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Traumatic peripheral nerve injury (TPNI) is quite common in various types of acral trauma. It mostly passes unnoticed at the time of the initial trauma. The patients are usually sent for an ultrasound (US) assessment about 4 weeks following the trauma, after the electrophysiological changes are established. This paper presents a 5‐year experience of US findings of TPNI through 60 cases, who were examined as an outpatient with clinical and electrodiagnostic (EDX) tests suggesting nerve injury. The study population includes 40 males, 20 females, and mean age 34.4 ± 16.3. Upper limb nerves were more affected than the lower ones, with no significant difference between the right and left sides. Mechanisms of injury include laceration in 53.4% of cases, 38.3% had history of traction injury and only 8.3% had history of compression/contusion injury. Regarding the severity grading of the injuries, long segments of thickened separate or matted fascicles (Grades I and II) was found in 27 (40.9%) nerves; partial disruption with interstitial neuroma (Grade III) in 15 (22.7%) nerves; complete disruption (neurotmesis) (Grade IV) in 24 (36.4%) case. The integrity of six repaired nerves was also assessed. Muscle states within the territory of the motor nerve were always assessed, 62.9% of cases had decreased muscle bulk, 28.6% had muscle atrophy, and the remaining was normal. EDX testing results of 44 out of 60 patients was severe in 14 cases (31.8%), moderate in 15 cases (34.1%), mild in 11 case (25%), and normal in four cases (9.1%). The purpose of this study is to demonstrate that the US is a convenient neuroimaging tool by which we can accurately determine the level and the degree of peripheral nerve damage to plan the appropriate treatment. [ABSTRACT FROM AUTHOR]

Dancers and musicians have unique physical demands that can lead to injury of the peripheral nerves. Specific dance movements and specific instrument positions, combined with countless hours of practice and repetition, create an environment for potential nerve injury. Familiarity with these variables and recognition of the common presentations of neuropathic syndromes are essential in the evaluation of a performing artist with a suspected peripheral nerve injury. Assessment should include an understanding and analysis of their dance style or instrument playing posture, particularly in the position or motion that recreates the symptoms if possible. Practice and performance schedules should also be considered. Diagnosis may require electrodiagnostic testing, imaging, or diagnostic injections. Treatment should be comprehensive and may include modifications in practice schedule, posture/position, and technique in addition to consideration of medications, splints/orthoses, physical therapy, and injections. The instructor/teacher should be involved in the treatment plan if applicable. Complete rest in this population may not be realistic or necessary. Early and accurate diagnosis of nerve injury is important for safe return to dance or instrumental music. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries in the upper extremities may be common in throwing athletes as the throwing motion places extreme stress on the dominant arm. The combination of extreme stress along with repetitive microtrauma from throwing uniquely places the throwing athlete at elevated risk of upper extremity peripheral nerve injury. However, because symptoms can be nonspecific and frequently coexist with pathology in the upper extremity, the diagnosis of peripheral nerve injury is often delayed. Diagnosis of peripheral nerve injuries may require a combination of history and physical examination, diagnostic imaging, electrodiagnostic testing, and diagnostic ultrasound-guided injections. The primary management should include physical therapy focusing on throwing mechanics and kinetic chain evaluation. However, some athletes require surgical intervention if symptoms do not improve with conservative management. The purpose of this focused narrative review is to highlight upper extremity peripheral neuropathies reported in throwing athletes and to provide an overview of the appropriate clinical diagnosis and management of the throwing athlete with a peripheral nerve injury. