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Our group identified nucleus accumbens myocyte enhancer factor 2C as a targetable regulator of maladaptive behaviors and physiological changes after prolonged nerve injury. Supplemental Digital Content is Available in the Text. Preclinical and clinical work has demonstrated altered plasticity and activity in the nucleus accumbens (NAc) under chronic pain states, highlighting critical therapeutic avenues for the management of chronic pain conditions. In this study, we demonstrate that myocyte enhancer factor 2C (MEF2C), a master regulator of neuronal activity and plasticity, is repressed in NAc neurons after prolonged spared nerve injury (SNI). Viral-mediated overexpression of Mef2c in NAc neurons partially ameliorated sensory hypersensitivity and emotional behaviors in mice with SNI, while also altering transcriptional pathways associated with synaptic signaling. Mef2c overexpression also reversed SNI-induced potentiation of phasic dopamine release and neuronal hyperexcitability in the NAc. Transcriptional changes induced by Mef2c overexpression were different than those observed after desipramine treatment, suggesting a mechanism of action different from antidepressants. Overall, we show that interventions in MEF2C-regulated mechanisms in the NAc are sufficient to disrupt the maintenance of chronic pain states, providing potential new treatment avenues for neuropathic pain. [ABSTRACT FROM AUTHOR]

Pain after brachial plexus injury (BPI) can be severely debilitating and is poorly understood. We hypothesized that pain interference (PI) ("the extent to which pain hinders engagement in life") would be predicted by depression, anxiety, severity of pain symptoms, and poorer preoperative muscle function. Among patients in a prospective multicenter BPI cohort study, 37 completed Patient-Reported Outcomes Measurement Information System (PROMIS) PI questionnaires before and 1 year after surgery. At both times, participants completed anxiety and depression questionnaires and BPI-specific measures of pain symptoms, physical limitations, and emotional recovery. Surgeon-graded muscle testing, injury severity, age at the time of injury, body mass index, and time from injury to surgery were included. We performed a bivariate analysis of predictors for preoperative and 1-year PROMIS PI followed by multivariable regression modeling using stepwise selection and Bayesian Information Criterion to select covariates. Before surgery, the mean PROMIS PI score was 60.8 ± 11.0, with moderate correlations between PROMIS PI and depression, as well as between PROMIS PI and functional limitations. At 1 year after surgery, the mean PROMIS PI score was 59.7 ± 9.5. There was no difference in preoperative and 1-year PROMIS PI. There were strong correlations between PROMIS PI and pain symptoms, functional limitations, and emotional aspects of recovery at the 1-year follow-up that remained significant in multivariable regression. There were no notable associations between muscle testing and PI. Pain interference remained substantial and elevated in BPI patients 1 year after surgery. We noted strong associations between PI and pain symptoms, functional limitations, and emotional aspects of recovery. These findings demonstrate the persistence of pain as a feature throughout life after BPI and that its treatment should be considered a priority alongside efforts to improve extremity function. Prognosis IV. [ABSTRACT FROM AUTHOR]

Cutaneous neurapraxia is the most common complication following distal biceps tendon repair (DBTR). Currently, no patient demographic factors have been implicated in its occurrence, course, or resolution. The purpose of this study is to explore various patient demographics and their association with postoperative neurapraxia. Further it investigates how mental health scores correlate with patient-reported outcomes, and whether occurrence of neurapraxia alters this association. This retrospective review evaluates a consecutive series of patients who underwent distal biceps repair with a single-incision cortical button technique. Patients with reported outcome data at a minimum of 1 year (n = 47) were included for analysis. Demographic data including age, sex, body mass index, diabetes, smoking status, and occurrence of neurapraxia were recorded. Patient-reported outcome measures include the American Shoulder and Elbow Surgeons-Elbow score, Single Assessment Numeric Evaluation score, Visual Analog Scale for pain, Disabilities of the Arm, Shoulder, and Hand Score, and Veterans RAND 12 (VR-12) Mental Component Score and Physical Component Score quality-of-life assessment. Postoperative neurapraxia of any duration occurred in 45% (21/47) of patients in this cohort following DBTR. Of these, 62% (13/21) reported resolution of symptoms by the latest follow-up. Mean time to resolution of neurapraxia was 148 days. Patient age, body mass index, smoking history, time to surgery, tear thickness, and increasing surgeon experience across the study period were not significantly associated with the incidence or time to resolution of postoperative neurapraxia. Scores for patient satisfaction, Visual Analog Scale, American Shoulder and Elbow Surgeons, Disabilities of the Arm, Shoulder, and Hand Score, Single Assessment Numeric Evaluation, VR-12 Mental Component Score, VR-12 Physical Component Score, and flexion ROM did not differ significantly between patients with and without postoperative neurapraxia. Patient satisfaction following DBTR was not significantly associated with postoperative neurapraxia. Patient and surgical characteristics did not influence the occurrence or time to resolution of neurapraxia. The occurrence of postoperative neurapraxia did not result in significant functional limitations. [ABSTRACT FROM AUTHOR]

Improved treatment options are urgently needed for neurological injuries resulting from trauma or iatrogenic events causing long-term disabilities that severely impact patients' quality of life. In vitro and animal studies have provided promising proof-of-concept examples of regenerative therapies using mesenchymal stromal cells (MSC) for a wide range of pathological conditions. Over the previous decade, various MSC-based therapies have been investigated in clinical trials to treat traumatic neurological injuries. However, while the safety and feasibility of MSC treatments has been established, the patient outcomes in these studies have not demonstrated significant success in the translation of MSC regenerative therapy for the treatment of human brain and spinal cord injuries. Herein, we have reviewed the literature and ongoing registered trials on the application of MSC for the treatment of traumatic brain injury, traumatic spinal cord injury, and peripheral nerve injury. We have focused on the shortcomings and technological hurdles that must be overcome to further advance clinical research to phase 3 trials, and we discuss recent advancements that represent potential solutions to these obstacles to progress. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury significantly impairs sensory and motor functions, leading to diminished quality of life. Traditional treatments like nerve suturing and grafting often have limited efficacy and require long recovery. Recent advances in electrical stimulation technology show promise in speeding nerve repair, but current devices usually require lengthy surgeries, risking secondary nerve injury from prolonged nerve exposure during electrode installation and removal. This study introduces a portable, absorbable electrical stimulation system (PAESS) that integrates a battery‐free, wirelessly powered flexible printed circuit board chip with a biodegradable organic electrode. PAESS enables multiple self‐administered nerve stimulation without the need for electrode installation or removal. Using animal models, its electrical performance, biocompatibility, and efficacy in nerve repair are evaluated. The findings indicate a considerable enhancement in the recovery of nerve function, as demonstrated by improved electrophysiological measurements, decreased muscle atrophy, and positive histological results. Transcriptomic analysis indicates that the PAESS initiates the nerve regeneration process. This research presents an innovative platform for electrical stimulation, laying the groundwork for exploring electrical parameters and their mechanisms. This may deepen understanding of nerve regeneration and foster innovation in therapies. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated a possible association between cognitive impairments and traumatic upper limb injuries. This study aims to track the cognitive changes in individuals with such injuries. In this longitudinal study, 36 participants with traumatic upper limb injuries and 36 uninjured participants were enrolled. Cognitive functions were assessed using the Rey Auditory Verbal Learning Test (RAVLT) and the Stroop Color and Word Test (SCWT) over a period of 6 months, with evaluations conducted on three occasions: 1 month (T1), 3 months (T2), and 6 months (T3). The results revealed that participants with nerve injuries exhibited significantly lower RAVLT scores overall and at each time point (Overall: Wald χ2 = 7.99, P < .05; T1: Wald χ2 = 7.61, P < .05; T2: Wald χ2 = 5.95, P < .05; T3: Wald χ2 = 5.76, P < .05). In contrast, no significant impairment in RAVLT performance was observed in participants without nerve injuries. Additionally, the SCWT showed no significant differences between injured and uninjured participants over the six-month period (P > .05). In conclusion, traumatic nerve injuries to the upper limbs negatively affect memory, and this impairment does not spontaneously recover within six months. [ABSTRACT FROM AUTHOR]

Introduction Method Results Discussion The epidermal growth factor receptor (EGFR; ErbB1), a membrane bound receptor tyrosine kinase, is hypothesized to have an inhibitory influence on peripheral nerve regeneration. This study examines the impact of EGFR inhibition on nerve regeneration using the commercially available small molecule inhibitor gefitinib.In vitro assays included neurite outgrowth of cultured dorsal root ganglion (DRG) neurons from adult C57Bl/6 wildtype mice on immobilized chondroitin sulfate proteoglycans (CSPG). Following forelimb median nerve injury, EGFR expression, number of regenerated neurons (using retrograde labeling) and myelination of motor and sensory neurons were compared between mice that received either gefitinib or vehicle. Functional recovery was assessed using grip strength.EGFR expression on DRG and spinal motor neurons was confirmed. Gefitinib significantly increased neurite outgrowth in medium sized (30–50 μm) DRG neurons, resulting in longer neurites (183 ± 36 μm) compared with CSPG alone (49 ± 9 μm). After median nerve injury, significantly greater numbers of sensory neurons (638 ± 112 vs. 301 ± 81), but not motor neurons (31 ± 12 vs. 42 ± 13) regenerated in animals treated with gefitinib compared with controls. Regenerated axons in gefitinib treated animals displayed significantly greater diameter and increased g‐ratio compared with controls. Grip strength recovered more quickly in animals receiving gefitinib compared with controls (27.6 vs. 19.1 g 18 days post‐injury).This study provides data supporting the role of EGFR as a negative regulator of sensory but not motor neuron regeneration. Further, it demonstrates versatile potential uses of existing pharmaceuticals. [ABSTRACT FROM AUTHOR]

