Effect of repeated sciatic nerve crush on the conditioning lesion response: Generating an experimental animal model to prolong the denervation period while maintaining peripheral nerve continuity.

Peripheral nerves exhibit long-term residual motor dysfunction following injury. The length of the denervation period before nerve and muscle reconnection is an important factor in motor function recovery. We aimed to investigate whether repeated nerve crush injuries to the same site every 7 days would preserve the conditioning lesion (CL) response and to determine the number of nerve crush injuries required to create an experimental animal model that would prolong the denervation period while maintaining peripheral nerve continuity. Rats were grouped according to the number of sciatic nerve crushes. A significant decrease in the soleus muscle fiber cross-sectional area was observed with increased crushes. After a single crush, macrophage accumulation and macrophage chemotaxis factor CCL2 expression in dorsal root ganglia were markedly increased, which aligned with the gene expression of Ccl2 and its receptor Ccr2. Macrophage numbers, histological CCL2 expression, and Ccl2 and Ccr2 gene expression levels decreased, depending on the number of repeated crushes. Histological analysis and gene expression analysis in the group with four repeated crushes did not differ significantly when compared with uninjured animals. Our findings indicated that repeated nerve crushes at the same site every 7 days sustained innervation loss and caused a loss of the CL response. The experimental model did not require nerve stump suturing and is useful for exploring factors causing prolonged denervation-induced motor dysfunction. SIGNIFICANCE STATEMENT: This study elucidates the effects of repeated nerve crush injury to the same site on innervation and conditioning lesion responses and demonstrates the utility of an experimental animal model that recapitulates the persistent residual motor deficits owing to prolonged denervation without requiring nerve transection and transection suturing.

Sciatic and tibial neuropathies.

The sciatic nerve is the body's largest peripheral nerve. Along with their two terminal divisions (tibial and fibular), their anatomic location makes them particularly vulnerable to trauma and iatrogenic injuries. A thorough understanding of the functional anatomy is required to adequately localize lesions in this lengthy neural pathway. Proximal disorders of the nerve can be challenging to precisely localize among a range of possibilities including lumbosacral pathology, radiculopathy, or piriformis syndrome. A correct diagnosis is based upon a thorough history and physical examination, which will then appropriately direct adjunctive investigations such as imaging and electrodiagnostic testing. Disorders of the sciatic nerve and its terminal branches are disabling for patients, and expert assessment by rehabilitation professionals is important in limiting their impact. Applying techniques established in the upper extremity, surgical reconstruction of lower extremity nerve dysfunction is rapidly improving and evolving. These new techniques, such as nerve transfers, require electrodiagnostic assessment of both the injured nerve(s) as well as healthy, potential donor nerves as part of a complete neurophysiological examination.

Implication of system xc- in neuroinflammation during the onset and maintenance of neuropathic pain.

BACKGROUND: Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system xc-) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain. METHODS: We examined the implication of system xc- by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc- (using mice lacking the system xc- specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers. RESULTS: The sciatic nerve lesion was found to upregulate system xc- at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc- had an analgesic effect in lesioned mice. CONCLUSION: Together, these observations provide evidence for a role of system xc- in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc-. These findings suggest that drugs targeting system xc- could contribute to prevent or reduce neuropathic pain.

Traumatic and iatrogenic sciatic nerve injury in 38 dogs and 10 cats: Clinical and electrodiagnostic findings.

BACKGROUND: Reports describing sciatic nerve injuries (SNI) and their outcome are scarce in veterinary medicine. HYPOTHESIS: Describe the causes of traumatic and iatrogenic SNI and evaluate which clinical and electrodiagnostic findings predict outcome. ANIMALS: Thirty-eight dogs and 10 cats with confirmed SNI referred for neurologic and electrodiagnostic evaluation. METHODS: Clinical and electrodiagnostic examination results, including electromyography (EMG), motor nerve conduction studies, muscle-evoked potential (MEP), F-waves, sensory nerve conduction studies, and cord dorsum potential (CDP), were retrospectively evaluated. Quality of life (QoL) was assessed based on owner interviews. RESULTS: Surgery (42%) and trauma (33%) were the most common causes of SNI; in dogs, 24% were caused by bites from wild boars. Ability to flex and extend the tarsus was significantly associated with positive outcome in dogs. Mean time from onset of clinical signs until electrodiagnostic evaluation was 67 ± 65 (range, 7-300) days and 65 ± 108 (range, 7-365) days for dogs and cats, respectively. A cut-off amplitude of 1.45 mV for compound motor action potentials (CMAP) was predictive of positive outcome in dogs (P = .01), with sensitivity of 58% and specificity of 100%. CONCLUSIONS AND CLINICAL IMPORTANCE: Clinical motor function predicts recovery better than sensory function. Electrodiagnostic findings also may play a role in predicting the outcome of SNI. Application of the proposed CMAP cut-off amplitude may assist clinicians in shortening the time to reassessment or for earlier suggestion of salvage procedures. Owners perceived a good quality of life (QoL), even in cases of hindlimb amputation.