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries in athletes affect the upper limb more commonly than the lower limb. Common mechanisms include compression, traction, laceration, and ischemia. Specific sports can have unique mechanisms of injury and are more likely to be associated with certain neuropathies. Familiarity with these sport‐specific variables and recognition of the common presentations of upper limb neuropathic syndromes are important in assessing an athlete with a suspected peripheral nerve injury. Evaluation may require imaging modalities and/or electrodiagnostic testing to confirm a nerve injury. In some cases, diagnostic injections may be needed to differentiate neuropathic versus musculoskeletal etiology. Early and accurate diagnosis is essential for treatment/management and increases the likelihood of a safe return‐to‐sport and avoidance of long‐term functional consequences. Most nerve injuries can be treated conservatively, however, severe or persistent cases may require surgical intervention. This monograph reviews key diagnostic, management, and preventative strategies for sports‐related peripheral nerve injuries involving the upper limb. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are common injuries that often have a drastic effect on patient's activities of daily living and physical function. While techniques for the surgical repair of these injuries have improved over time, rehabilitation methods following these repairs have been non‐standardized and under researched. Electronic searches were conducted in Ovid/Medline and SCOPUS to identify articles that discuss rehabilitation and exercise following peripheral nerve injury in animal models and its effects on peripheral nerve regeneration and recovery of function. Thirty‐eight articles met inclusion criteria; all were prospective studies in animal models. This systematic review suggests that exercise is a useful tool in returning autonomy to the individual and has beneficial effects in the recovery from peripheral nerve injury. It is beneficial to use rehabilitation exercises following the repair of peripheral nerve injuries to promote regeneration, and timing of that exercise may be just as important as the exercise prescribed. However, further studies with standardized models and outcome measures need to be conducted before translation to clinical trials. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to investigate the potential therapeutic applications of stigmasterol for treating neuropathic pain., Methods: Related mechanisms were investigated by DRG single-cell sequencing analysis and the use of specific inhibitors in cellular experiments. In animal experiments, 32 male Sprague-Dawley rats were randomly divided into the sham operation group, CCI group, ibuprofen group, and stigmasterol group. We performed behavioral tests, ELISA, H&E staining and immunohistochemistry, and western blotting., Results: Cell communication analysis by single-cell sequencing reveals that after peripheral nerve injury, Schwann cells secrete IL-34 to act on CSF1R in macrophages. After peripheral nerve injury, the mRNA expression levels of CSF1R pathway and NLRP3 inflammasome in macrophages were increased in DRG. In vitro studies demonstrated that stigmasterol can reduce the secretion of IL-34 in LPS-induced RSC96 Schwann cells; stigmasterol treatment of LPS-induced Schwann cell-conditioned medium (L-S-CM) does not induce the proliferation and migration of RAW264.7 macrophages; L-S-CM reduces CSF1R signaling pathway (CSF1R, P38MAPK, and NFκB) activation, NLRP3 inflammasome activation, and ROS production. In vivo experiments have verified that stigmasterol can reduce thermal and cold hyperalgesia in rat chronic compressive nerve injury (CCI) model; stigmasterol can reduce IL-1β, IL-6, TNF-α, CCL2, SP, and PGE2 in serum of CCI rats; immunohistochemistry and western blot confirmed that stigmasterol can reduce the levels of IL-34/CSF1R signaling pathway and NLRP3 inflammasome in DRG of CCI rats., Conclusion: Stigmasterol alleviates neuropathic pain by reducing Schwann cell-macrophage cascade in DRG by modulating IL-34/CSF1R axis., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims Methods Results Interpretation Peripheral nerve injuries often require bridging when direct repair is not feasible. Nerve autografts are the gold standard, but they can lead to donor site morbidity. Silk fibroin‐based nerve conduits, like the novel SILKBridge, offer a promising alternative. This pilot study evaluates the mid‐term outcomes of the first in‐human digital nerve reconstruction using the SILKBridge, focusing on sensory recovery, complication rates, patient‐reported outcomes, and biological integration.This study included four patients with digital nerve defects reconstructed using the SILKBridge. Clinical