Recovery Of Peripheral Nerve Injury Research Articles

The reduction of imidazole propionate induced by intermittent fasting promotes recovery of peripheral nerve injury by enhancing migration of Schwann cells

Peripheral nerve injury (PNI) accompanied with sensory and motor dysfunction has serious effect on the quality of life of patients. Intermittent fasting (IF), as a dietary pattern, has rarely been reported to influence imidazole propionate (ImP), a microbial metabolite, in vivo. To date, the link between ImP and PNI is unknown. This study aimed to explore the impact of ImP on the recovery after PNI and determine whether IF could reduce the concentration of ImP in vivo. Sciatic nerve injury rat model and RSC96 cells were utilized with 16s RNA seq, HE staining, CCK-8 assay, Western blot (WB), Transmission electron microscopy (TEM), immunofluorescence, transwell and scratch wound healing assays as read outs. WB, TEM, transwell and wound healing assay showed an inhibitory effect of ImP on autophagy and migration of Schwann cells. This negative effect on migration was reversed by rapamycin. Detection of p-Erk and p-mTOR confirmed that the MAPK/Erk/mTOR pathway was involved in this process. In vivo, IF changed the composition of gut microbiome, including bacteria related to ImP production and reduced the concentration of ImP in serum. In sum, IF influenced the composition of gut microbiome and reduced the concentration of ImP in vivo. The reduction of ImP promoted migration of SCs through enhancing autophagy which involved MAPK/Erk/mTOR pathway.

HIF-1α Induced by Hypoxia Promotes Peripheral Nerve Injury Recovery Through Regulating Ferroptosis in DRG Neuron.

Peripheral nerve injury (PNI) usually has a poor effect on functional recovery and severely declines the patient's quality of life. Our prior findings indicated that hypoxia remarkably promoted nerve regeneration of rats with sciatic nerve transection. However, the underlying molecular mechanisms of hypoxia in functional recovery of PNI still remain elusive. In this research, we tried to explain the functional roles and mechanisms of hypoxia and the hypoxia-inducible factor-1α (HIF-1α) in PNI. Our results indicated that hypoxia promoted proliferation and migration of dorsal root ganglia (DRG) and increased the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Mechanistically, hypoxia suppressed ferroptosis through activating HIF-1α in DRG neurons. Gain and loss of function studies were performed to evaluate the regulatory roles of HIF-1α in ferroptosis and neuron recovery. The results revealed that up-regulation of HIF-1α enhanced the expression of solute carrier family membrane 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) and increased the contents of cysteine and glutathione, while inhibiting the accumulation of reactive oxygen species (ROS). Our findings provided novel light on the mechanism of ferroptosis involved in PNI and manifest hypoxia as a potential therapeutic strategy for PNI recovery.

HIF-1α-induced upregulation of m6A reader IGF2BP1 facilitates peripheral nerve injury recovery by enhancing SLC7A11 mRNA stabilization.

The recovery of peripheral nerve injury (PNI) is not ideal in clinic. Our previous study revealed that hypoxia treatment promoted PNI repair by inhibiting ferroptosis. The aim of this study was to investigate the underlying molecular mechanism of HIF-1α in hypoxia-PNI recovery. M6A dot blot was used to determine the total level of m6A modification. Besides, HIF-1α small interfering RNA (siRNA) or IGF2BP1 overexpression vector was transfected into dorsal root ganglion (DRG) neurons to alter the expression of HIF-1α and IGF2BP1. Subsequently, MeRIP-PCR analysis was applied to validate the m6A methylation level of SLC7A11. We demonstrated the hypoxia stimulated HIF-1α-dependent expression of IGF2BP1 and promoted the overall m6A methylation levels of DRG neurons. Overexpression of HIF-1α increased the expressions of neurotrophic factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial-derived neurotrophic factor (GDNF), which could be effectively reversed by siRNA knockdown of IGF2BP1. Moreover, upregulation of HIF-1α contributed to the m6A methylation level and mRNA stabilization of SLC7A11. This study revealed that the HIF-1α/IGF2BP1/SLC7A11 regulatory axis facilitated the recovery of injured DRG neurons. Our findings suggest a novel insight for the m6A methylation modification in PNI recovery.