Sleep disturbance correlated with severity of neuropathic pain in sciatic nerve crush injury model.

The association between sleep and pain has been investigated widely. However, inconsistent results from animal studies compared with human data show the need for a validated animal model in the sleep-pain association field. Our study aims to validate common neuropathic pain models as a tool for evaluating the sleep-pain association. Electrodes electroencephalogram (EEG) and electromyogram (EMG) were surgically implanted to measure sleep. The von Frey test was used to measure pain sensitivity. Following the baseline data acquisition, two pain-modelling procedures were performed: sciatic nerve crush injury (SCI) and common peroneal nerve ligation (CPL). Post-injury measurements were performed on days 1, 5, 10, and 15 post-surgery. The results presented decreased paw withdrawal thresholds and reduced NREM sleep duration in both models on the first post-surgery day. In the SCI model, NREM sleep duration was negatively correlated with paw withdrawal thresholds (p = 0.0466), but not in the CPL model. Wake alpha and theta EEG powers were also correlated with the pain threshold. The results confirm that the SCI model shows disturbed sleep patterns associated with increased pain sensitivity, suggesting it is a reliable tool for investigating sleep disturbances associated with neuropathic pain.

The Role and Mechanism of Aspirin Combined with Rehabilitation Training in the Repair of Sciatic Nerve Injury and the Changes in the Schwannocytus (Schwann Cells) in Rats / Rol y Mecanismo de la Aspirina Combinados con Entrenamiento de Rehabilitación en la Reparación de la Lesión del Nervio Ciático y los Cambios en los Schwannocitos (Células de Schwann) en Ratas

SUMMARY: This study investigated the role and mechanism of aspirin combined with rehabilitation training in the nerve injury repair and Schwann cell changes in rats with sciatic nerve injury. Totally, 120 male healthy SD rats were randomly divided into sham, model, aspirin, and aspirin + rehabilitation groups, with 30 rats in each group. The sciatic nerve function index (SFI), photothermal pain tolerance threshold and inclined plane test results at 4, 6, and 8 weeks after operation were compared. The distance of sensory nerve regeneration and the expression of S100B protein in Schwann cells were analyzed. Compared with the sham group, the SFI of the model, aspirin, and aspirin+rehabilitation groups were significantly lower at 4, 6, and 8 weeks after operation. However, the aspirin and aspirin+rehabilitation groups had significantly higher SFI than the model group. The SFI at 6 and 8 weeks after operation was higher in the aspirin+rehabilitation group than that in the aspirin group (P<0.05). The photothermal pain tolerance threshold of the sham, aspirin, and aspirin+rehabilitation groups were significantly higher than those of the model group at 4, 6, and 8 weeks after operation (P<0.05). The inclination angles of the model, aspirin, and aspirin+rehabilitation groups were significantly lower than those of the sham group at 4, 6, and 8 weeks after operation, and the inclination angle of the aspirin+rehabilitation group was significantly higher than that of the model and aspirin groups (P<0.05). The sensory nerve regeneration distance in aspirin and aspirin+rehabilitation groups was higher than that in the sham and model groups (P<0.05). The expression of S100B protein in the aspirin and aspirin+rehabilitation groups was higher than that in the model group (P<0.05). Aspirin combined with rehabilitation training can promote the functional recovery of sciatic nerve injury, and the mechanism may be related to the increase of the expression of S100B protein in Schwann cells.