• Comprehensively synthesize the functional features of OECs. • The function and mechanism of OECs in the repair of peripheral nerve injury were discussed. • Application of OECs in the treatment of pathological pain induced by peripheral nerve injury was discussed. Direct or indirect injury of peripheral nerve can lead to sensory and motor dysfunction, which can lead to pathological pain and seriously affect the quality of life and psychosomatic health of patients. While the internal repair function of the body after peripheral nerve injury is limited. Nerve regeneration is the key factor hindering the recovery of nerve function. At present, there is no effective treatment. Therefore, more and more attention have been paid to the development of foreground treatment to achieve functional recovery after peripheral nerve injury, including relief of pathological pain. Cell transplantation strategy is a therapeutic method with development potential in recent years, which can exert endogenous alternative repair by transplanting exogenous functional bioactive cells to the site of nerve injury. Olfactory ensheathing cells (OECs) are a special kind of glial cells, which have the characteristics of continuous renewal and survival. The mechanisms of promoting nerve regeneration and functional repair and relieving pathological pain by transplantation of OECs to peripheral nerve injury include secretion of a variety of neurotrophic factors, axonal regeneration and myelination, immune regulation, anti-inflammation, neuroprotection, promotion of vascular growth and improvement of inflammatory microenvironment around nerve injury. Different studies have shown that OECs combined with biomaterials have made some progress in the treatment of peripheral nerve injury and pathological pain. These biomaterials enhance the therapeutic effect of OECs. Therefore, the functional role of OECs in peripheral nerve injury and pathological pain was discussed in this paper. Although OECs are in the primary stage of exploration in the repair of peripheral nerve injury and the application of pain, but OECs transplantation may become a prospective therapeutic strategy for the treatment of peripheral nerve injury and pathological pain. [ABSTRACT FROM AUTHOR]

Peripheral neuropathic pain is common in patients with peripheral nerve injury and can significantly impact both their function and quality of life. There is a wide variety of non‐interventional treatment approaches, including pharmacologic therapy, physical/occupational therapy, modalities (therapeutic, mechanical, thermal, etc.), psychology, and lifestyle modification. First line pharmacologic therapy for peripheral neuropathic pain includes gabapentinoids, tricyclic antidepressants, and serotonin‐norepinephrine reuptake inhibitors. Other classes of medications, such as topical treatments, opioids, and cannabinoids, have more limited usefulness in treatment but remain part of a treatment regimen. Physical and occupational therapy, psychological interventions, and lifestyle medicine are important adjuncts in the treatment and prevention of future peripheral neuropathic pain. The strength of the evidence supporting each intervention varies, with that for pharmacologic intervention being the strongest. A combination of these options tailored to the individual needs of the patient likely will result in the best treatment outcome for peripheral neuropathic pain. [ABSTRACT FROM AUTHOR]

Injury to the peripheral nervous system disconnects targets to the central nervous system, disrupts signal transmission, and results in functional disability. Although surgical and therapeutic treatments improve nerve regeneration, it is generally hard to achieve fully functional recovery after severe peripheral nerve injury. A better understanding of pathological changes after peripheral nerve injury helps the development of promising treatments for nerve regeneration. Single-cell analyses of the peripheral nervous system under physiological and injury conditions define the diversity of cells in peripheral nerves and reveal cell-specific injury responses. Herein, we review recent findings on the single-cell transcriptome status in the dorsal root ganglia and peripheral nerves following peripheral nerve injury, identify the cell heterogeneity of peripheral nerves, and delineate changes in injured peripheral nerves, especially molecular changes in neurons, glial cells, and immune cells. Cell-cell interactions in peripheral nerves are also characterized based on ligand-receptor pairs from coordinated gene expressions. The understanding of cellular changes following peripheral nerve injury at a single-cell resolution offers a comprehensive and insightful view for the peripheral nerve repair process, provides an important basis for the exploration of the key regulators of neuronal growth and microenvironment reconstruction, and benefits the development of novel therapeutic drugs for the treatment of peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Introduction: Ferroptosis is a new type of cell death characterized by lipid peroxidation and iron dependency, representing an emerging disease regulation mechanism. The limited understanding of ferroptosis in peripheral nerve injury (PNI) complicates the management of such injuries. Mitochondrial dysfunction, which contributes to ferroptosis, further exacerbates the challenges of peripheral nerve repair Methods: In this study, we established an in vitro model of Schwann cells model treated with TBHP and an in vivo sciatic nerve crush injury model in rats. These models were used to investigate the effects of fibroblast growth factor 21 (FGF21) on PNI, both in vitro and in vivo, and to explore the potential mechanisms linking injury-induced ferroptosis and mitochondrial dysfunction. Results: Our findings reveal that PNI triggers abnormal accumulation of lipid reactive oxygen species (ROS) and inactivates mitochondrial respiratory chain complex III, leading to mitochondrial dysfunction. This dysfunction catalyzes the oxidation of excessive polyunsaturated fatty acids, resulting in antioxidant imbalance and loss of ferroptosis suppressor protein 1 (FSP1), which drives lipid peroxidation. Additionally, irregular iron metabolism, defective mitophagy, and other factors contribute to the induction of ferroptosis. Importantly, we found that FGF21 attenuates the abnormal accumulation of lipid ROS, restores mitochondrial function, and suppresses ferroptosis, thus promoting PNI repair. Notably, glutathione peroxidase 4 (GPX4), a downstream target of nuclear factor E2-related factor 2 (Nrf2), and the ERK/Nrf2 pathway are involved in the regulation of ferroptosis by FGF21. Conclusion: FGF21 promotes peripheral nerve repair by inhibiting ferroptosis caused by mitochondrial dysfunction. Therefore, targeting mitochondria and ferroptosis represents a promising therapeutic strategy for effective PNI repair. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to determine the incidence, necessity for neurosurgical intervention, and overall results of the treatment of pediatric peripheral nerve injuries associated with dislocated supracondylar fractures of the distal humerus. Method: A retrospective analysis of pediatric patients with supracondylar fractures treated from April 2019 to April 2022 with a minimum follow-up of 3 months was conducted. Results: Of 453 included patients, there were 51 recorded peripheral nerve injuries. The ulnar nerve was the most frequently injured nerve. Nine patients required neurosurgical intervention, with the most common procedure being the release of entrapped nerves. The combination of a supracondylar fracture and arterial injury was identified as a significant risk factor for peripheral nerve injury (p < 0.001). Only one patient experienced an unsatisfactory outcome. Conclusion: Although the prognosis for peripheral nerve injuries in children with supracondylar fractures is generally favorable, these injuries must be properly identified. We recommend an active neurosurgical approach in children with persisting neurological deficits to minimize the risk of permanent neurological impairment. [ABSTRACT FROM AUTHOR]

Background: Muscle atrophy caused by denervation is common in neuromuscular diseases, leading to loss of muscle mass and function. However, a comprehensive understanding of the overall molecular network changes during muscle denervation atrophy is still deficient, hindering the development of effective treatments. Method: In this study, a sciatic nerve transection model was employed in male C57BL/6 J mice to induce muscle denervation atrophy. Gastrocnemius muscles were harvested at 3 days, 2 weeks, and 4 weeks post-denervation for transcriptomic and proteomic analysis. An integrative multi-omics approach was utilized to identify key genes essential for disease progression. Targeted proteomics using PRM was then employed to validate the differential expression of central genes. Combine single-nucleus sequencing results to observe the expression levels of PRM-validated genes in different cell types within muscle tissue.Through upstream regulatory analysis, NRF2 was identified as a potential therapeutic target. The therapeutic potential of the NRF2-targeting drug Omaveloxolone was evaluated in the mouse model. Result: This research examined the temporal alterations in transcripts and proteins during muscle atrophy subsequent to denervation. A comprehensive analysis identified 54,534 transcripts and 3,218 proteins, of which 23,282 transcripts and 1,852 proteins exhibited statistically significant changes at 3 days, 2 weeks, and 4 weeks post-denervation. Utilizing multi-omics approaches, 30 hubgenes were selected, and PRM validation confirmed significant expression variances in 23 genes. The findings highlighted the involvement of mitochondrial dysfunction, oxidative stress, and metabolic disturbances in the pathogenesis of muscle atrophy, with a pronounced impact on type II muscle fibers, particularly type IIb fibers. The potential therapeutic benefits of Omaveloxolone in mitigating oxidative stress and preserving mitochondrial morphology were confirmed, thereby presenting novel strategies for addressing muscle atrophy induced by denervation. GSEA analysis results show that Autophagy, glutathione metabolism, and PPAR signaling pathways are significantly upregulated, while inflammation-related and neurodegenerative disease-related pathways are significantly inhibited in the Omaveloxolone group.GSR expression and the GSH/GSSG ratio were significantly higher in the Omaveloxolone group compared to the control group, while MuSK expression was significantly lower than in the control group. Conclusion: In our study, we revealed the crucial role of oxidative stress, glucose metabolism, and mitochondrial dysfunction in denervation-induced muscle atrophy, identifying NRF2 as a potential therapeutic target. Omaveloxolone was shown to stabilize mitochondrial function, enhance antioxidant capacity, and protect neuromuscular junctions, thereby offering promising therapeutic potential for treating denervation-induced muscle atrophy. [ABSTRACT FROM AUTHOR]