assessments included two‐point discrimination, Semmes–Weinstein monofilament testing, and pain evaluation using the Numeric Rating Scale. Sonographic assessments were also performed to evaluate the conduit's biointegration and potential complications.At a mean follow‐up of 32 months, all patients demonstrated satisfactory sensory recovery and reported minimal to no pain. Sonographic assessments confirmed effective biointegration with no signs of inflammation or scarring.The mid‐term evaluation of the first in‐human digital nerve reconstruction with the SILKBridge revealed safety, efficiency, and favorable biocompatibility properties. Further studies with larger cohorts are needed to validate these findings and compare them with other nerve repair methods. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries (PNIs) are common, costly, and cause significant pain. Effective management of PNIs involves tailoring medications to the injury type as well as understanding the pharmacokinetics/pharmacodynamics to support nerve regeneration and reduce pain. Opioids act on opioid receptors to significantly reduce pain for many patients, but there are significant addiction risks and side effects. In addition, opioids may exacerbate pain sensitivity and affect nerve regeneration. Non‐steroidal anti‐inflammatory drugs or acetaminophen act on cyclooxygenase enzymes and are commonly used for nerve pain, with 34.7% of people using them for neuropathic pain. While effective for mild pain, they are often combined with opioids, gamma‐aminobutyric acid (GABA) analogs, lidocaine, or corticosteroids for more severe pain. Corticosteroids, mimicking adrenal hormones like cortisol, treat PNI‐related inflammation and pain. Their pharmacokinetics are complex, often requiring local injections in order to minimize systemic risks while effectively treating PNIs. Lidocaine, a common local anesthetic, blocks ion channels in the central nervous system (CNS) and peripheral nerves, providing strong analgesic and anti‐inflammatory effects. If used improperly, lidocaine can cause neuronal toxicity instead of anesthetic effect. GABA acts as an inhibitory neurotransmitter in the CNS and its drug analogs like pregabalin and gabapentin can alleviate neuropathic pain by binding to voltage‐gated Ca2+ channels, inhibiting neurotransmitter release. These pain medications are commonly prescribed for PNIs despite a limited guidance on their effects on nerve regeneration. This review will discuss these drug's mechanisms of action, pharmacokinetics/pharmacodynamics, and their clinical application to highlight their effect on the PNI recovery. [ABSTRACT FROM AUTHOR]

The management of peripheral nerve injuries is an important concern due to the their incidence of nerve lesions and inappropriate regeneration that follows severe injuries, which ultimately reduces the lives of patients with this condition. Different strategies have been investigated to repair severe nerve injuries with the improvement of motor and sensory regeneration. Although autograft remains the gold standard technique, an emerging number of research articles concerning nerve conduit use have been reported in the last few years. Nerve conduits aim to overcome autograft disadvantages, but they satisfy some requirements to be suitable for nerve repair. A universal ideal conduit does not exist since conduit properties have to be evaluated case by case; nevertheless, because of their high biocompatibility and biodegradability, natural‐based biomaterials have great potential to be used to produce nerve guides. Although they have many characteristics with synthetic biomaterials, natural‐based biomaterials are preferable because of their extraction sources; indeed, these biomaterials are obtained from different renewable sources or food waste, thus reducing environmental impact and enhancing sustainability in comparison to synthetic ones. This review highlights the recent progress in the development of natural‐based biomaterials and their derivatives for the management of peripheral nerve injuries. [ABSTRACT FROM AUTHOR]