En este estudio se investigó el papel y el mecanismo que desempeña la aspirina combinada, con el entrenamiento de rehabilitación en la reparación de lesiones nerviosas y los cambios en los schwannocitos en ratas con lesiones en el nervio ciático. En total, 120 ratas SD macho sanas se dividieron aleatoriamente en cuatro grupos de 30 ratas en cada uno: simulación, modelo, aspirina y aspirina + rehabilitación. Se compararon el índice de función del nervio ciático (SFI), el umbral de tolerancia al dolor fototérmico y los resultados de la prueba del plano inclinado a las 4, 6 y 8 semanas después de la operación. Se analizó la distancia de regeneración del nervio sensorial y la expresión de la proteína S100B en los schwannocitos. En comparación con el grupo simulado, el SFI de los grupos modelo, aspirina y aspirina+rehabilitación fue significativamente menor a las 4, 6 y 8 semanas después de la operación. Sin embargo, los grupos de aspirina y aspirina + rehabilitación tuvieron un SFI significativamente más alto que el grupo modelo. El SFI a las 6 y 8 semanas después de la operación fue mayor en el grupo de aspirina + rehabilitación que en el grupo de aspirina (P<0,05). El umbral de tolerancia al dolor fototérmico de los grupos simulado, aspirina y aspirina+rehabilitación fue significativamente mayor que el del grupo modelo a las 4, 6 y 8 semanas después de la operación (P<0,05). Los ángulos de inclinación de los grupos modelo, aspirina y aspirina+rehabilitación fueron significativamente menores que los del grupo simulado a las 4, 6 y 8 semanas después de la operación, y el ángulo de inclinación del grupo aspirina+rehabilitación fue significativamente mayor que el de los grupos modelo y aspirina (P<0.05). La distancia de regeneración del nervio sensorial en los grupos de aspirina y aspirina+rehabilitación fue mayor que en los grupos simulado y modelo (P<0,05). La expresión de la proteína S100B en los grupos de aspirina y aspirina+rehabilitación fue mayor que en el grupo modelo (P<0,05). La aspirina combinada con el entrenamiento de rehabilitación puede promover la recuperación funcional de la lesión del nervio ciático, y el mecanismo puede estar relacionado con el aumento de la expresión de la proteína S100B en los schwannocitos.

Nerve conduction assessment and magnetic resonance imaging for the diagnosis of localized hypertrophic neuropathy of the sciatic nerve and the lumbo-sacral plexus.

Localized hypertrophic neuropathy (LHN) are slowly growing nerve lesions causing progressive nerve deficit and weakness. We present the case of a 32-year old woman with long history of motor and sensory deficit complains along the sciatic nerve territory. The muscles involved were featured by delay in F waves at nerve conduction assessment. Magnetic resonance imaging (MRI) showed specific patterns, low intense on T1 and abnormally hyper intense on short tau inversion recovery (STIR) and T2, with no obvious enhancement, features compatible with either LHN or intraneural perineurioma (IP) of the sciatic nerve and/or the lumbosacral plexus. Focal thickening and hypertrophy of the sciatic nerve with preserved fascicular configuration and progressive enlargement of the right lumbosacral plexus could be noted. A nerve conduction assessment followed by an MRI eventually allowed to diagnose LHN, without performing a nerve biopsy. Although similar, LHN and IP are two distinct lesions which should be diagnosed and differentiated as soon as possible, to avoid potential complications due to delayed diagnosis and/or misdiagnosis.

Differential effects of rat ADSCs encapsulation in fibrin matrix and combination delivery of BDNF and Gold nanoparticles on peripheral nerve regeneration.

BACKGROUND: Fibrin as an extracellular matrix feature like biocompatibility, creates a favorable environment for proliferation and migration of cells and it can act as a reservoir for storage and release of growth factors in tissue engineering. METHODS: In this study, the inner surface of electrospun poly (lactic-co-glycolic acid) (PLGA) nanofibrous conduit was biofunctionalized with laminin containing brain derived neurotrophic factor (BDNF) and gold nanoparticles in chitosan nanoparticle. The rats were randomly divided into five groups, including autograft group as the positive control, PLGA conduit coated by laminin and filled with DMEM/F12, PLGA conduit coated by laminin and filled with rat-adipose derived stem cells (r-ADSCs), PLGA conduit coated by laminin containing gold-chitosan nanoparticles (AuNPs-CNPs), BDNF-chitosan nanoparticles (BDNF-CNPs) and filled with r-ADSCs or filled with r-ADSCs suspended in fibrin matrix, and they were implanted into a 10 mm rat sciatic nerve gap. Eventually, axonal regeneration and functional recovery were assessed after 12 weeks. RESULTS: After 3 months post-surgery period, the results showed that in the PLGA conduit filled with r-ADSCs without fibrin matrix group, positive effects were obtained as compared to other implanted groups by increasing the sciatic functional index significantly (p < 0.05). In addition, the diameter nerve fibers had a significant difference mean in the PLGA conduit coated by laminin and conduit filled with r-ADSCs in fibrin matrix groups relative to the autograft group (p < 0.001). However, G-ratio and amplitude (AMP) results showed that fibrin matrix might have beneficial effects on nerve regeneration but, immunohistochemistry and real-time RT-PCR outcomes indicated that the implanted conduit which filled with r-ADSCs, with or without BDNF-CNPs and AuNPs-CNPs had significantly higher expression of S100 and MBP markers than other conduit implanted groups (p < 0.05). CONCLUSIONS: It seems, in this study differential effects of fibrin matrix, could be interfered it with other factors thereby and further studies are required to determine the distinctive effects of fibrin matrix combination with other exogenous factors in peripheral nerve regeneration.

