the acute phase of injury.

Salvianolic acid B protects the myelin sheath around injured spinal cord axons

Salvianolic acid B,an active pharmaceutical compound present in Salvia miltiorrhiza,exerts a neuroprotective effect in animal models of brain and spinal cord injury.Salvianolic acid B can promote recovery of neurological function;however,its protective effect on the myelin sheath after spinal cord injury remains poorly understood.Thus,in this study,in vitro tests showed that salvianolic acid B contributed to oligodendrocyte precursor cell differentiation,and the most effective dose was 20 μg/m L.For in vivo investigation,rats with spinal cord injury were intraperitoneally injected with 20 mg/kg salvianolic acid B for 8 weeks.The amount of myelin sheath and the number of regenerating axons increased,neurological function recovered,and caspase-3 expression was decreased in the spinal cord of salvianolic acid B-treated animals compared with untreated control rats.These results indicate that salvianolic acid B can protect axons and the myelin sheath,and can promote the recovery of neurological function.Its mechanism of action is likely to be associated with inhibiting apoptosis and promoting the differentiation and maturation of oligodendrocyte precursor cells.

Axon regeneration impediment: the role of paired immunoglobulin-like receptor B

Regenerative capacity is weak after central nervous system injury because of the absence of an enhancing microenvironment and presence of an inhibitory microenvironment for neuronal and axonal repair. In addition to the Nogo receptor（Ng R）, the paired immunoglobulin-like receptor B（Pir B） is a recently discovered coreceptor of Nogo, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein. Concurrent blocking of Ng R and Pir B almost completely eliminates the inhibitory effect of myelin-associated inhibitory molecules on axonal regeneration. Pir B participates in a key pathological process of the nervous system, specifically axonal regeneration inhibition. Pir B is an inhibitory receptor similar to Ng R, but their effects are not identical. This study summarizes the structure, distribution, relationship with common nervous system diseases, and known mechanisms of Pir B, and concludes that Pir B is also distributed in cells of the immune and hematopoietic systems. Further investigations are needed to determine if immunomodulation and blood cell migration involve inhibition of axonal regeneration.

Effect of glial cells on remyelination after spinal cord injury

Remyelination plays a key role in functional recovery of axons after spinal cord injury.Glial cells are the most abundant cells in the central nervous system.When spinal cord injury occurs,many glial cells at the lesion site are immediately activated,and different cells differentially affect inflammatory reactions after injury.In this review,we aim to discuss the core role of oligodendrocyte precursor cells and crosstalk with the rest of glia and their subcategories in the remyelination process.Activated astrocytes influence proliferation,differentiation,and maturation of oligodendrocyte precursor cells,while activated microglia alter remyelination by regulating the inflammatory reaction after spinal cord injury.Understanding the interaction between oligodendrocyte precursor cells and the rest of glia is necessary when designing a therapeutic plan of remyelination after spinal cord injury.

miR-30c promotes Schwann cell remyelination following peripheral nerve injury

Differential expression of mi RNAs occurs in injured proximal nerve stumps and includes mi RNAs that are firstly down-regulated and then gradually up-regulated following nerve injury.These mi RNAs might be related to a Schwann cell phenotypic switch.mi R-30 c,as a member of this group,was further investigated in the current study.Sprague-Dawley rats underwent sciatic nerve transection and proximal nerve stumps were collected at 1,4,7,14,21,and 28 days post injury for analysis.Following sciatic nerve injury,mi R-30 c was down-regulated,reaching a minimum on day 4,and was then upregulated to normal levels.Schwann cells were isolated from neonatal rat sciatic nerve stumps,then transfected with mi R-30 c agomir and co-cultured in vitro with dorsal root ganglia.The enhanced expression of mi R-30 c robustly increased the amount of myelin-associated protein in the co-cultured dorsal root ganglia and Schwann cells.We then modeled sciatic nerve crush injury in vivo in Sprague-Dawley rats and tested the effect of perineural injection of mi R-30 c agomir on myelin sheath regeneration.Fourteen days after surgery,sciatic nerve stumps were harvested and subjected to immunohistochemistry,western blot analysis,and transmission electron microscopy.The direct injection of mi R-30 c stimulated the formation of myelin sheath,thus contributing to peripheral nerve regeneration.Overall,our findings indicate that mi R-30 c can promote Schwann cell myelination following peripheral nerve injury.The functional study of mi R-30 c will benefit the discovery of new therapeutic targets and the development of new treatment strategies for peripheral nerve regeneration.

The occurrence of diffuse axonal injury in the brain:associated with the accumulation and clearance of myelin debris

The accumulation of myelin debris may be a major contributor to the inlfammatory response after diffuse axonal injury. In this study, we examined the accumulation and clearance of myelin debris in a rat model of diffuse axonal injury. Oil Red O staining was performed on sections from the cerebral cortex, hippocampus and brain stem to identify the myelin debris. Seven days after diffuse axonal injury, many Oil Red O-stained particles were observed in the cerebral cortex, hippocampus and brain stem. In the cerebral cortex and hippocampus, the amount of myelin debris peaked at 14 days after injury, and decreased signiifcantly at 28 days. In the brain stem, the amount of myelin debris peaked at 7 days after injury, and decreased signiifcantly at 14 and 28 days. In the cortex and hippocampus, some myelin debris could still be observed at 28 days after diffuse axonal injury. Our ifndings suggest that myelin debris may persist in the rat central ner-vous system after diffuse axonal injury, which would hinder recovery.

Distribution of paired immunoglobulin-like receptor B in the nervous system related to regeneration difficulties after unilateral lumbar spinal cord injury

Paired immunoglobulin-like receptor B（Pir B） is a functional receptor of myelin-associated inhibitors for axonal regeneration and synaptic plasticity in the central nervous system, and thus suppresses nerve regeneration. The regulatory effect of Pir B on injured nerves has received a lot of attention. To better understand nerve regeneration inability after spinal cord injury, this study aimed to investigate the distribution of Pir B（via immunofluorescence） in the central nervous system and peripheral nervous system 10 days after injury. Immunoreactivity for Pir B increased in the dorsal root ganglia, sciatic nerves, and spinal cord segments. In the dorsal root ganglia and sciatic nerves, Pir B was mainly distributed along neuronal and axonal membranes. Pir B was found to exhibit a diffuse, intricate distribution in the dorsal and ventral regions. Immunoreactivity for Pir B was enhanced in some cortical neurons located in the bilateral precentral gyri. Overall, the findings suggest a pattern of Pir B immunoreactivity in the nervous system after unilateral spinal transection injury, and also indicate that Pir B may suppress repair after injury.