Nerve injury-induced changes in gene expression in the dorsal root ganglion (DRG) contribute to the genesis of neuropathic pain. SYNCRIP, an RNA-binding protein, is critical for the stabilisation of gene expression. Whether SYNCRIP participates in nerve injury-induced alterations in DRG gene expression and nociceptive hypersensitivity is unknown. The expression and distribution of SYNCRIP in mouse DRG after chronic constriction injury (CCI) of the unilateral sciatic nerve were assessed. Effect of microinjection of Syncrip small interfering RNA into the ipsilateral L3 and L4 DRGs on the CCI-induced upregulation of chemokine (C-C motif) receptor 2 (CCR2) and nociceptive hypersensitivity were examined. Additionally, effects of microinjection of adeno-associated virus 5 expressing full length Syncrip mRNA (AAV5- Syncrip) on basal DRG CCR2 expression and nociceptive thresholds were observed. SYNCRIP is expressed predominantly in DRG neurones, where it co-exists with CCR2. Levels of Syncrip mRNA and SYNCRIP protein in injured DRG increased time-dependently on days 3–14 after CCI. Blocking this increase through microinjection of Syncrip small interfering RNA into injured DRG attenuated CCI-induced upregulation of DRG CCR2 and development and maintenance of nociceptive hypersensitivities. Mimicking this increase through DRG microinjection of AAV5- Syncrip elevated CCR2 expression in microinjected DRGs, enhanced the responses to mechanical, heat, and cold stimuli, and induced ongoing pain in naive mice. Mechanistically, SYNCRIP bound to 3-UTR of Ccr2 mRNA and stabilised its expression in DRG neurones. SYNCRIP contributes to the induction and maintenance of neuropathic pain likely through stabilising expression of CCR2 in injured DRG. SYNCRIP may be a potential target for treating this disorder. [ABSTRACT FROM AUTHOR]

Background We explore a minimally invasive method (combined ultrasound detection, electrode placement and electrophysiologic nerve examination) to evaluate the early-stage quality of a nerve suture site. Methods Ten patients with median and/or ulnar nerve injuries who had undergone nerve suture were recruited. Postoperative ultrasound examination found that the nerve injury was sutured. Then, a stimulating electrode and recording electrode were located beside the nerve proximal and distal to the suture site guided by ultrasound. Measurement of nerve action potentials (NAP) were performed with these electrodes, followed by surgical exploration. The pre- and intraoperative electrophysiologic findings were compared, together with amplitude, latency, and wave shape of NAP. Results Of the 10 patients, 3 patients were diagnosed with median nerve injury, 2 with ulnar nerve injury, and 5 with the median nerve and ulnar nerve injury. NAP could not be detected pre- and intraoperatively in three median nerves from three patients and in two ulnar nerves from two patients. NAP was detected in 10 nerves from the remaining 5 patients. The pre- and intraoperative NAP results showed consistent results concerning the status of the nerve suture. Wilcoxon's signed-rank test indicated no significant difference in the amplitude and latency detected via sonographically placed electrodes and during surgical exploration. The number of negative-phase waves were equally distributed. Conclusion Ultrasound-guided electrode placement and NAP detection can substitute surgery and serve as a minimally invasive approach to evaluate the regeneration of a sutured nerve. [ABSTRACT FROM AUTHOR]

• IL-35 reduces mechanical pain more prominently in male than female mice with CCI. • CCI induces inflammatory microglial markers in the spinal cord dorsal horn. • IL-35 dampens expression of inflammatory microglial markers in male mice. • IL-35 promotes expression of anti-inflammatory microglial markers in male mice. • IL-35 alters phenotype, phagocytosis, and cytokines in male microglial cultures. Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomic analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro , suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain. [ABSTRACT FROM AUTHOR]

Peripheral nerve repair is daily activity for several microsurgeons. Numerous nerve repair techniques are applied, including neurorrhaphy, nerve grafting and nerve transfer, depending on the nature and extent of the injury. However, these techniques become unfeasible when the distal nerve end is not preserved during the peripheral nerve injury or a segment of the muscle is transferred without the nerve supplying it. However, direct muscle neurotization (DMN) achieves muscle reinnervation by suturing the nerve directly into the muscle tissue, without requiring a distal nerve end for coaptation. Despite promising results in the literature, DMN is not widely adopted in clinical practice. Animal models may help in advancing novel therapeutic approaches, due to their anatomic and physiologic similarities to humans. This review highlights the current scientific understanding and recent advancements in DMN as well as the animal models and target muscle that have been used in the past to investigate the basic principles behind this surgical technique. The presented information should aid in establishing the clinical importance of DMN in peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Background: Taste buds' innervation is necessary to sustain their cell turnover, differentiated taste buds and nerve fibers in circumvallate papilla (CVP) disappear following glossopharyngeal nerve transection. Normally, taste buds recover to baseline number in about 70 days. Bone marrow stem cell (BM-MSC) derived exosomes or their combination with Zinc chloride are used to assess their potential to speed up the regeneration process of CVP following bilateral deafferentation. Methods: Twenty-eight male Sprague-Dawley rats were randomly divided into four groups; Group I: subjected to sham operation followed by IP injection of saline. The other experimental groups (II, III and IV) were subjected to surgical bilateral transection of glossopharyngeal nerve. Group II received single IP injection of saline. Group III received single IV injection of BM-MSC-derived exosomes (100 µg). Group IV received single IV injection of BM-MSC-derived exosomes and single IP injection of zinc chloride (5 mg/kg). After 28 days, CVP was dissected and prepared for histological and histomorphometric analysis, RT-PCR for cytokeratin 8 gene expression, ELISA to assess protein level of brain-derived neurotrophic factor, redox state analysis of malondialdehyde and glutathione content, followed by statistical analysis. Results: Histopathologically, group II exhibited great tissue damage with marked reduction in taste buds and signs of degeneration in the remaining ones. Group III was close to control group with marked improvement in taste buds' number and structure. Group IV showed inferior results when compared to group III, with many immature taste buds and signs of degeneration. Statistical results showed that groups I and III have significantly higher values than groups II and IV regarding taste buds' number, cytokeratin 8, and reduced glutathione. However, malondialdehyde demonstrated high significant values in group IV compared to groups I and III. Regarding brain-derived neurotrophic factor, group III had significantly higher values than group II. Conclusion: BM-MSC-derived exosomes have superior regenerative potentials in acceleration of CVP and nerve healing following bilateral transection of glossopharyngeal nerve in contrary to its combination with zinc chloride. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Interpretation After peripheral nerve stretch injury, most degenerating axons are thought to become disconnected at the time of injury, referred to as primary axotomy. The possibility of secondary axotomy—a delayed and potentially reversible form of disconnection—has not been evaluated. Here, we investigated secondary axotomy in a rat model of sciatic nerve stretch injury. We also evaluated whether axon sparing and functional improvement results from pharmacological blockade of the sodium‐calcium exchanger 1 (NCX1), which is widely believed to contribute to traumatic axon degeneration but was previously only investigated in vitro.We studied peripheral nerve secondary axotomy in a clinically relevant rat model of sciatic nerve rapid stretch injury with immunolabeling and fluorescence microscopy. The role of NCX1 in secondary axotomy was studied with pharmacological inhibition with SEA0400 and immunolabeling, immunoblot, and behavioral assays.We found that early after injury, many axons remained in‐continuity and that degeneration of axons was delayed, consistent with the occurrence of secondary axotomy. βAPP, a marker of secondary axotomy, accumulated at regions of axon swelling and disconnection, and NCX1 was upregulated and co‐localized to βAPP axonal swellings. Pharmacological blockade of NCX1 after injury reduced calpain activation, proteolytic degradation of neurofilaments, βAPP accumulation, distal axon degeneration, and improved hindlimb function.Our data demonstrate a major role for secondary axotomy in peripheral nerve stretch injury and identify NCX1 as a promising therapeutic target to reduce secondary axotomy and improve functional outcome after nerve injury. [ABSTRACT FROM AUTHOR]