Schwann Cells Provide Iron to Axonal Mitochondria and Its Role in Nerve Regeneration.

Iron is an essential cofactor for several metabolic processes, including the generation of ATP in mitochondria, which is required for axonal function and regeneration. However, it is not known how mitochondria in long axons, such as those in sciatic nerves, acquire iron in vivo Because of their close proximity to axons, Schwann cells are a likely source of iron for axonal mitochondria in the PNS. Here we demonstrate the critical role of iron in promoting neurite growth in vitro using iron chelation. We also show that Schwann cells express the molecular machinery to release iron, namely, the iron exporter, ferroportin (Fpn) and the ferroxidase ceruloplasmin (Cp). In Cp KO mice, Schwann cells accumulate iron because Fpn requires to partner with Cp to export iron. Axons and Schwann cells also express the iron importer transferrin receptor 1 (TfR1), indicating their ability for iron uptake. In teased nerve fibers, Fpn and TfR1 are predominantly localized at the nodes of Ranvier and Schmidt-Lanterman incisures, axonal sites that are in close contact with Schwann cell cytoplasm. We also show that lack of iron export from Schwann cells in Cp KO mice reduces mitochondrial iron in axons as detected by reduction in mitochondrial ferritin, affects localization of axonal mitochondria at the nodes of Ranvier and Schmidt-Lanterman incisures, and impairs axonal regeneration following sciatic nerve injury. These finding suggest that Schwann cells contribute to the delivery of iron to axonal mitochondria, required for proper nerve repair.SIGNIFICANCE STATEMENT This work addresses how and where mitochondria in long axons in peripheral nerves acquire iron. We show that Schwann cells are a likely source as they express the molecular machinery to import iron (transferrin receptor 1), and to export iron (ferroportin and ceruloplasmin [Cp]) to the axonal compartment at the nodes of Ranvier and Schmidt-Lanterman incisures. Cp KO mice, which cannot export iron from Schwann cells, show reduced iron content in axonal mitochondria, along with increased localization of axonal mitochondria at Schmidt-Lanterman incisures and nodes of Ranvier, and impaired sciatic nerve regeneration. Iron chelation in vitro also drastically reduces neurite growth. These data suggest that Schwann cells are likely to contribute iron to axonal mitochondria needed for axon growth and regeneration.

Dynamic Change of Endocannabinoid Signaling in the Medial Prefrontal Cortex Controls the Development of Depression After Neuropathic Pain.

Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxious inputs after injury compromise activity-dependent eCB signaling in the mPFC, resulting in depression. Depression-like behaviors were tested in male and female rats with traumatic neuropathy [spared nerve injury (SNI)], and neuronal activity in the mPFC was monitored using the immediate early gene c-fos and in vivo electrophysiological recordings. mPFC eCB Concentrations were determined using mass spectrometry, and behavioral and electrophysiological experiments were used to evaluate the role of alterations in eCB signaling in depression after pain. SNI-induced pain induced the development of depression phenotypes in both male and female rats. Pyramidal neurons in mPFC showed increased excitability followed by reduced excitability in the onset and prolonged phases of pain, respectively. Concentrations of the eCBs, 2-arachidonoylglycerol (2-AG) in the mPFC, were elevated initially after SNI, and our results indicate that this resulted in a loss of CB1R function on GABAergic interneurons in the mPFC. These data suggest that excessive release of 2-AG as a result of noxious stimuli triggers use-dependent loss of function of eCB signaling leading to excessive GABA release in the mPFC, with the final result being behavioral depression.SIGNIFICANCE STATEMENT Pain has both somatosensory and affective components, so the complexity of mechanisms underlying chronic pain is best represented by a biopsychosocial model that includes widespread CNS dysfunction. Many patients with chronic pain conditions develop depression. The mechanism by which pain causes depression is unclear. Although manipulation of the eCB signaling system as an avenue for providing analgesia per se has not shown much promise in previous studies. An important limitation of past research has been inadequate consideration of the dynamic nature of the connection between pain and depression as they develop. Here, we show that activity-dependent synthesis of eCBs during the initial onset of persistent pain is the critical link leading to depression when pain is persistent.