Skeletal muscle is striated muscle that moves autonomously and is innervated by peripheral nerves. Peripheral nerve injury is very common in clinical treatment. However, the commonly used treatment methods often focus on the regeneration of the injured nerve but overlook the pathological changes in the injured skeletal muscle. Acupuncture, as the main treatment for denervated skeletal muscle atrophy, is used extensively in clinical practice. In the present study, a mouse model of lower limb sciatic nerve detachment was constructed and treated with electroacupuncture Stomach 36 to observe the atrophy of lower limb skeletal muscle and changes in skeletal muscle fibre types before and after electroacupuncture Stomach 36 treatment. Mice with skeletal muscle denervation showed a decrease in the proportion of IIa muscle fibres and an increase in the proportion of IIb muscle fibres, after electroacupuncture Stomach 36. The changes were reversed by specific activators of p38 MAPK, which increased IIa myofibre ratio. The results suggest that electroacupuncture Stomach 36 can reverse the change of muscle fibre type from IIb to IIa after denervation of skeletal muscle by inhibiting p38 MAPK. The results provide an important theoretical basis for the treatment of clinical peripheral nerve injury diseases with electroacupuncture, in addition to novel insights that could facilitate the study of pathological changes of denervated skeletal muscle., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Active‐duty service members (ADSM) and military Veterans represent a population with increased occupational risk for nerve injuries sustained both during training operations and wartime. Mechanisms of war‐related nerve injuries have evolved over time, from the musket ball‐related traumas described by S.W. Mitchell to complex blast injuries and toxic exposures sustained during Middle East conflicts in the 21st century. Commonly encountered nerve injury etiologies in this population currently include compression, direct trauma, nutritional deficits, traumatic limb amputation, toxic chemical exposures, or blast‐related injuries. Expeditious identification and comprehensive, interdisciplinary treatment of combat‐associated neuropathies, as well as prevention of these injuries whenever possible is critical to reduce chronic morbidity and disability for service members and to maintain a well‐prepared military. However, diagnosis of a combat‐associated nerve injury may be particularly challenging due to comorbid battlefield injuries or delayed presentation of neuropathy from military toxic exposures. Advances in imaging for nerve injury, including MRI and ultrasound, provide useful tools to compliment EMG in establishing a diagnosis of combat‐associated nerve injury, particularly in the setting of anatomic disruption or edema. Surgical techniques can improve pain control or restoration of function. In all cases, comprehensive interdisciplinary rehabilitation provides the best framework for optimization of recovery. Further work is needed to prevent combat‐associated nerve injuries and promote nerve recovery following injury. [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]

Animal models of peripheral nerve injury (PNI) serve as the fundamental basis for the investigations of nerve injury, regeneration, and neuropathic pain. The injury properties of such models, including the intensity and duration, significantly influence the subsequent pathological changes, pain development, and therapeutic efficacy. However, precise control over the intensity and duration of nerve injury remains challenging within existing animal models, thereby impeding accurate and comparative assessments of relevant cases. Here, a new model that provides quantitative and off‐body controllable injury properties via a magnetically controlled clamp, is presented. The clamp can be implanted onto the rat sciatic nerve and exert varying degrees of compression under the control of an external magnetic field. It is demonstrated that this model can accurately simulate various degrees of pathology of human patients by adjusting the magnetic control and reveal specific pathological changes resulting from intensity heterogeneity that are challenging to detect previously. The controllability and quantifiability of this model may significantly reduce the uncertainty of central response and inter‐experimenter variability, facilitating precise investigations into nerve injury, regeneration, and pain mechanisms. [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]