Injury to the peripheral nervous system disconnects targets to the central nervous system, disrupts signal transmission, and results in functional disability. Although surgical and therapeutic treatments improve nerve regeneration, it is generally hard to achieve fully functional recovery after severe peripheral nerve injury. A better understanding of pathological changes after peripheral nerve injury helps the development of promising treatments for nerve regeneration. Single-cell analyses of the peripheral nervous system under physiological and injury conditions define the diversity of cells in peripheral nerves and reveal cellspecific injury responses. Herein, we review recent findings on the single-cell transcriptome status in the dorsal root ganglia and peripheral nerves following peripheral nerve injury, identify the cell heterogeneity of peripheral nerves, and delineate changes in injured peripheral nerves, especially molecular changes in neurons, glial cells, and immune cells. Cell-cell interactions in peripheral nerves are also characterized based on ligand-receptor pairs from coordinated gene expressions. The understanding of cellular changes following peripheral nerve injury at a single-cell resolution offers a comprehensive and insightful view for the peripheral nerve repair process, provides an important basis for the exploration of the key regulators of neuronal growth and microenvironment reconstruction, and benefits the development of novel therapeutic drugs for the treatment of peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Background: Although peripheral nerve injury is not life-threatening, it causes significant disability. Following these damages, ischemia and inflammatory processes occur, resulting in neurological dysfunction. Several medications have been explored to alleviate the symptoms of peripheral nerve injury. Objectives: This study aimed to investigate how crocin (CR) and azithromycin (AZ) affected sciatic nerve crush injuries in rats. Materials & Methods: Five groups were established using 40 adult male rats: control, lesion, AZ, CR and AZ+CR. Except for the control group, sciatic nerve injury was surgically induced in the other groups. AZ and CR were administered alone or together to three treatment groups for seven days. Following the behavioral evaluations, sections of the sciatic nerve were stained for immunohistochemical, histological and morphometric assessment. Results: CR treatment's efficacy was more pronounced than AZ's (P=0.001). CR was found to be less efficacious than combination therapy involving AZ and CR, as determined by sciatic functional index (P=0.001), hot plate (P=0.001), and immunohistochemical analysis (P=0.001). In the remaining evaluations, no significant difference existed between the AZ+CR and CR groups (P> 0.05). Conclusion: This study found that both AZ and CR significantly improved the recovery of sciatic nerve injuries in rats, with CR being more effective. The combination of AZ and CR showed even greater benefits in some assessments compared to CR alone, although no significant differences were observed in other evaluations. These findings suggest that CR is a promising treatment for peripheral nerve injury and that combination therapy may enhance certain aspects of recovery. [ABSTRACT FROM AUTHOR]

Objective: To observe the effects of Jiaji electroacupuncture combined with treadmill running training on tibial bone density, volume and number of blood vessels and VEGF expression after sciatic nerve amputation injury in rats, and provide theoretical basis for promoting tibial reconstruction after Jiaji electroacupuncture combined with treadmill running training. Method: A total of 180 SD rats were randomly divided into normal control group, model control group, Jiaji electroacupuncture group, treadmill group, combination treatment group (Jiaji electroacupuncture + treadmill), with 36 rats in each group. After 2, 4 and 8 weeks of postoperative intervention, the rats were divided into 3 subgroups, 12 in each subgroup. The model was made by suture of sciatic nerve dissociation injury. The normal control group received no intervention; the model control group received no intervention post-modeling. The Jiaji electroacupuncture group, treadmill group and combined group began to receive Jiaji electroacupunc ture, treadmill training and combined treatment respectively on the 3rd day after surgery. Bone density of tibia was analyzed by Micro-CT scan. The number and volume of the proximal tibial vessels were analyzed by angiography. The expression of VEGF mRNA and protein in tibia was detected by RT- PCR and Western Blot. VEGF concentration in tibial bone marrow was determined by ELISA. Result: At 2, 4 and 8 weeks post- intervention, the model control group showed significantly lower tibial bone mineral density, proximal vascular volume and quantity, VEGF mRNA and protein expression in bone tissue, and VEGF concentration in bone marrow compared to the normal control group at the same time point (P<0.05). However, overtime, the tibial bone mineral density, the volume and number of proximal blood vessels, VEGF mRNA and protein expression in bone tissue and VEGF concentration in bone marrow of rats in the Jiaji electroacupuncture group, treadmill group and combination group were significantly higher than those in the model control group at the same time point (P<0.05), and the combination group showed the most pronounced effects (P<0.05). Conclusion: Jiaji electroacupuncture combined with treadmill training may improve tibial bone mineral density by up-regulating the expression of VEGF in tibia and bone marrow. [ABSTRACT FROM AUTHOR]

Simple Summary: Radixin is a cytoskeletal-associated protein, a member of the ERM (ezrin, radixin, and moesin) protein family. Radixin plays important roles in cell shape, growth, and motility after activation by phosphorylation of its conserved threonine residues. Radixin functions as a relay in cell signaling pathways by binding to membrane proteins and transferring the cell signals into the cells. The pathogenic function of radixin has been found in central nervous system diseases, peripheral nerve injury, and cancers. We recently found significantly altered radixin in Schwann cells during elevated glucose, suggesting that it may be related to diabetes-induced nerve injury. As a result, the insight review into the roles of radixin and its associated cell signaling pathways may facilitate finding novel therapeutic targets for associated diseases. Background: Radixin is an ERM family protein that includes radixin, moesin, and ezrin. The importance of ERM family proteins has been attracting more attention, and studies on the roles of ERM in biological function and the pathogenesis of some diseases are accumulating. In particular, we have found that radixin is the most dramatically changed ERM protein in elevated glucose-treated Schwann cells. Method: We systemically review the literature on ERM, radixin in focus, and update the roles of radixin in regulating cell morphology, interaction, and cell signaling pathways. The potential of radixin as a therapeutic target in neurodegenerative diseases and cancer was also discussed. Results: Radixin research has focused on its cell functions, activation, and pathogenic roles in some diseases. Radixin and other ERM proteins maintain cell shape, growth, and motility. In the nervous system, radixin has been shown to prevent neurodegeneration and axonal growth. The activation of radixin is through phosphorylation of its conserved threonine residues. Radixin functions in cell signaling pathways by binding to membrane proteins and relaying the cell signals into the cells. Deficiency of radixin has been involved in the pathogenic process of diseases in the central nervous system and diabetic peripheral nerve injury. Moreover, radixin also plays a role in cell growth and drug resistance in multiple cancers. The trials of therapeutic potential through radixin modulation have been accumulating. However, the exact mechanisms underlying the roles of radixin are far from clarification. Conclusions: Radixin plays various roles in cells and is involved in developing neurodegenerative diseases and many types of cancers. Therefore, radixin may be considered a potential target for developing therapeutic strategies for its related diseases. Further elucidation of the function and the cell signaling pathways that are linked to radixin may open the avenue to finding novel therapeutic strategies for diseases in the nervous system and other body systems. [ABSTRACT FROM AUTHOR]

Abstract Improved treatment options are urgently needed for neurological injuries resulting from trauma or iatrogenic events causing long-term disabilities that severely impact patients’ quality of life. In vitro and animal studies have provided promising proof-of-concept examples of regenerative therapies using mesenchymal stromal cells (MSC) for a wide range of pathological conditions. Over the previous decade, various MSC-based therapies have been investigated in clinical trials to treat traumatic neurological injuries. However, while the safety and feasibility of MSC treatments has been established, the patient outcomes in these studies have not demonstrated significant success in the translation of MSC regenerative therapy for the treatment of human brain and spinal cord injuries. Herein, we have reviewed the literature and ongoing registered trials on the application of MSC for the treatment of traumatic brain injury, traumatic spinal cord injury, and peripheral nerve injury. We have focused on the shortcomings and technological hurdles that must be overcome to further advance clinical research to phase 3 trials, and we discuss recent advancements that represent potential solutions to these obstacles to progress.