Electrospun polycaprolactone (PCL)-amnion nanofibrous membrane prevents adhesions and promotes nerve repair in a rat model of sciatic nerve compression.

Adhesion and scarring after neural surgery are detrimental to nerve regeneration and functional recovery. Amniotic membranes have been used in tissue repair due to their immunogenicity and richness in cytokines. In this study, an electrospun polycaprolactone (PCL)-amnion nanofibrous membrane was prepared for the treatment of sciatic nerve compression in a rat model. The effects of the PCL-amnion nanofibrous membrane on the prevention of adhesion formation and nerve regeneration were evaluated using electrophysiology and histological analyses. Compared with the medical chitosan hydrogel dressing, the PCL-amnion nanofibrous membrane significantly reduced peripheral nerve adhesion and promoted the rapid recovery of nerve conduction. Moreover, the immunohistochemical analysis identified more Schwann cells and less pro-inflammatory M1 macrophages in the PCL-amnion group. Western blot and RT-PCR results showed that the expression levels of type-Ⅰ and Ⅲ collagen in the PCL-treated rats were half of those in the control group after 12 weeks, while the expression level of nerve growth factor was approximately 3.5 times that found in the rats treated with medical chitosan hydrogel. In summary, electrospun PCL-amnion nanofibrous membranes can effectively reduce adhesion after neural surgery and promote nerve repair and regeneration. The long-term retention in vivo and sustained release of cytokines make PCL-amnion a promising biomaterial for clinical application.

Effect of PKC/NF-κB on the Regulation of P2X3 Receptor in Dorsal Root Ganglion in Rats with Sciatic Nerve Injury.

Background: Protein kinase C (PKC), nuclear factor-kappa B p65 (NF-κB p65), and P2X3 receptor (P2X3R) play significant roles in the sensitization and transduction of nociceptive signals, which are considered as potential targets for the treatment of neuropathic pain. However, the mechanisms and relationships among them have not been clearly clarified. Methods: 80 rats were randomized and divided into 10 groups (n = 8). Sciatic chronic constriction injury (CCI) rats were intrathecally administered with bisindolylmaleimide I (GF109203X), a PKC-selective antagonist once a day, or pyrrolidine dithiocarbamate (PDTC), an NF-κB inhibitor twice a day. Sham-operated rats were intrathecally administered with saline. Thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) were evaluated in all the groups before CCI operation (baseline) and on the 1st, 3rd, 7th, 10th, and 14th day after CCI operation. Protein levels of p-PKCα, p-NF-κB p65, and P2X3R were analyzed in the CCI ipsilateral L4-6 dorsal root ganglions (DRGs). Results: Intrathecal injection of GF109203X or PDTC alleviated the TWL and MWT in the following 2 weeks after CCI surgery. The protein levels of p-PKCα, p-NF-κB p65, and P2X3R in the ipsilateral DRGs significantly increased after CCI operation, which could be partly reversed by intrathecal administration of GF109203X or PDTC. Conclusion: The upregulation of p-PKCα, p-NF-κB p65, and P2X3R expression in the DRGs of CCI rats was involved in the occurrence and development of neuropathic pain. Phosphorylated PKCα and phosphorylated NF-κB p65 regulated with each other. Phosphorylated NF-κB p65 and PKCα have a mutual regulation relationship with P2X3R, respectively, while the specific regulatory mechanism needs further research.

Low-Level Laser Therapy in Different Wavelengths on the Tibialis Anterior Muscle of Wistar Rats After Nerve Compression Injury.