Peripheral nerve damage can cause debilitating symptoms ranging from numbness and pain to sensory loss and atrophy. To uncover the underlying mechanisms of peripheral nerve injury, our research aims to develop a relationship between biomechanical peripheral nerve damage and function through finite element modeling. A noncontact, ex vivo electrophysiology chamber, capable of axially stretching explanted nerves while recording electrical signals, was used to investigate peripheral nerve injury. Successive stretch trials were run on eight sciatic nerves (four females and four males) excised from Sprague–Dawley rats. Nerves were stretched until 50% compound action potential (CAP) amplitude reduction was obtained. A constitutive model developed by Raghavan and Vorp was suitable for rat sciatic nerves, with an average α and β of 0.183 MPa and 1.88 MPa, respectively. We then generated 95% confidence intervals for the stretch at which specific CAP amplitude reductions would occur, which compares well to previous studies. We also developed a finite element model that can predict stretch‐induced signaling deficits, applicable for complex nerve geometries and injuries. This relationship between nerve biomechanics and function can be expanded upon to create a clinical model for peripheral nerve dysfunction due to stretch. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) often leads to significant functional impairment. Here, we investigated the impact of epidermal growth factor‐like domain‐containing protein 7 (EGFL7) on angiogenesis and nerve regeneration following PNI. Using a sciatic nerve injury model, we assessed nerve function using the sciatic nerve function index. We analyzed the expression levels of EGFL7, forkhead box proteins A1 (FOXA1), nerve growth factor (NGF), brain‐derived neurotrophic factors (BDNF), Neurofilament 200 (NF200), myelin protein zero (P0), cell adhesion molecule 1 (CD31), vascular endothelial growth factor (VEGF), and NOTCH‐related proteins in tissues and cells. Cell proliferation, migration, and angiogenesis were evaluated through cell counting kit assays, 5‐ethynyl‐2′deoxyuridine staining, and Transwell assays. We investigated the binding of FOXA1 to the EGFL7 promoter using dual‐luciferase assays and chromatin immunoprecipitation. We observed decreased EGFL7 expression and increased FOXA1 expression in PNI, and EGFL7 overexpression alleviated gastrocnemius muscle atrophy, increased muscle weight, and improved motor function. Additionally, EGFL7 overexpression enhanced Schwann cell and endothelial cell proliferation and migration, promoted tube formation, and upregulated NGF, BDNF, NF200, P0, CD31, and VEGF expression. FOXA1 was found to bind to the EGFL7 promoter region, inhibiting EGFL7 expression and activating the NOTCH signaling pathway. Notably, FOXA1 overexpression counteracted the effects of EGFL7 on Schwann cells and endothelial cells. In conclusion, EGFL7 holds promise as a therapeutic molecule for treating sciatic nerve injury. [ABSTRACT FROM AUTHOR]

Magnetic resonance neurography (MRN) is increasingly used in clinical practice for the evaluation of patients with a wide spectrum of peripheral nerve disorders. This review article discusses the technical aspects of MRN highlighting the core sequences performed for clinical care. A robust, high‐resolution, heavily T2‐weighted fluid‐sensitive sequence performed on a 3.0 Tesla magnet system remains the main workhorse MRN sequence. In specific clinical scenarios, adjunct techniques such as diffusion‐weighted imaging can be added to a protocol for disease characterization. In addition, gadolinium‐based contrast material can also be administered for the purposes of image optimization (suppress adjacent vascular signal) and disease characterization. Technical modifications to field of view and planes of imaging can be made based on the clinical question and discussion with the radiologist(s). On fluid‐sensitive MRN sequences, a normal peripheral nerve exhibits iso‐ to minimally hyperintense signal relative to skeletal muscle with a predictable trajectory, preserved “fascicular” architecture, and tapered caliber from proximal to distal. Peripheral nerve abnormalities on MRN include alterations in signal, caliber, architecture, diffusion characteristics as well as enhancement and provide information regarding the underlying etiology. Although some MRN findings including nerve hyperintensity and long‐segmental enlargement are nonspecific, there are certain diagnoses that can be made with high certainty based on imaging including benign peripheral nerve tumors, high‐grade peripheral nerve injury, and intraneural ganglia. The purpose of this article is to familiarize a neuromuscular clinician with fundamentals of MRN acquisition and interpretation to facilitate communication with the neuromuscular radiologist and optimize patient care. [ABSTRACT FROM AUTHOR]