Clinical evaluation of the perception of post-trauma paresthesia in the mandible, using a biomimetic material: A preliminary study in humans

There is a great effort from numerous research groups in the development of materials and therapeutic strategies for the functional recovery of patients who have suffered peripheral nerve injuries (PNI). In an article in vivo, the formation of a nerve bridge was observed, reconnecting the distal and proximal stumps, in the sciatic nerve of rats, indicating the effective participation of the biomaterial in the recovery of peripheral nerve injuries. For the current pilot study, 15 cases of multiple fractures of the mandible, with involvement of the inferior alveolar nerve (IAN) were selected and studied: JC (control cases) n = 6 with conventional treatment, and JT (treated cases) n = 9, with the use of biomimetic biomaterial. The evaluation of the return to sensitivity was measured through a self-assessment, where the patients assigned scores from 0 to 10, where zero (0) represented the complete absence of sensitivity and ten (10) the normality of the perception of local sensitivity. Patients were evaluated from the preoperative period to the 360th day. The statistical results obtained by the t-Student, Shapiro-Wilk normality and non-parametric One-Way ANOVA tests indicated statistically significant differences (p < 0.005; 0.005 e 0.5 respectively), between the two treatments, which were reflected in the clinical results observed, we also calculate the size of the effect represented by ϵ2, calculated by Cohen's d. The results indicate a great difference between the treatments performed,ϵ2 = 1.00. In the 6 cases followed up in the JC group, four remained with a significant deficit until the end of the evaluations and two indicated the remission of the lack of sensitivity in this period. In the JT group, in 28 days, all cases indicated complete remission of the lack of sensitivity with healing concentration. In one of the cases where there was a complete rupture of the mental nerve, the (score-10) was observed in 60 days. The observed results indicate the existence of a statistical significance between the groups and an important relationship when using the biomimetic biomaterial during the recovery of the perception of sensitivity in polytraumatized patients, compatible with the results observed in laboratory animals, which may indicate its clinical feasibility in the reduction of sequelae in PNI.

Gelatin nanofiber-reinforced decellularized amniotic membrane promotes axon regeneration and functional recovery in the surgical treatment of peripheral nerve injury

Effective recovery of peripheral nerve injury (PNI) after surgical treatment relies on promoting axon regeneration and minimizing the fibrotic response. Decellularized amniotic membrane (dAM) has unique features as a natural matrix for promoting PNI repair due to its pro-regenerative extracellular matrix (ECM) structure and anti-inflammatory properties. However, the fragile nature and rapid degradation rate of dAM limit its widespread use in PNI surgery. Here we report an engineered composite membrane for PNI repair by combining dAM with gelatin (Gel) nanofiber membrane to construct a Gel nanofiber-dAM composite membrane (Gel-dAM) through interfacial bonding. The Gel-dAM showed enhanced mechanical properties and reduced degradation rate, while retaining maximal bioactivity and biocompatibility of dAM. These factors led to improved axon regeneration, reduced fibrotic response, and better functional recovery in PNI repair. As a fully natural materials-derived off-the-shelf matrix, Gel-dAM exhibits superior clinical translational potential for the surgical treatment of PNI.

BDNF and Krox20 as Indicators of Platelet-rich Plasma-Induced Nerve Regeneration in a Neuropathic Orofacial Pain Model.