OBJECTIVE: Traumatic injuries are common and may promote disruption of neuromuscular communication, triggering phenomena that lead to nerve degeneration and affect muscle function. A laser accelerates tissue recovery; however, the parameters used are varied, making it difficult to compare studies. The purpose of this study was to evaluate the effect of low-level laser therapy, at 660- and 830-nm wavelengths, on the tibialis anterior muscle of Wistar rats after sciatic nerve compression. METHODS: Twenty animals were separated into 4 groups: control, sciatic nerve injury, lesion + 660-nm laser, and lesion + 830-nm laser. In the lesion groups, the right sciatic nerve was surgically exposed and compressed with hemostatic forceps for 30 seconds. After the third postoperative day, the groups with laser therapy were submitted to treatment for 2 weeks totaling 10 applications, performed directly on the surgical scar of the nerve injury. Grip strength was analyzed before and after the nerve injury and during the treatment period. The tibialis anterior muscle was processed for light microscopy, area measurement, smaller diameter, number of fibers, nuclei, and connective tissue. RESULTS: The animals submitted to the injury experienced muscular atrophy and morphological changes in the number of muscle fibers and nuclei. In the connective tissue morphometry, there was a decrease in the treated groups compared with the untreated groups. CONCLUSION: The laser treatment at different wavelengths showed no improvement in the tibialis anterior muscle of Wistar rats within the morphological and functional aspects evaluated.

Umbelliprenin relieves paclitaxel-induced neuropathy.

OBJECTIVES: Umbelliprenin (UMB) is a prenylated coumarin that acts as an in vitro antioxidant and inhibits lipoxygenase managing the inflammation pathways, while in vivo it exerts anti-inflammatory activities. METHODS: In this study, neuropathic pain was induced by four intraperitoneal doses of 2 mg/kg per day of paclitaxel (PTX) on days 1, 3, 5 and 7. Here, 49 male mice were randomly divided in the following groups: sham (not treated animals), negative control (PTX-treated receiving normal saline), single-dose UMB 6.25, 12.5 and 25 mg/kg groups (PTX-treated receiving UMB 6.25, 12.5 and 25 mg/kg, respectively), prevention (PTX-treated receiving PTX along with UMB 12.5 mg/kg on days 1, 3, 5 and 7) and positive control group (PTX-treated receiving imipramine 10 mg/kg as acute treatment). Hot-plate test was done to assess response to heat. Finally, interleukin (IL)-6 levels in the sciatic nerve and lipid peroxidation in sera were assessed. KEY FINDINGS: Umbelliprenin was found equally effective for acute treatment with imipramine, when comparing the prevention group and the positive control group. Single, 25 mg/kg UMB effectively attenuated hyperalgesia, lipid peroxidation and IL-6 levels. CONCLUSIONS: Umbelliprenin alleviated neuropathic pain, and decreased serum IL-6 levels and oxidative stress. UMB deserves further investigations, especially in clinical settings.

Inhibition of PTEN activity promotes IB4-positive sensory neuronal axon growth.

Traumatic nerve injuries have become a common clinical problem, and axon regeneration is a critical process in the successful functional recovery of the injured nervous system. In this study, we found that peripheral axotomy reduces PTEN expression in adult sensory neurons; however, it did not alter the expression level of PTEN in IB4-positive sensory neurons. Additionally, our results indicate that the artificial inhibition of PTEN markedly promotes adult sensory axon regeneration, including IB4-positive neuronal axon growth. Thus, our results provide strong evidence that PTEN is a prominent repressor of adult sensory axon regeneration, especially in IB4-positive neurons.

Pediatric sciatic neuropathy: Clinical presentation and long term follow up. / Neuropatía ciática en pediatría: Presentación clínica y seguimiento a largo plazo.