Abstract Background Muscle atrophy caused by denervation is common in neuromuscular diseases, leading to loss of muscle mass and function. However, a comprehensive understanding of the overall molecular network changes during muscle denervation atrophy is still deficient, hindering the development of effective treatments. Method In this study, a sciatic nerve transection model was employed in male C57BL/6 J mice to induce muscle denervation atrophy. Gastrocnemius muscles were harvested at 3 days, 2 weeks, and 4 weeks post-denervation for transcriptomic and proteomic analysis. An integrative multi-omics approach was utilized to identify key genes essential for disease progression. Targeted proteomics using PRM was then employed to validate the differential expression of central genes. Combine single-nucleus sequencing results to observe the expression levels of PRM-validated genes in different cell types within muscle tissue.Through upstream regulatory analysis, NRF2 was identified as a potential therapeutic target. The therapeutic potential of the NRF2-targeting drug Omaveloxolone was evaluated in the mouse model. Result This research examined the temporal alterations in transcripts and proteins during muscle atrophy subsequent to denervation. A comprehensive analysis identified 54,534 transcripts and 3,218 proteins, of which 23,282 transcripts and 1,852 proteins exhibited statistically significant changes at 3 days, 2 weeks, and 4 weeks post-denervation. Utilizing multi-omics approaches, 30 hubgenes were selected, and PRM validation confirmed significant expression variances in 23 genes. The findings highlighted the involvement of mitochondrial dysfunction, oxidative stress, and metabolic disturbances in the pathogenesis of muscle atrophy, with a pronounced impact on type II muscle fibers, particularly type IIb fibers. The potential therapeutic benefits of Omaveloxolone in mitigating oxidative stress and preserving mitochondrial morphology were confirmed, thereby presenting novel strategies for addressing muscle atrophy induced by denervation. GSEA analysis results show that Autophagy, glutathione metabolism, and PPAR signaling pathways are significantly upregulated, while inflammation-related and neurodegenerative disease-related pathways are significantly inhibited in the Omaveloxolone group.GSR expression and the GSH/GSSG ratio were significantly higher in the Omaveloxolone group compared to the control group, while MuSK expression was significantly lower than in the control group. Conclusion In our study, we revealed the crucial role of oxidative stress, glucose metabolism, and mitochondrial dysfunction in denervation-induced muscle atrophy, identifying NRF2 as a potential therapeutic target. Omaveloxolone was shown to stabilize mitochondrial function, enhance antioxidant capacity, and protect neuromuscular junctions, thereby offering promising therapeutic potential for treating denervation-induced muscle atrophy. Graphical Abstract

Abstract Background Taste buds’ innervation is necessary to sustain their cell turnover, differentiated taste buds and nerve fibers in circumvallate papilla (CVP) disappear following glossopharyngeal nerve transection. Normally, taste buds recover to baseline number in about 70 days. Bone marrow stem cell (BM-MSC) derived exosomes or their combination with Zinc chloride are used to assess their potential to speed up the regeneration process of CVP following bilateral deafferentation. Methods Twenty-eight male Sprague-Dawley rats were randomly divided into four groups; Group I: subjected to sham operation followed by IP injection of saline. The other experimental groups (II, III and IV) were subjected to surgical bilateral transection of glossopharyngeal nerve. Group II received single IP injection of saline. Group III received single IV injection of BM-MSC-derived exosomes (100 µg). Group IV received single IV injection of BM-MSC-derived exosomes and single IP injection of zinc chloride (5 mg/kg). After 28 days, CVP was dissected and prepared for histological and histomorphometric analysis, RT-PCR for cytokeratin 8 gene expression, ELISA to assess protein level of brain-derived neurotrophic factor, redox state analysis of malondialdehyde and glutathione content, followed by statistical analysis. Results Histopathologically, group II exhibited great tissue damage with marked reduction in taste buds and signs of degeneration in the remaining ones. Group III was close to control group with marked improvement in taste buds’ number and structure. Group IV showed inferior results when compared to group III, with many immature taste buds and signs of degeneration. Statistical results showed that groups I and III have significantly higher values than groups II and IV regarding taste buds’ number, cytokeratin 8, and reduced glutathione. However, malondialdehyde demonstrated high significant values in group IV compared to groups I and III. Regarding brain-derived neurotrophic factor, group III had significantly higher values than group II. Conclusion BM-MSC-derived exosomes have superior regenerative potentials in acceleration of CVP and nerve healing following bilateral transection of glossopharyngeal nerve in contrary to its combination with zinc chloride. Graphical Abstract

BACKGROUND: Pravastatin is a clinically effective drug for the treatment of hypercholesterolemia and is now found to play a beneficial role in the treatment of CNS injury; however, the mechanism remains unknown. OBJECTIVE: To ascertain the possible mechanism of action and whether pravastatin medication can expedite functional recovery following sciatic nerve crush injury. METHODS: Male Sprague-Dawley rats were randomly assigned into: pravastatin (sciatic nerve crush injury+pravastatin gavage), negative control (sciatic nerve crush injury+saline gavage), and sham operation (sciatic nerve exposure but no injury+saline gavage). While the other two groups received comparable amounts of saline gavage, the pravastatin group received postoperative pravastatin (5 mg/kg) by gavage for 1 week. The general conditions of the rats in each group were observed after operation. Sciatic function index was evaluated at the end of the 2nd, 4th, 6th, and 8th week after operation, and the wet mass ratio of the gastrocnemius muscle was measured at the end of the 8th week after operation. The levels of inflammatory cytokines in serum were measured using ELISA. Histomorphometrics was used to measure the number of myelinated nerve fibers, fiber diameter, axon diameter, and myelin sheath thickness. RT-qPCR assay was used to measure the relative mRNA expression of nerve growth factor and brain-derived neurotrophic factor, and western blot was used to measure the protein expression of growth-associated protein 43. RESULTS AND CONCLUSION: Compared with the negative control group, the sciatic function index in the pravastatin group recovered faster (P < 0.05) and was closer to the level of the sham operation group, the expression of tumor necrosis factor α and interleukin 6 in serum was lower (P < 0.05) and close to that of the sham operation group, and the relative mRNA expression of nerve growth factor and brain-derived neurotrophic factor in the sciatic nerve increased (P < 0.05 or P < 0.01), the relative protein expression of growth-associated protein 43 in the sciatic nerve was also significantly increased (P < 0.05), the number of myelinated nerve fibers was increased more, and the values of fiber diameter, axon diameter, and myelin sheath thickness were larger (P < 0.01) and closer to those of the sham operation group. To conclude, treatment with pravastatin accelerates functional recovery from sciatic nerve crush injury by a possible mechanism of inhibiting the expression of tumor necrosis factor α and interleukin 6 and promoting the secretion of neurotrophic factors nerve growth factor and brain-derived neurotrophic factor. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries affect a significant number of patients who experience trauma affecting the hand and upper extremity. Improving unsatisfactory outcomes from repair of these injuries remains a clinical challenge despite advancements in microsurgical repair. Imperfections of the nerve regeneration process, including imprecise reinnervation, distal axon degradation, and muscular atrophy, complicate the repair process. However, the capacity for peripheral nerves to regenerate offers an avenue for therapeutic advancement. Regeneration is a temporally and spatially dynamic process coordinated by Schwann cells and neurons among other cell types. Neurotrophic factors are a primary means of controlling cell growth and differentiation in the repair setting. Sustained axon survival and regrowth and consequently functional outcomes of nerve repair in animal models are improved by the administration of neurotrophic factors, including glial cell-derived neurotrophic factor, nerve growth factor, sterile alpha and TIR motif containing 1, and erythropoietin. Targeted and sustained delivery of neurotrophic factors through gelatin-based nerve conduits, multiluminal conduits, and hydrogels have been shown to enhance the innate roles of these factors to promote expedient and accurate peripheral nerve regeneration in animal models. These delivery methods may help address the practical limitations to clinical use of neurotrophic factors, including systemic side effects and the need for carefully timed, precisely localized release schedules. In addition, tacrolimus has also improved peripheral nerve regrowth in animal models and has recently shown promise in addressing human disease. Ultimately, this realm of adjunct pharmacotherapies provides ample promise to improve patient outcomes and advance the field of peripheral nerve repair.

Reconstruction of peripheral mixed motor/sensory nerves using autografts has remained the gold standard. Inconsistent and nonphysiologic results across nerve allograft studies, including successful and failed motor reinnervation, have limited the current clinical application of nerve allografts to noncritical small-diameter sensory nerve defects less than 3 cm. This scoping review aimed to compare outcomes in both basic science and clinical applications of autograft and allograft nerve reconstruction for mixed motor/sensory nerves.

Abstract Peripheral nerve injury (PNI) occurs due to damage of peripheral nerves, with healthcare professionals playing significant roles in PNI rehabilitation. This study aimed to explore the knowledge, attitudes, and practices (KAP) towards PNI rehabilitation among healthcare professionals. This cross-sectional study was conducted on June 2023 in China and healthcare professionals were enrolled. A total of 611 valid questionnaires were collected, with 62.52% female respondents. Mean scores for KAP were 14.26 ± 2.044 (possible range: 0–19), 29.77 ± 3.622 (possible range: 7–35), and 41.55 ± 9.523 (possible range: 11–55), respectively. Multivariate logistic regression revealed positive associations of professional titles (OR = 1.743, 95% CI: 1.083–2.804), occupation (OR = 1.833, 95% CI: 1.151–2.919), and involvement in treatment or care of PNI patients (OR = 1.462, 95% CI: 1.024–2.088) with knowledge. Knowledge (OR = 1.155, 95% CI: 1.042–1.280), gender (OR = 2.140, 95% CI: 1.255–3.646), education (OR = 2.258, 95% CI: 1.131–4.507), and involvement in treatment or care of PNI patients (OR = 2.463, 95% CI: 1.460–4.155) were positively associated with attitude. Attitude (OR = 1.214, 95% CI: 1.148–1.283), bachelor's degree education (OR = 0.548, 95% CI: 0.326–0.919), master's degree or higher (OR = 0.545, 95% CI: 0.308–0.964), having rehabilitation training for PNI (OR = 2.485, 95% CI: 1.633–3.781), and involvement in treatment or care of PNI patients (OR = 2.093, 95% CI: 1.395–3.138) were independently associated with practice. Healthcare professionals exhibited moderate knowledge, positive attitudes, and moderate practices towards the PNI rehabilitation. Those involved in the treatment or care of PNI have significantly higher KAP. Targeted interventions were needed to enhance understanding and promote proactive engagement in clinical practice.