Various growth factors contained in PRP can increase angiogenesis and cell proliferation, which plays an essential role in the process of neuroregeneration and peripheral nerve injury recovery. This study analyzed PRP effects in the neuro-regeneration of axonotmesis through brain-derived neurotrophic factor (BDNF) and Krox20 expressions. Freeze-dried allogeneic platelet-rich plasma (PRP) were prepared from allogeneic sources. Forty-two Rattus norvegicus were divided into three groups: negative control group, positive control group (crushing infraorbital nerve) and treatment group (crushing infraorbital nerve without PRP injection). Each group was observed for fourteen and twenty-one days after injury. Infraorbital nerve tissue is isolated for indirect immunohistochemistry examination with BDNF and Krox20 antibodies. Data analysis was performed using One-Way ANOVA and Mann-Whitney tests with significant value as p < 0.05. The PRP group showed BDNF expression significantly higher than control positive groups, both observation days (p = 0.00). A higher Korx20 expression showed by the PRP group after 21 days than in the control positive groups (p = 0.002). PRP can potentially improve neuroregeneration of axonotmesis through increased BDNF and Krox20 expression on the twenty-one days after injury.

Longitudinal traumatic peripheral nerve injury recovery: quantitative description, classificationand prediction.

Aim: Repair of peripheral nerves is recommended following transection. Systematic evaluation of longitudinal recovery in injury models is needed to improve patient management. Gompertz function provided straightforward interpretation and prediction of recovery outcomes. Materials & methods: Behavioural sciatic function index, measured 3days postinjury, and weekly for 12weeks following full nerve transection and repair (n=6) as well as crush injuries (n=6). Results: Gompertz parametrization provided early classification between types of traumatic peripheral nerve injuries following surgical repair. Results distinguished injury nerves (A: p<0.01;Ti: p<0.05; Ic: p<0.05 and outcome: p<0.01). Early prognostication of outcomes (crush: 5.5±0.3 and cut/repair: 8±1weeks) preceded current methods. Conclusion: Our findings identify injury type, state of recovery and early prognostication of outcome.

Exercise facilitates regeneration after severe nerve transection and further modulates neural plasticity

Patients with severe traumatic peripheral nerve injury (PNI) always suffer from incomplete recovery and poor functional outcome. Physical exercise-based rehabilitation, as a non-invasive interventional strategy, has been widely acknowledged to improve PNI recovery by promoting nerve regeneration and relieving pain. However, effects of exercise on chronic plastic changes following severe traumatic PNIs have been limitedly discussed. In this study, we created a long-gap sciatic nerve transection followed by autograft bridging in rats and tested the therapeutic functions of treadmill running with low intensity and late initiation. We demonstrated that treadmill running effectively facilitated nerve regeneration and prevented muscle atrophy and thus improved sensorimotor functions and walking performance. Furthermore, exercise could reduce inflammation at the injured nerve as well as prevent the overexpression of TRPV1, a pain sensor, in primary afferent sensory neurons. In the central nervous system, we found that PNI induced transcriptive changes at the ipsilateral lumber spinal dorsal horn, and exercise could reverse the differential expression for genes involved in the Notch signaling pathway. In addition, through neural imaging techniques, we found volumetric, microstructural, metabolite, and neuronal activity changes in supraspinal regions of interest (i.e., somatosensory cortex, motor cortex, hippocampus, etc.) after the PNI, some of which could be reversed through treadmill running. In summary, treadmill running with late initiation could promote recovery from long-gap nerve transection, and while it could reverse maladaptive plasticity after the PNI, exercise may also ameliorate comorbidities, such as chronic pain, mental depression, and anxiety in the long term.

The Impact of Supplements on Recovery After Peripheral Nerve Injury: A Review of the Literature.

Peripheral nerve injury (PNI) can result from trauma, surgical resection, iatrogenic injury, and/or local anesthetic toxicity. Damage to peripheral nerves may result in debilitating weakness, numbness, paresthesia, pain, and/or autonomic instability. As PNI is associated with inflammation and nerve degeneration, means to mitigate this response could result in improved outcomes. Numerous nutrients have been investigated to prevent the negative sequelae of PNI. Alpha-lipoic acid, cytidine diphosphate-choline (CDP Choline), curcumin, melatonin, vitamin B12, and vitamin E have demonstrated notable success in improving recovery following PNI within animal models. While animal studies show ample evidence that various supplements may improve recovery after PNI, similar evidence in human patients is limited. The goal of this review is to analyze supplements that have been used successfully in animal models of PNI to serve as a reference for future studies on human patients. By analyzing supplements that have shown efficacy in animal studies, healthcare providers will have a resource from which to guide decision-making regarding future human studies investigating the role that supplements could play in PNI recovery. Ultimately, establishing a comprehensive understanding of these supplements in human patients following PNI may significantly improve post-surgical outcomes, quality of life, and peripheral nerve regeneration.