Low‐intensity pulsed ultrasound (LIPUS) and electrical stimulation (ES) are effective methods that promote neural repair. However, ES usually requires electrode implantation and a power supply, which are an inconvenience to future applications. Meanwhile, it is difficult to combine ultrasound and ES through traditional methods. Herein, a nanopatch consisting of an oriented barium titanate (BTO)‐incorporated polycaprolactone (PCL) nanofiber membrane for electricity generation and a layer of graphene oxide (GO)‐doped gelatin methacryloyl (GelMA) for neural interaction is developed. This band‐aid‐like BTO@PCL/GO@GelMA nanopatch has an excellent piezoelectric performance. In vitro, the nanopatches significantly promote axonal growth under LIPUS treatment. In a rat model of erectile dysfunction caused by peripheral nerve injury, the nanopatch is easily attached to a damaged nerve similar to a band‐aid. With the assistance of ultrasound, some mechanical energy is converted into electricity by the nanopatch, and synergistic neural stimulation of ultrasound and electricity is achieved. In this way, the nanopatch significantly promoted corpus cavernosum nerve repair, resulting in the improvement of tissue structure and erectile function as well as increased conception rate in female rats. In conclusion, the nanopatch offers a synergistic ultrasound‐ES for nerve repair easily and represents a novel strategy for peripheral nerve repair. [ABSTRACT FROM AUTHOR]

Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Limited axon regeneration following peripheral nerve injury may be related to activation of the lysosomal protease, asparaginyl endopeptidase (AEP, δ-secretase) and its degradation of the microtubule associated protein, Tau. Activity of AEP was increased at the site of sciatic nerve transection and repair but blocked in mice treated systemically with a specific AEP inhibitor, compound 11 (CP11). Treatments with CP11 enhanced axon regeneration in vivo. Amplitudes of compound muscle action potentials recorded 4 weeks after nerve transection and repair and 2 weeks after daily treatments with CP11 were double those of vehicle-treated mice. At that time after injury, axons of significantly more motor and sensory neurons had regenerated successfully and reinnervated the tibialis anterior and gastrocnemius muscles in CP11-treated mice than vehicle-treated controls. In cultured adult dorsal root ganglion neurons derived from wild type mice that were treated in vitro for 24 h with CP11, neurites were nearly 50% longer than in vehicle-treated controls and similar to neurite lengths in cultures treated with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF). Combined treatment with CP11 and 7,8-DHF did not enhance outgrowth more than treatments with either one alone. Enhanced neurite outgrowth produced by CP11 was found also in the presence of the TrkB inhibitor, ANA-12, indicating that the enhancement was independent of TrkB signalling. Longer neurites were found after CP11 treatment in both TrkB+ and TrkB- neurons. Delta secretase inhibition by CP11 is a treatment for peripheral nerve injury with great potential., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Objective: Clinical treatment of erectile dysfunction (ED) caused by cavernous nerve (CN) injury during pelvic surgery is difficult. Low-intensity pulsed ultrasound (LIPUS) can be a potential strategy for neurogenic ED (NED). However, whether Schwann cells (SCs) can respond to LIPUS stimulation signals is unclear. This study aims to elucidate the signal transmission between SCs paracrine exosome (Exo) and neurons stimulated by LIPUS, as well as to analyze the role and potential mechanisms of exosomes in CN repair after injury., Methods: The major pelvic ganglion (MPG) neurons and MPG/CN explants were stimulated with LIPUS of different energy intensities to explore the appropriate LIPUS energy intensity. The exosomes were isolated and purified from LIPUS-stimulated SCs (LIPUS-SCs-Exo) and non-stimulated SCs (SCs-Exo). The effects of LIPUS-SCs-Exo on neurite outgrowth, erectile function, and cavernous penis histology were identified in bilateral cavernous nerve crush injury (BCNI)-induced ED rats., Results: LIPUS-SCs-Exo group can enhance the axon elongation of MPG/CN and MPG neurons compared to SCs-Exo group in vitro. Then, the LIPUS-SCs-Exo group showed a stronger ability to promote the injured CN regeneration and SCs proliferation compared to the SCs-Exo group in vivo. Furthermore, the LIPUS-SCs-Exo group increased the Max intracavernous pressure (ICP)/mean arterial pressure (MAP), lumen to parenchyma and smooth muscle to collagen ratios compared to the SCs-Exo group