Abstract Peripheral nerve injury (PNI) often leads to retrograde cell death in the spinal cord and dorsal root ganglia (DRG), hindering nerve regeneration and functional recovery. Repetitive magnetic stimulation (rMS) promotes nerve regeneration following PNI. Therefore, this study aimed to investigate the effects of rMS on post-injury neuronal death and nerve regeneration. Seventy-two rats underwent autologous sciatic nerve grafting and were divided into two groups: the rMS group, which received rMS and the control (CON) group, which received no treatment. Motor neuron, DRG neuron, and caspase-3 positive DRG neuron counts, as well as DRG mRNA expression analyses, were conducted at 1-, 4-, and 8-weeks post-injury. Functional and axon regeneration analyses were performed at 8-weeks post-injury. The CON group demonstrated a decreased DRG neuron count starting from 1 week post-injury, whereas the rMS group exhibited significantly higher DRG neuron counts at 1- and 4-weeks post-injury. At 8-weeks post-injury, the rMS group demonstrated a significantly greater myelinated nerve fiber density in autografted nerves. Furthermore, functional analysis showed significant improvements in latency and toe angle in the rMS group. Overall, these results suggest that rMS can prevent DRG neuron death and enhance nerve regeneration and motor function recovery after PNI.

The increasing incidence of peripheral nerve injuries brought on by trauma or tumors is substantially interfering with people's lives due to the causal sensory and motor dysfunctions. Peripheral nerves have some self-repair ability after injury, but they are limited by the degree of injury and the body's condition. The postoperative recovery of nerve function in patients is not satisfactory, which is closely related to the local inflammatory microenvironment after injury. Melatonin, a compound naturally synthesized in the pineal gland, protects peripheral nervous system cells from oxidative inflammation after injury and regulates their behavior and fate.Therefore, it has good application prospect in nerve tissue engineering. In this paper, we review the synthesis, metabolic processes underlying melatonin, mechanism of action as well as the current status of its application in peripheral nerve regeneration as well as potential application for oral diseases. In this way, it further provides a new idea for the clinical treatment of peripheral nerve injury.

Peripheral nerve injuries result in significant loss of motor and sensory function, and the slow rate of nerve regeneration can prolong recovery time. Thus, approaches that promote axonal regeneration are critical to improve the outcomes for patients with peripheral nerve injuries. In this study, we investigated the effects of Ficus carica L. (fig) and Vaccinium macrocarpon Ait. (cranberry), which are rich in phytochemicals with demonstrable and diverse medicinal properties, on nerve regeneration in a mouse model of sciatic nerve crush. Our investigation revealed that fig extract, but not cranberry extract, prevented the decline in muscle weight and nerve conduction velocity induced by nerve crush. The fig extract also mitigated motor function impairment, myelin thinning, and axon diameter reduction, indicating its potential to promote nerve regeneration. Furthermore, the fig extract enhanced macrophage infiltration into the nerve tissue, suggesting that it could ameliorate nerve injury by promoting tissue repair via increased macrophage infiltration. The study provides valuable insights into the potential of the fig extract as a novel agent promoting nerve regeneration. Further investigation into the mechanisms underlying the action of fig extracts is needed to translate these findings into clinical applications for patients with peripheral nerve injuries.

Although several methods are being applied to treat peripheral nerve injury, a perfect treatment that leads to full functional recovery has not yet been developed. SMAD (Suppressor of Mothers Against Decapentaplegic Homolog) plays a crucial role in nerve regeneration by facilitating the survival and growth of nerve cells following peripheral nerve injury. We conducted a systematic literature review on the role of SMAD in this context. Following peripheral nerve injury, there was an increase in the expression of SMAD1, -2, -4, -5, and -8, while SMAD5, -6, and -7 showed no significant changes; SMAD8 expression was decreased. Specifically, SMAD1 and SMAD4 were found to promote nerve regeneration, whereas SMAD2 and SMAD6 inhibited it. SMAD exerts its effects by promoting neuronal survival and growth through BMP/SMAD1, BMP/SMAD4, and BMP/SMAD7 signaling pathways. Furthermore, it activates nerve regeneration programs via the PI3K/GSK3/SMAD1 pathway, facilitating active regeneration of nerve cells and subsequent functional recovery after peripheral nerve damage. By leveraging these mechanisms of SMAD, novel strategies for treating peripheral nerve damage could potentially be developed. We aim to further elucidate the precise mechanisms of nerve regeneration mediated by SMAD and explore the potential for developing targeted nerve treatments based on these findings.

Zhihong Cheng,1,&ast; Song Feng,1,2,&ast; Linfeng Yang,1 Jing Huang,3 Xilei Chen,4 Yang Guo,1 Yu Xiang,1 Bin Peng1 1Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China; 2Department of Neurosurgery, Dazhou Third People’s Hospital, Dazhou, Sichuan, People’s Republic of China; 3Innovation Center for Science and Technology, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China; 4Department of Clinical Medicine, North Sichuan Medical College, Nanchong, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bin Peng, Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, No. 234 Fujiang Road, Shunqing District, Nanchong, Sichuan, People’s Republic of China, Tel/Fax +86-817-2242781, Email binpeng01@sina.comPurpose: The spinal nerve ligation (SNL) model is a typical peripheral neuropathic pain model. During its construction, the removal of paraspinal muscles and transverse processes typically occurs, resulting in additional trauma that may potentially affect the pathophysiologic process of neuropathic pain. This study aimed to investigate the feasibility of establishing a more reliable SNL model using an oblique lateral approach.Methods: 36 adult male Sprague-Dawley rats were randomly divided into three groups: the traditional SNL (T-SNL) group, the new SNL (N-SNL) group (where the left L5 spinal nerve was ligated with a titanium clip via an oblique lateral approach), and the sham-operated (Sham) group. The operation time, Intraoperative bleeding, the number of rats that died, gait behavior, mechanical and cold pain threshold were recorded and measured. Stereology technology was used to calculate the number of microglia in spinal dorsal horn, and the Enzyme-linked immunosorbent assay (ELISA) technology was used to detect the expression of TNF-α and IL-1β in spinal cord as well as C-reactive protein (CRP) in serum in order to assess the effect of surgery on animal inflammation.Results: Compared with the T-SNL group, operative time and intraoperative bleeding were significantly decreased in the N-SNL group. Within 14 days postoperation, one rat in the N-SNL group was died, two rats in the T-SNL group were died. Compared with the Sham group, the N-SNL group showed obvious spontaneous pain behavior, decreased the pain thresholds, the number of microglia and the expression of TNF-α and IL-1β were significantly increased, and there was no significant difference in these indexes compared with T-SNL group. There was no significant difference in serum CRP levels among the three groups.Conclusion: This study suggests that the oblique lateral approach SNL model is a reliable NP model with the advantages of good reproducibility, accessibility, and low trauma.Keywords: animal model, mechanical pain threshold, hyperpathia, microglial, peripheral nerve injury, inflammatory

Abstract Background High ulnar nerve injuries is known to have unfavorable motor outcomes compared to other peripheral nerve injuries in the upper extremity. Functional muscle recovery after peripheral nerve injury depends on the time to motor end plate reinnervation and the number of motor axons that successfully reach the target muscle. The purpose of this study is to assess the functional recovery, and complications following performing supercharge end-to-side (SETS) anastomosis for proximal ulnar nerve injuries. Our study focuses on the role of SETS in the recovery process of high ulnar nerve injury. Patient and methods This study is a prospective, single-arm, open-label, case series. The original proximal nerve pathology was dealt with according to the cause of injury, then SETS was performed distally. The follow-up period was 18 months. We compared the neurological findings before and after the procedure. A new test was used to show the effect of SETS on recovery by performing a Lidocaine proximal ulnar nerve block test. Results Recovery of the motor function of the ulnar nerve was evident in 33 (86.8%) patients. The mean time to intrinsic muscle recovery was 6.85 months ± 1.3, only 11.14% of patients restored protective sensation to the palm and finger and 86.8% showed sensory level at the wrist level at the end of the follow-up period. Lidocaine block test was performed on 35 recovered patients and showed no change in intrinsic hand function in 31 patients. Conclusion SETS exhibit a remarkable role in the treatment of high ulnar nerve damage. SETS transfer can act as a nerve transfer that can supply intrinsic muscles by its fibers and allows for proximal nerve regeneration. We believe that this technique improves recovery of hand motor function and allows recovery of sensory fibers when combined with treating the proximal lesion. Trial registration Approved by Research Ethics Committee of Faculty of Medicine- Cairo University on 01/09/2021 with code number: MD-215–2021.