Gastrodin promotes the regeneration of peripheral nerves by regulating miR-497/BDNF axis

BackgroundGastrodin (GAS), is a kind of phenolic compound extracted from the traditional Chinese herbal medicine Gastrodia elata Blume (GEB). This study was aimed at probing into the protective effect of GAS on peripheral nerve injury (PNI) and the underlying mechanism.MethodsA rat model with PNI was established, followed by intraperitoneal injection of GAS (20 mg/kg/day). Sciatic nerve function index (SFI) was used to analyze the function of sciatic nerve. The amplitude and latency of compound muscle action potential (CMAP) were examined by electrophysiology. Schwann cells (SCs) were isolated from fetal rats and treated with GAS 200 μg/mL, and H2O2-induced model of oxidative stress injury was established. EdU and Transwell assays were adopted to detect the viability and migration of SCs. Dual-luciferase reporter gene assays were applied to verify the binding site between miR-497 and brain-derived neurotrophic factor (BDNF) 3’UTR. MiR-497 expression was probed by quantitative real-time polymerase chain reaction (qRT-PCR). BDNF, neurofilament-200 (NF-200) and myelin basic protein (MBP) expression levels were detected by Western blotting. Malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, glutathione content (GSH) and catalase (CAT) activity in SCs were also measured.ResultsGAS treatment could significantly increase the SFI and amplitude of CMAP, shorten the refractory period, and ameliorate muscle atrophy of the rats with PNI. GAS treatment could markedly restrain miR-497 expression and increase the expression levels of BDNF, NF-200 and MBP in SCs. BDNF was confirmed as the target of miR-497 and BDNF overexpression could reverse the impacts of miR-497 overexpression on the proliferation, migration, and oxidative stress response of SCs.ConclusionsGAS promotes the recovery of PNI via modulating miR-497 / BDNF axis and inhibiting oxidative stress.Graphical abstract

Upregulation of Neurotrophic Factors and Myelin Basic Protein in Schwann-like Cells by T3 Hormone Following Transdifferentiation of Human Adipose-derived Stem Cells.

Peripheral nerve regeneration is a complicated phenomenon. Thyroid hormones are known as critical regulators in the nervous system development. The Schwann cells have the regenerative potency in the peripheral nervous system. In this study, the human adipose-derived stem cells were assessed in vitro, for transdifferentiation potency into Shwann-like cells (SLCs) as a candidate source for clinical cell therapy, under the treatment of triiodothyronine (T3) hormone, and compared with the untreated cells. The cell viability rate, myelination and neurotrophic factors expression of SLCs were evaluated two weeks post- induction by MTT assay, immunocytochemistry and real-time RT-PCR techniques, respectively. The obtained results revealed a significant decrease in SLCs viability, compared to the adipose-derived stem cells (P < 0.001). Immunocytochemistry technique was applied to detect SLCs markers, such as S100β, GFAP and myelin basic proteins (MBP) in the presence and absence of T3 treatment. The results indicated that administering T3 can significantly increase the differentiation and myelination potency of SLCs (P < 0.01). The findings of real-time RT-PCR technique indicated that the expression of Schwann cells markers, MBP, brain-derived neurotrophic factor and glial cell-derived neurotrophic factor were upregulated significantly with T3 hormone administration in comparison with the untreated cells (P < 0.05). The SLCs were able to express the neurotrophic factors and myelination related genes in the presence of T3 hormone. Furthermore, T3 administration improved myelination potency of adipose-derived stem cells, in vitro. Further in vivo experiments are necessary to confirm the advantages of using a combination of autologous SLCs and T3 hormone for peripheral nerve injury recovery.