in vivo. Additionally, high-throughput sequencing combined with bioinformatics analysis revealed the differential expression of 1689 miRNAs between the SCs-Exo group and the LIPUS-SCs-Exo group. After LIPUS-SCs-Exo treatment, the phosphorylated levels of Phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) and forkhead box O (FoxO) in MPG neurons increased significantly compared to negative control (NC) and SCs-Exo groups., Conclusion: Our study revealed that LIPUS stimulation could regulate the gene of MPG neurons by changing miRNAs derived from SCs-Exo, then activating the PI3K-Akt-FoxO signal pathway to enhance nerve regeneration and restore erectile function. This study had important theoretical and practical significance for improving the NED treatment., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aims: Nerve injury-induced maladaptive changes in gene expression in the spinal neurons are essential for neuropathic pain genesis. Circular RNAs (ciRNA) are emerging as key regulators of gene expression. Here, we identified a nervous-system-tissues-specific ciRNA-Kat6 with conservation in humans and mice. We aimed to investigate whether and how spinal dorsal horn ciRNA-Kat6b participates in neuropathic pain., Methods: Unilateral sciatic nerve chronic constrictive injury (CCI) surgery was used to prepare the neuropathic pain model. The differentially expressed ciRNAs were obtained by RNA-Sequencing. The identification of nervous-system-tissues specificity of ciRNA-Kat6b and the measurement of ciRNA-Kat6b and microRNA-26a (miRNA-26a) expression level were carried out by quantitative RT-PCR. The ciRNA-Kat6b that targets miRNA-26a and miRNA-26a that targets Kcnk1 were predicted by bioinformatics analysis and verified by in vitro luciferase reports test and in vivo experiments including Western-blot, immunofluorescence, and RNA-RNA immunoprecipitation. The correlation between neuropathic pain and ciRNA-Kat6b, miRNA-26a, or Kcnk1 was examined by the hypersensitivity response to heat and mechanical stimulus., Results: Peripheral nerve injury downregulated ciRNA-Kat6b in the dorsal spinal horn of male mice. Rescuing this downregulation blocked nerve injury-induced increase of miRNA-26a, reversed the miRNA-26a-triggered decrease of potassium channel Kcnk1, a key neuropathic pain player, in the dorsal horn, and alleviates CCI-induced pain hypersensitivities. On the contrary, mimicking this downregulation increased the miRNA-26a level and decreased Kcnk1 in the spinal cord, resulting in neuropathic pain-like syndrome in naïve mice. Mechanistically, the downregulation of ciRNA-Kat6b reduced the accounts of miRNA-26a binding to ciRNA-Kat6b, and elevated the binding accounts of miRNA-26a to the 3' untranslated region of Kcnk1 mRNA and degeneration of Kcnk1 mRNA, triggering in the reduction of KCNK1 protein in the dorsal horn of neuropathic pain mice., Conclusion: The ciRNA-Kat6b/miRNA-26a/Kcnk1 pathway in dorsal horn neurons regulates the development and maintenance of neuropathic pain, ciRNA-Kat6b may be a potential new target for analgesic and treatment strategies., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Myelin sheath plays important roles in information conduction and nerve injury repair in the peripheral nerve system (PNS). Enhancing comprehension of the structure and components of the myelin sheath in the PNS during development would contribute to a more comprehensive understanding of the developmental and regenerative processes. In this research, the structure of sciatic nerve myelin sheath in C57BL/6 mice from embryonic day 14 (E14) to postnatal 12 months (12M) was observed with transmission electron microscopy. Myelin structure appeared in the sciatic nerve as early as E14, and the number and thickness of myelin lamellar gradually increased with the development until 12M. Transcriptome analysis was performed to show the expressions of myelin‐associated genes and transcriptional factors involved in myelin formation. The genes encoding myelin proteins (Mag, Pmp22, Mpz, Mbp, Cnp and Prx) showed the same expression pattern, peaking at postnatal day 7 (P7) and P28 after birth, whereas the negative regulators of myelination (c‐Jun, Tgfb1, Tnc, Cyr61, Ngf, Egr1, Hgf and Bcl11a) showed an opposite expression pattern. In addition, the expression of myelin‐associated proteins and transcriptional factors was measured by Western blot and immunofluorescence staining. The protein expressions of MAG, PMP22, MPZ, CNPase and PRX increased from E20 to P14. The key transcriptional factor c‐Jun co‐localized with the Schwann cells Marker S100β and decreased after birth, whereas Krox20/Egr2 increased during development. Our data characterized the structure and components of myelin sheath during the early developmental stages, providing insights for further understanding of PNS development. [ABSTRACT FROM AUTHOR]