Abstract Background A favorable regenerative microenvironment is essential for peripheral nerve regeneration. Neural tissue-specific extracellular matrix (ECM) is a natural material that helps direct cell behavior and promote axon regeneration. Both bone marrow-derived mesenchymal stem cells (BMSCs) and adipose-derived mesenchymal stem cells (ADSCs) transplantation are effective in repairing peripheral nerve injury (PNI). However, there is no study that characterizes the in vivo microenvironmental characteristics of these two MSCs for the early repair of PNI when combined with neural tissue-derived ECM materials, i.e., acellular nerve allograft (ANA). Methods In order to investigate biological characteristics, molecular mechanisms of early stage, and effectiveness of ADSCs- or BMSCs-injected into ANA for repairing PNI in vivo, a rat 10 mm long sciatic nerve defect model was used. We isolated primary BMSCs and ADSCs from bone marrow and adipose tissue, respectively. First, to investigate the in vivo response characteristics and underlying molecular mechanisms of ANA combined with BMSCs or ADSCs, eighty-four rats were randomly divided into three groups: ANA group, ANA+BMSC group, and ANA+ADSC group. We performed flow cytometry, RT-PCR, and immunofluorescence staining up to 4 weeks postoperatively. To further elucidate the underlying molecular mechanisms, changes in long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) were systematically investigated using whole transcriptome sequencing. We then constructed protein–protein interaction networks to find 10 top ranked hub genes among differentially expressed mRNAs. Second, in order to explore the effectiveness of BMSCs and ADSCs on neural tissue-derived ECM materials for repairing PNI, sixty-eight rats were randomized into four groups: ANA group, ANA+BMSC group, ANA+ADSC group, and AUTO group. In the ANA+BMSC and ANA+ADSC groups, ADSCs/BMSCs were equally injected along the long axis of the 10-mm ANA. Then, we performed histological and functional assessments up to 12 weeks postoperatively. Results The results of flow cytometry and RT-PCR showed that ANA combined with BMSCs exhibited more significant immunomodulatory effects, as evidenced by the up-regulation of interleukin (IL)-10, down-regulation of IL-1β and tumor necrosis factor-alpha (TNF-α) expression, promotion of M1-type macrophage polarization to M2-type, and a significant increase in the number of regulatory T cells (Tregs). ANA combined with ADSCs exhibited more pronounced features of pro-myelination and angiogenesis, as evidenced by the up-regulation of myelin-associated protein gene (MBP and MPZ) and angiogenesis-related factors (TGF-β, VEGF). Moreover, differentially expressed genes from whole transcriptome sequencing results further indicated that ANA loaded with BMSCs exhibited notable immunomodulatory effects and ANA loaded with ADSCs was more associated with angiogenesis, axonal growth, and myelin formation. Notably, ANA infused with BMSCs or ADSCs enhanced peripheral nerve regeneration and motor function recovery with no statistically significant differences. Conclusions This study revealed that both ANA combined with BMSCs and ADSCs enhance peripheral nerve regeneration and motor function recovery, but their biological characteristics (mainly including immunomodulatory effects, pro-vascular regenerative effects, and pro-myelin regenerative effects) and underlying molecular mechanisms in the process of repairing PNI in vivo are different, providing new insights into MSC therapy for peripheral nerve injury and its clinical translation.

Background: Peripheral nerve injury is a recognized complication after reverse shoulder arthroplasty (RSA) that has mainly been studied at the level of the brachial plexus and its proximal branches. However, the impact of RSA on distal peripheral nerves and the influence of elbow and wrist position is not known. This cadaveric study aimed to analyze the effect of RSA implantation and upper limb position on tension in the distal median and radial nerves. The hypothesis was that RSA increased distal nerve tension, which could be further affected by elbow and wrist position. Methods: 12 upper limbs in 9 full fresh-frozen cadavers were dissected. Nerve tension was measured in the median nerve at the level of the proximal arm, elbow, and distal forearm, and in the radial nerve at the level of the elbow, using a customized three-point tensiometer. Measurements were carried out before and after RSA implantation, using a semi-inlay implant (Medacta, Castel San Pietro, Switzerland). Two different configurations were tested, using the smallest and largest available implant sizes. Three upper-limb key positions were considered (plexus at risk, plexus relief, and neutral), from which the effect of elbow and wrist position was further tested. Results: RSA implantation significantly increased median and radial nerve tension throughout the upper limb. The distal nerve segments were particularly dependent on elbow and wrist position. The plexus at risk position induced the most tension in all nerve segments, especially with the large implant configuration. On the other hand, the plexus relief position induced the least amount of tension. Flexing the elbow was the most efficient way to decrease nerve tension in all tested nerve segments and key positions. Wrist flexion significantly decreased nerve tension in the median nerve, whereas wrist extension decreased tension in the radial nerve. Conclusion: RSA significantly increases tension in the median and radial nerves and makes them more susceptible to wrist and elbow positioning. The mechanism behind distal peripheral neuropathy after RSA may thus result from increased compression of tensioned nerves against anatomical fulcrums rather than nerve elongation alone. Elbow flexion was the most effective way to decrease nerve tension, while elbow extension should be avoided when implanting the humeral component. Further studies are needed to assess the ulnar nerve.

Peripheral nerve damage is a common medical problem that frequently leads to significant functional limitations and long-term disabilities. Platelet-rich plasma (PRP), a growth factor-rich substance, promotes axonal regeneration in peripheral nerve injuries. This study aimed to investigate the effect of PRP on axonal regeneration in Wistar rats (Rattus norvegicus) after peripheral nerve injury via histomorphometric analysis. This study used a post-test-only control-group design. Twenty-five white rats were randomly assigned to the control or treatment groups (n=5). The control group consisted of the sham-operated and saline groups. The treatment groups consisted of local, intraperitoneal, or combined PRP. A single dose of PRP was administered after axonotmesis of the sciatic nerve. After 21 days, a surgical procedure was performed to extract sciatic nerve tissue, which was then stained with Luxol fast blue for histomorphometric analysis. The mean diameter of the fibers, diameter of the axons, number of axons, and myelin sheath thickness were analyzed using MANOVA (p<0.05). Compared with the saline group, the PRP treatment group presented a greater number of regenerating myelinated axons with larger fiber and axon diameters, and thicker myelin (p<0.05). The myelinated axons in the sham-operated group showed a typical morphology, whereas those in the saline group showed a decrease in myelinated axons, smaller fiber and axon diameters, and thinner, irregular myelin sheaths. Injection of a combination of PRP, both intraperitoneally and locally, promoted the regeneration of damaged nerves in rats. [ABSTRACT FROM AUTHOR]

Background/Aim: One of the most common consequences of diabetes mellitus is diabetic neuropathy, which is triggered on by nerve damage. The characteristic of neuropathies is a progressive loss of nerve fibre function resulting in numbness, tingling, aching, burning and throbbing sensations. In addition, it adds to the risk of falls, joint deformities, muscular atrophy and foot ulcers. The study aimed to analyse the incidence of motor and sensory dysfunctions in patients with diabetes mellitus in Chennai, India. Methods: This was an observational study of analytic type. Clinically diagnosed diabetic patients between the age of 45 to 60 years were considered for this study. Patients who consented to participate in this study, with a history of diabetes mellitus spanning more than ten years were chosen. Patients found to have other causes of neuropathy, diabetic ulceration, lactating (or) pregnant women and non-cooperative patients were excluded from this study. All the subjects enrolled in the study at the mentioned centres were given the Michigan neuropathy screening instrument (MNSI). Total score of MNSI was calculated and interpreted for the prevalence. Results: A total of 246 subjects have participated in this study out of which 54 % were male and 46 % were female, 127 (51 %) had diabetic peripheral neuropathy, 41 (17 %) had partial diabetic neuropathy and 78 (32 %) had no symptoms of diabetic neuropathy. Conclusion: Through the questionnaire and physical examination, the current study demonstrated a high prevalence of motor and sensory impairments as well as diabetic neuropathy symptoms in the diabetic population. [ABSTRACT FROM AUTHOR]

This study aimed to assess the effects of the timing of administering botulinum neurotoxin A (BoNT/A) on nerve regeneration in rats. Sixty 6-week-old rats with a sciatic nerve injury were randomly divided into four groups: the immediately treated (IT) group (BoNT/A injection administered immediately post-injury), the delay-treated (DT) group (BoNT/A injection administered one week post-injury), the control group (saline administered one week post-injury), and the sham group (only skin and muscle incisions made). Nerve regeneration was assessed 3, 6, and 9 weeks post-injury using various techniques. The levels of glial fibrillary acid protein (GFAP), astroglial calcium-binding protein S100β (S100β), growth-associated protein 43 (GAP43), neurofilament 200 (NF200), and brain-derived neurotrophic factor (BDNF) in the IT and DT groups were higher. ELISA revealed the highest levels of these proteins in the IT group, followed by the DT and control groups. Toluidine blue staining revealed that the average area and myelin thickness were higher in the IT group. Electrophysiological studies revealed that the CMAP in the IT group was significantly higher than that in the control group, with the DT group exhibiting significant differences starting from week 8. The findings of the sciatic functional index analysis mirrored these results. Thus, administering BoNT/A injections immediately after a nerve injury is most effective for neural recovery. However, injections administered one week post-injury also significantly enhanced recovery. BoNT/A should be administered promptly after nerve damage; however, its administration during the non-acute phase is also beneficial. [ABSTRACT FROM AUTHOR]