Physiologically Self-Regulated, Fully Implantable, Battery-Free System for Peripheral Nerve Restoration.

The long-segment peripheral nerve injury (PNI) represents a global medical challenge, leading to incomplete nerve tissue recovery and unsatisfactory functional reconstruction. However, the current electrical stimulation (ES) apparatuses fail perfect nerve repair due to their inability of the variable synchronous self-regulated function with physiological states. It is urgent to develop an implantable ES platform with physiologically adaptive function to provide instantaneous and nerve-preferred ES. Here, a physiologically self-regulated electrical signal is generated by integrating a novel tribo/piezoelectric hybrid nanogenerator with a nanoporous nerve guide conduit to construct a fully implantable neural electrical stimulation (FI-NES) system. The optimal neural ES parameters completely originate from the body itself and are highly self-responsive to different physiological states. The morphological evaluation, representative protein expression level, and functional reconstruction of the regenerated nerves are conducted to assess the PNI recovery process. Evidence shows that the recovery effect of 15mm length nerve defects under the guidance of the FI-NES system is significantly close to the autograft. The designed FI-NES system provides an effective method for long-term accelerating the recovery of PNI in vivo and is also appropriate for other tissue injury or neurodegenerative diseases.

A Review on the Mechanism of Tuina Promoting the Recovery of Peripheral Nerve Injury.

Tuina, as one of the characteristic external therapies of Traditional Chinese Medicine (TCM), has been used to treat the disease caused by peripheral nerve injury (PNI) for thousands of years. An increasing number of clinical trials and animal experiments have demonstrated that tuina can improve the symptoms and promote the recovery of damaged nerves. This review focuses on the mechanistic studies of tuina in promoting the recovery of PNI, which might provide a neurobiological foundation for the effects of tuina. Although many mechanisms underlying the effects of tuina on nerve repair have been identified, there are still many unknown problems, such as the key substance or way for tuina to work, so further investigation is warranted.

Injectable, antioxidative, and neurotrophic factor-deliverable hydrogel for peripheral nerve regeneration and neuropathic pain relief

Although peripheral nerve system has intrinsic regeneration potential, recovery from peripheral nerve injury (PNI) is often far from optimal, leading to partial or complete loss of sensorimotor function and neuropathic pain. The failure for PNI repair can be due to multiple reasons. Excessively elevated oxidative stress in injured tissue is one of primary causes for poor nerve regeneration and pain by damaging neurons and myelin structure. In addition, deprivation in various neurotrophic factors (NTFs) in chronic nerve denervation will lose support for nerve regrowth. Here, we developed a multifunctional hyaluronic acid-phenylboronic acid-poly (vinyl alcohol) -heparin (HA-PVA-Hep) hydrogel by mixing cysteamine and phenylboronic acid modified hyaluronic acid, commercially available poly (vinyl alcohol) and maleimide functionalized heparin. This hydrogel is biocompatible, stable, injectable, antioxidative, anti-inflammatory, and capable of sustainably releasing NTFs (i.e. glial cell derived neurotrophic factor-GDNF in this study). The therapeutic effect of HA-PVA-Hep hydrogel to repair acute PNI was tested by using a mouse sciatic nerve crush model. We found the hydrogel effectively improved sensorimotor function during the recovery period and significantly prevented muscular atrophy, protected neurons from injury and promoted nerve regeneration as well as remyelination at 28 days post injury. In addition, the hydrogel could also alleviate PNI-induced pain as hydrogel treatment reversed pain-related changes induced by PNI, including increased expression of a proinflammatory modulator, TNF-α, at injured nerve, activation of microglia and upregulation of pain-sensor receptor, TRPA1 at ipsilateral spinal dorsal horn. Nevertheless, supplementing the hydrogel with GDNF interrupted the PNI recovery process and probably counteracted the pain alleviation effect of the hydrogel. Thus, therapeutic effect of GDNF through local administration on PNI treatment needs to be further determined. In summary, our work provides a hydrogel delivery system with inherent therapeutic effect for PNI therapy.