INTRODUCTION: Sciatic neuropathy is rare and difficult to diagnose in pediatrics, and its long-term course has not been completely understood. OBJECTIVE: To analyze the clinical presentation and evolution of a group of pediatric patients with sciatic neuropathy. PATIENTS AND METHOD: Retrospective anal ysis of the clinical characteristics of pediatric patients with sciatic neuropathy treated in two hospitals of Santiago between 2014 and 2018. Locomotor examination, muscle trophism, deep tendon reflexes, gait, sensation, and pain were assessed. Sciatic nerve conduction study and electromyography (EMG) were performed, and magnetic resonance imaging (MRI) in three patients. RESULTS: Six patients were included with an average age of 11.8 years. The etiologies were traumatic (N = 2), by compression (N = 2), vascular (N = 1), and tumor (N = 1). All of the 6 patients presented foot drop and Achilles tendon hyporeflexia/areflexia, and 5 patients presented severe neuropathic pain. The EMG showed involvement of the sciatic nerve rami and dependent muscles. In two patients, a pelvic girdle and lower limbs MRI was performed, showing selective muscle involvement in sciatic territory. One patient underwent a lumbosacral plexus MRI, and subsequently histological study showing a benign neural tumor. Out of the three patients who were followed-up longer than one year presented motor sequelae and gait disorder. CONCLUSION: Sciatic neuropathy in the study group was secondary to different causes, predominantly traumatic and compressive etiologies. The three patients that were ina long-term follow-up presented significant motor sequelae. In most of the cases, neural injury wasassoci- ated with preventable causes, such as accidents and positioning in unconscious children, which is crucial in the prevention of a pathology with a high sequelae degree.

Mechanical properties of the sciatic nerve following combined transplantation of analytically extracted acellular allogeneic nerve and adipose-derived mesenchymal stem cells.

PURPOSE: To investigate the effects of Chemically Extracted Acellular Nerves (CEANs) when combined with Adipose-Derived mesenchymal Stem Cell (ADSC) transplantation on the repair of sciatic nerve defects in rabbits. METHODS: A total of 71 six-month-old Japanese rabbit were used in this study. Twenty rabbits served as sciatic nerve donors, while the other 51 rabbits were randomly divided into Autologous Nerve Transplantation Group (ANT, n=17), CEAN group (n=17) and CEAN-ADSCs group (n=17). In all these groups, the rabbit's left sciatic nerves were injured before the experiment, and the uninjured sciatic nerves on their right side were used as the control (CON). Electrophysiological tests were carried out and sciatic nerves were prepared for histomorphology and stretch testing at 24 weeks post-transplant. RESULTS: There were significant differences between ANT and Con groups in amplitude (AMP): P=0.031; motor nerve conduction velocity (MNCV): P=0.029; Maximum stress: P=0.029; and Maximum strain P=0.027. There were also differences between the CEAN and CEAN+ADSCs groups in AMP: P=0.026, MNCV: P=0.024; Maximum stress: P=0.025 and Maximum strain: P=0.030. No significant differences in these parameters were observed when comparing the ANT and CEAN+SACN groups (MNCV: P=0.071) or the CEAN and ANT groups (Maximum stress: P=0.069; Maximum strain P=0.077). CONCLUSION: Addition of ADSCs has a significant impact on the recovery of nerve function, morphology, and tensile mechanical properties following sciatic nerve injury.

Reduced inflammatory response and accelerated functional recovery following sciatic nerve crush lesion in CXCR3-deficient mice.

Despite the regenerative capacity of the peripheral nerve system (PNS), functional recovery after mechanical nerve trauma is often incomplete, resulting in motor, sensory, and autonomic deficits. The elucidation of key molecules involved in trauma-induced Wallerian degeneration and the ensuing regeneration processes is a prerequisite for the development of disease modifying drugs. The chemokine (C-X-C motif) receptor 3 (CXCR3) has been implicated in the recruitment of macrophages, the major immune cell population during the process of Wallerian degeneration. In this study, we examined whether deletion of CXCR3 affects macrophage recruitment, the expression of the proinflammatory cytokine tumor necrosis factor (TNF)- α and the CXCR3 agonist interferon gamma-induced protein 10 (CXCL10), and functional recovery in the sciatic nerve crush model. CXCR3 mice displayed significantly reduced macrophage counts preceded by diminished expression of CXCL10 and TNF- α. Furthermore, functional recovery of sciatic nerve motor function was significantly accelerated. In summary, these data indicate that the deletion of CXCR3 leads to a diminished inflammatory response and an accelerated functional recovery following sciatic nerve crush injury. Therefore, CXCR3 may be an interesting target for therapeutic interventions after traumatic nerve lesions.

Differentiated adipose-derived stem cells promote peripheral nerve regeneration.