The restoration of adequate function and sensation in nerves following an injury is often insufficient. Electrical stimulation (ES) applied during nerve repair can promote axon regeneration, which may enhance the likelihood of successful functional recovery. However, increasing operation time and complexity are associated with limited clinical use of ES. This study aims to better assess whether short-duration ES types (voltage mode vs. current mode) are able to produce enhanced regenerative activity following peripheral nerve repair in rat models. Wistar rats were randomly divided into 3 groups: no ES (control), 30-minute ES with a current pulse, and 30-minute ES with a voltage pulse. All groups underwent sciatic nerve transection and repair using a silicone tube to bridge the 6-mm gap between the stumps. In the 2 groups other than the control, ES was applied after the surgical repair. Outcomes were evaluated using electrophysiology, histology, and serial walking track analysis. Biweekly walking tracks test over 12 weeks revealed that subjects that underwent ES experienced more rapid functional improvement than subjects that underwent repair alone. Electrophysiological analysis of the newly intratubular sciatic nerve at week 12 revealed strong motor function recovery in rats that underwent 30-minute ES. Histologic analysis of the sciatic nerve and its tibial branch at 12 weeks demonstrated robust axon regrowth in all groups. Both types of short-duration ES applied during nerve repair can promote axon regrowth and enhance the chances of successful functional recovery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The prognosis of peripheral nerve injury (PNI) is usually poor, and currently, there is no effective treatment for PNI. Studies have shown that exosomes derived from mesenchymal stem cells could promote nerve regeneration by optimizing the function of endogenous Schwann cells (SCs), while the mechanism is unclear. Autophagy, a highly conserved intracellular catabolic process responsible for maintaining cellular homeostasis, has been proved to be involved in the regulation of nerve repair after injury. We explored the effect of exosomes derived from dental pulp stem cells (DPSC-Exos) on the regeneration of myelin sheath in rats with sciatic nerve injury (SNI). In vitro and in vivo experiments were performed to clarify whether the effect of DPSC-Exos is associated with autophagy of SCs and to reveal the mechanism at the molecular level. Our results showed that the SCs of SNI rats exhibited the obvious autophagic characteristics, and the increase of P53 expression was an internal factor of autophagy. Our mechanism research indicated that DPSC-Exos could deliver miR-122-5p from DPSCs into SCs and suppressed the rapamycin (RAPA)-induced autophagy in SCs by inhibiting P53 expression. Rescue experiments showed that both the use of GW4869 and overexpression of exogenous P53 in SCs could reverse the inhibitory effect of DPSCs on the autophagy in SCs from co-culture system. In short, our study indicated that DPSC-Exos could promote the regeneration of the myelin sheath through suppressing the autophagy in SCs caused by PNI via miR-122-5p/P53 pathway; this provides researchers with another option for precise repair of PNI. [ABSTRACT FROM AUTHOR]

Critical-sized peripheral nerve injuries pose a significant clinical challenge and lead to functional loss and disability. Current regeneration strategies, including autografts, synthetic nerve conduits, and biologic treatments, encounter challenges such as limited availability, donor site morbidity, suboptimal recovery, potential immune responses, and sustained stability and bioactivity. An obstacle in peripheral nerve regeneration is the immune response that can lead to inflammation and scarring that impede the regenerative process. Addressing both the immunological and regenerative needs is crucial for successful nerve recovery. Here, we introduce a novel biodegradable tacrolimus-eluting nerve guidance conduit engineered from a blend of poly (L-lactide-co-caprolactone) to facilitate peripheral nerve regeneration and report the testing of this conduit in 15-mm critical-sized gaps in the sciatic nerve of rats. The conduit's diffusion holes enable the local release of tacrolimus, a potent immunosuppressant with neuro-regenerative properties, directly into the injury site. A series of in vitro experiments were conducted to assess the ability of the conduit to maintain a controlled tacrolimus release profile that could promote neurite outgrowth. Subsequent in vivo assessments in rat models of sciatic nerve injury revealed significant enhancements in nerve regeneration, as evidenced by improved axonal growth and functional recovery compared to controls using placebo conduits. These findings indicate the synergistic effects of combining a biodegradable conduit with localized, sustained delivery of tacrolimus, suggesting a promising approach for treating peripheral nerve injuries. Further optimization of the design and long-term efficacy studies and clinical trials are needed before the potential for clinical translation in humans can be considered. [ABSTRACT FROM AUTHOR]

Purpose of Review: Postoperative nerve injury after nerve block is complex and multifactorial. The mechanisms, etiologies, and risk factors are explored. This review article conducts a literature search and summarizes current evidence and best practices in prevention of nerve injury. Recent Findings: Emerging technology such as ultrasound, injection pressure monitors, and nerve stimulators for peripheral nerve block have been incorporated into regular practice to reduce the rate of nerve injury. Studies show avoidance of intrafascicular injection, limiting concentrations/volumes of local anesthetic, and appropriate patient selection are the most significant controllable factors in limiting the negative consequences of nerve block. Summary: Peripheral nerve injury is an uncommon occurrence after nerve block and is obscured by surgical manipulation, positioning, and underlying neural integrity. Underlying neural integrity is not always evident despite an adequate history and physical exam. Surgical stress, independently of nerve block, may exacerbate these neurologic disease processes and make diagnosing a postoperative nerve injury more challenging. Prevention of nerve injury by surgical teams, care with positioning, and avoidance of intrafascicular injection with nerve block are the most evidence-based practices. [ABSTRACT FROM AUTHOR]

Objectives: Vitamin B complexes are frequently used in clinical practice for peripheral nerve trauma. However, there is a lack of scientific data on their effectiveness. This study aims to investigate the impact of the vitamin B complex on nerve recovery in a rat model of peripheral nerve paralysis. Materials and Methods: Sixty male Wistar Albino rats were divided into six groups. Models of nerve injury, including blunt trauma, nerve incision, and autograft, were performed on all rats approximately 1 cm distal to the sciatic notch. B-complex vitamins were injected intraperitoneally at 0.2 mL/day to the treatment groups. The control groups were given 0.2 mL/day saline. After 1 month, the study was terminated, electromyography (EMG) was performed to measure the conduction velocity, and nerve tissue was taken from the repair line. The sciatic function indexes (SFIs) were calculated and analyzed. The histopathological samples were stained with hematoxylin and eosin and Toluidine blue and examined with a light microscope. Pathologically, myelination, fibrosis, edema, and mast cell densities in the nervous tissue were evaluated. Results: The vitamin B treatment groups demonstrated significant improvements in SFI compared to the control groups, indicating functional improvement in nerve damage (p < 0.05). In the nerve graft group, the vitamin B group showed a shorter latency, higher velocity, and larger peak-to-peak compared to the controls (p < 0.05). In the nerve transection group, the vitamin B group had better latency, velocity, and peak-to-peak values than the controls (p < 0.05). In the crush injury group, the vitamin B group exhibited an improved latency, velocity, and peak-to-peak compared to the controls (p < 0.05). Better myelination, less fibrosis, edema, and mast cells were also in the vitamin B group (p < 0.05). Conclusions: Vitamin B treatment significantly improves nerve healing and function in peripheral nerve injuries. It enhances nerve conduction, reduces fibrosis, and promotes myelination, indicating its therapeutic potential in nerve regeneration. [ABSTRACT FROM AUTHOR]

Introduction: Anesthetic conditioning has been shown to provide neuroprotection in several neurological disorders. Whether anesthetic conditioning provides protection against peripheral nerve injuries remains unknown. The aim of our current study is to investigate the impact of isoflurane conditioning on the functional outcomes after peripheral nerve injury (PNI) in a rodent sciatic nerve injury model. Methods: Adult male Lewis rats underwent sciatic nerve cut and repair and exposed to none (Group 1, sham), single isoflurane exposure (Group 2), threetime isoflurane exposure (Group 3), and six-time isoflurane exposure (Group 4). Isoflurane conditioning was established by administration of 2% isoflurane for 1 hour, beginning 1-hour post sciatic nerve cut and repair. Groups 3 and 4 were exposed to isoflurane for 1 hour, 3 and 6 consecutive days respectively. Functional outcomes assessed included compound muscle action potential (CMAP), evoked muscle force (tetanic and specific tetanic force), wet muscle mass, and axonal counting. Results: We observed an increase in axons, myelin width and a decrease in G-ratio in the isoflurane conditioning groups (3- and 6-days). This correlated with a significant improvement in tetanic and specific tetanic forces, observed in both groups 3 and 4. Discussion: Isoflurane conditioning (3- and 6-day groups) resulted in improvement in functional outcomes at 12 weeks post peripheral nerve injury and repair in a murine model. Future experiments should be focused on identifying the therapeutic window of isoflurane conditioning and exploring the underlying molecular mechanisms responsible for isoflurane conditioning induced neuroprotection in PNI. [ABSTRACT FROM AUTHOR]