Impaired Limb Functional Outcome of Peripheral Nerve Regeneration Is Marked by Incomplete Recovery of Paw Muscle Atrophy and Brain Functional Connectivity in a Rat Forearm Nerve Repair Model.

Skilled sensorimotor deficit is an unsolved problem of peripheral nerve injury (PNI) led by limb trauma or malignancies, despite the improvements in surgical techniques of peripheral nerve anastomosis. It is now accepted that successful functional recovery of PNI relies tremendously on the multilevel neural plasticity from the muscle to the brain. However, animal models that recapitulate these processes are still lacking. In this report, we developed a rat model of PNI to longitudinally assess peripheral muscle reinnervation and brain functional reorganization using noninvasive imaging technology. Based on such model, we compared the longitudinal changes of the rat forepaw intrinsic muscle volume and the seed-based functional connectivity of the sensorimotor cortex after nerve repair. We found that the improvement of skilled limb function and the recovery of paw intrinsic muscle following nerve regeneration are incomplete, which correlated with the functional connectivity between the primary motor cortex and dorsal striatum. Our results were highly relevant to the clinical observations and provided a framework for future investigations that aim to study the peripheral central sensorimotor circuitry underlying skilled limb function recovery after PNI.

Cortical plasticity and nerve regeneration after peripheral nerve injury.

With the development of neuroscience, substantial advances have been achieved in peripheral nerve regeneration over the past decades. However, peripheral nerve injury remains a critical public health problem because of the subsequent impairment or absence of sensorimotor function. Uncomfortable complications of peripheral nerve injury, such as chronic pain, can also cause problems for families and society. A number of studies have demonstrated that the proper functioning of the nervous system depends not only on a complete connection from the central nervous system to the surrounding targets at an anatomical level, but also on the continuous bilateral communication between the two. After peripheral nerve injury, the interruption of afferent and efferent signals can cause complex pathophysiological changes, including neurochemical alterations, modifications in the adaptability of excitatory and inhibitory neurons, and the reorganization of somatosensory and motor regions. This review discusses the close relationship between the cerebral cortex and peripheral nerves. We also focus on common therapies for peripheral nerve injury and summarize their potential mechanisms in relation to cortical plasticity. It has been suggested that cortical plasticity may be important for improving functional recovery after peripheral nerve damage. Further understanding of the potential common mechanisms between cortical reorganization and nerve injury will help to elucidate the pathophysiological processes of nerve injury, and may allow for the reduction of adverse consequences during peripheral nerve injury recovery. We also review the role that regulating reorganization mechanisms plays in functional recovery, and conclude with a suggestion to target cortical plasticity along with therapeutic interventions to promote peripheral nerve injury recovery.

Obligatory role of Schwann cell‐specific erythropoietin receptors in erythropoietin‐induced functional recovery and neurogenic muscle atrophy after nerve injury

Erythropoietin (EPO) promotes myelination and functional recovery in rodent peripheral nerve injury (PNI). While EPO receptors (EpoR) are present in Schwann cells, the role of EpoR in PNI recovery is unknown because of the lack of EpoR antagonists or Schwann cell-specific EpoR knockout animals. Using the Cre-loxP system, we developed a myelin protein zero (Mpz) promoter-driven knockout mouse model of Schwann cell EpoR (MpzCre-EpoRflox/flox , Mpz-EpoR-KO). Mpz-EpoR-KO and control mice were assigned to sciatic nerve crush injury followed by EPO treatment. EPO treatment significantly accelerated functional recovery in control mice in contrast to significantly reduced functional recovery in Mpz-EpoR-KO mice. Significant muscle atrophy was found in the injured hindlimb of EPO-treated Mpz-EpoR-KO mice but not in EPO-treated control mice. These preliminary findings provide direct evidence for an obligatory role of Schwann-cell specific EpoR for EPO-induced functional recovery and muscle atrophy following PNI.