INTRODUCTION: Many reports have indicated that adipose-derived stem cells (ADSCs) are effective for nerve regeneration. We investigated nerve regeneration by combining a polyglycolic acid collagen (PGA-c) tube, which is approved for clinical use, and Schwann cell-like differentiated ADSCs (dADSCs). METHODS: Fifteen-millimeter-long gaps in the sciatic nerve of rats were bridged in each group using tubes (group I), with tubes injected with dADSCs (group II), or by resected nerve (group III). RESULTS: Axonal outgrowth was greater in group II than in group I. Tibialis anterior muscle weight revealed recovery only in group III. Latency in nerve conduction studies was equivalent in group II and III, but action potential was lower in group II. Transplanted dADSCs maintained Schwann cell marker expression. ATF3 expression level in the dorsal root ganglia was equivalent in groups II and III. DISCUSSION: dADSCs maintained their differentiated state in the tubes and are believed to have contributed to nerve regeneration.

Neuropatía ciática en pediatría: presentación clínica y seguimiento a largo plazo / Pediatric sciatic neuropathy: clinical presentation and long term follow up

Resumen: Introducción: La neuropatía ciática es una entidad infrecuente y de difícil diagnóstico en Pediatría. Su evolución a largo plazo no ha sido claramente definida. Objetivo: Analizar la presentación clínica y evolución de un grupo de niños con neuropatía ciática. Pacientes y Método: Análisis retrospectivo de las características clínicas de pacientes pediátricos con neuropatía ciática atendidos en 2 hospitales de Santiago, entre 2014-2018. Se evaluó examen motor, trofismo muscular, reflejos osteotendíneos, marcha, sensibilidad y dolor. Se estudió neuroconducción de nervio ciático, electromiografía (EMG) y en 3 pacientes, Resonancia Magnética (RM). Resultados: Se incluyeron 6 pacientes, edad promedio 11,8 años. Hubo 2 causas traumáticas, 2 compresivas, 1 vascular y 1 tumoral. Los 6 pa cientes debutaron con pie caído e hiporreflexia/arreflexia aquiliana; 5 pacientes presentaron dolor neuropático severo. La EMG mostró en todos los casos compromiso en nervios y musculatura de pendientes del nervio ciático. En 2 casos se realizó RM de cintura pélvica y extremidades inferiores, mostrando compromiso muscular selectivo en pierna en territorio ciático. En 1 caso, se realizó RM de plexo lumbosacro, y luego estudio histológico, que concluyeron un tumor neural benigno. En los 3 pacientes que tuvieron seguimiento mayor a un año, se observaron secuelas motoras, con marcha alterada. Conclusión: La neuropatía ciática en este grupo fue secundaria a diversas etiologías, predominando las traumático-compresivas. En los 3 casos que tuvieron seguimiento a largo plazo se observaron secuelas motoras significativas. En la mayoría la lesión se asoció a causas prevenibles como accidentes y posicionamiento en niños con compromiso de conciencia, lo que resulta fundamental en la prevención de una patología con alto grado de secuelas.

Abstract: Introduction: Sciatic neuropathy is rare and difficult to diagnose in pediatrics, and its long-term course has not been completely understood. Objective: To analyze the clinical presentation and evolution of a group of pediatric patients with sciatic neuropathy. Patients and Method: Retrospective anal ysis of the clinical characteristics of pediatric patients with sciatic neuropathy treated in two hospitals of Santiago between 2014 and 2018. Locomotor examination, muscle trophism, deep tendon reflexes, gait, sensation, and pain were assessed. Sciatic nerve conduction study and electromyography (EMG) were performed, and magnetic resonance imaging (MRI) in three patients. Results: Six patients were included with an average age of 11.8 years. The etiologies were traumatic (N = 2), by compression (N = 2), vascular (N = 1), and tumor (N = 1). All of the 6 patients presented foot drop and Achilles tendon hyporeflexia/areflexia, and 5 patients presented severe neuropathic pain. The EMG showed involvement of the sciatic nerve rami and dependent muscles. In two patients, a pelvic girdle and lower limbs MRI was performed, showing selective muscle involvement in sciatic territory. One patient underwent a lumbosacral plexus MRI, and subsequently histological study showing a benign neural tumor. Out of the three patients who were followed-up longer than one year presented motor sequelae and gait disorder. Conclusion: Sciatic neuropathy in the study group was secondary to different causes, predominantly traumatic and compressive etiologies. The three patients that were ina long-term follow-up presented significant motor sequelae. In most of the cases, neural injury wasassoci- ated with preventable causes, such as accidents and positioning in unconscious children, which is crucial in the prevention of a pathology with a high sequelae degree.