High molecular weight form of hyaluronic acid reduces neuroinflammatory response in injured sciatic nerve via the intracellular domain of CD44.

Inflammatory response after peripheral nerve injury is required for clearance of tissue debris and effective regeneration. Studies have revealed that hyaluronic acid (HA) may exert different properties depending on their molecular size. High molecular weight HA (>>1,000 kDa; HMW-HA) displays immunosuppressive properties, whereas low molecular weight HA (<800 kDa; LMW-HA) induces proinflammatory responses. The role of HMW-HA interaction with CD44, a major HA receptor, in neuroinflammatory responses has not been fully elucidated. The purpose of this experimental study was to investigate the effects of topical applications of HMW-HA on the sciatic nerve injury in an adult rat model. At the crush site on the sciatic nerve, the recordings of compound muscle action potential (CMAP) and the levels of several proteins related to inflammatory response were assessed at time intervals of 2, 4, and 6 weeks postsurgery. Here, we show that the recovery effect of HMW-HA treatment had significantly shortened latency and increased amplitude of CMAP compared with crushed alone, crushed plus γ-secretase inhibitor with or without HA treatment at 6 weeks after surgery. Our data reveal that HMW-HA could downregulate the expression of IL1-β, TLR4, and MMP-9, whereas these proteins expression were increased when the CD44-ICD activity was inhibited using γ-secretase inhibitor. Our findings demonstrated a novel role of CD44-ICD in HA-mediated recovery of peripheral nerve injury. Clinical relevance: an alternative for the regeneration of peripheral nerve injury.

Melatonin promotes Schwann cell dedifferentiation and proliferation through the Ras/Raf/ERK and MAPK pathways, and glial cell‑derived neurotrophic factor expression

Upon peripheral nerve injury (PNI), continuous proliferation of Schwann cells is critical for axon regeneration and tubular reconstruction for nerve regeneration. Melatonin is a hormone that is able to induce proliferation in various cell types. In the present study, the effects of melatonin on promoting Schwann cell proliferation and the molecular mechanism involved were investigated. The present results showed that melatonin enhanced the melatonin receptors (MT1 and MT2) expression in Schwann cells. Melatonin induced Schwann cell dedifferentiation into progenitor-like Schwann cells, as observed by immunofluorescence staining, which showed Sox2 marker expression. In addition, melatonin enhanced Schwann cell proliferation, mediated by the upregulation of glial cell-derived neurotropic factor (GNDF) and protein kinase C (PKC). Furthermore, the Ras/Raf/ERK and MAPK signaling pathways were also involved in Schwann cell dedifferentiation and proliferation. In conclusion, melatonin induced Schwann cell dedifferentiation and proliferation via the Ras/Raf/ERK, MAPK and GDNF/PKC pathways. The present results suggested that melatonin could be used to enhance the recovery of PNI.

Brain plasticity after peripheral nerve injury treatment with massage therapy based on resting-state functional magnetic resonance imaging.

Massage therapy is an alternative treatment for chronic pain that is potentially related to brain plasticity. However, the underlying mechanism remains unclear. We established a peripheral nerve injury model in rats by unilateral sciatic nerve transection and direct anastomosis. The experimental rats were treated over the gastrocnemius muscle of the affected hindlimb with a customized massage instrument (0.45 N, 120 times/min, 10 minutes daily, for 4 successive weeks). Resting-state functional magnetic resonance imaging revealed that compared with control rats, the amplitude of low-frequency fluctuations in the sensorimotor cortex contralateral to the affected limb was significantly lower after sciatic nerve transection. However, amplitudes were significantly higher in the massage group than in a sham-massage group. These findings suggest that massage therapy facilitated adaptive change in the somatosensory cortex that led to the recovery of peripheral nerve injury and repair. This study was approved by the Animal Ethics Committee of Shanghai University of Traditional Chinese Medicine of China (approval No. 201701001) on January 12, 2017.