Background: Postherpetic neuralgia (PHN) is a classic chronic condition with multiple signs of peripheral and central neuropathy. Unfortunately, the pathogenesis of PHN is not well defined, limiting clinical treatment and disease management. Objective: To describe the peripheral and central pathological axes of PHN, including peripheral nerve injury, inflammation induction, central nervous system sensitization, and brain functional and structural network activity. Methods: A bibliographic survey was carried out, selecting relevant articles that evaluated the characterization of the pathogenesis of PHN, including peripheral and central pathological axes. Results: Currently, due to the complexity of the pathophysiological mechanisms of PHN and the incomplete understanding of the exact mechanism of neuralgia. Conclusion: It is essential to conduct in‐depth research to clarify the origins of PHN pathogenesis and explore effective and comprehensive therapies for PHN. [ABSTRACT FROM AUTHOR]

Laryngeal electromyography (LEMG) is a technique used to characterize neuropathic injuries to the recurrent laryngeal nerve (RLN) and superior laryngeal nerve (SLN). The RLN and SLN innervate the laryngeal muscles to produce vocal fold (VF) motion and elongation, respectively. VF motion deficiencies can affect voice, swallowing, and breathing, which can greatly affect a patient's quality of life. Neuropathy‐related VF motion deficiencies most often result from surgical interventions to the skull base, neck, or chest likely due to the circuitous route of the RLN. LEMG is ideally conducted by an electromyographer and an otolaryngologist using a team‐approach. LEMG is a powerful diagnostic tool to better characterize the extent of neuropathic injury and thus clarify the prognosis for VF motion recovery. This updated review discusses current techniques to improve the positive and negative predictive values of LEMG using laryngeal synkinesis and quantitative LEMG. Synkinesis can be diagnosed by comparing motor unit potential amplitude during vocalization and sniff maneuvers when recording within adductor muscles. Quantitative turns analysis can measure motor unit recruitment to avoid subjective descriptions of reduced depolarization during vocalization, and normal values are >400 turns/s. By integrating qualitative, quantitative, and synkinetic data, a robust prognosis can help clinicians determine if VF weakness will recover. Based on LEMG interpretation, patient‐centered treatment can be developed to include watchful waiting, temporary VF augmentation, or definitive medialization procedures and laryngeal reinnervation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study? Although fibroblasts are involved in the regenerative process associated with peripheral nerve injury, detailed information regarding their characteristics is largely lacking. What is the main finding and its importance? Nerve-derived fibroblasts have a greater neurite-promoting effect than skin-derived fibroblasts, and epineurium-derived fibroblasts can promote neurite outgrowth more effectively than parenchyma-derived fibroblasts. The epineurium-derived fibroblasts and parenchyma-derived fibroblasts have distinctly different molecular profiles, including genes of soluble factors to promote axonal growth. Fibroblasts are molecularly and functionally different depending on their localization in nerve tissue, and epineurium-derived fibroblasts might be involved in axon regeneration after peripheral nerve injury more than previously thought., Abstract: Although fibroblasts (Fb) are components of a peripheral nerve involved in the regenerative process associated with peripheral nerve injury, detailed information regarding their characteristics is largely lacking. The objective of the present study was to investigate the capacity of Fb derived from peripheral nerves to stimulate the outgrowth of neurites from adult dorsal root ganglion neurons and to clarify their molecular characteristics. Fibroblasts were prepared from the epineurium and parenchyma of rat sciatic nerves and skin. The Fb derived from epineurium showed the greatest effect on neurite outgrowth, followed by the Fb derived from parenchyma, indicating that Fb derived from nerves promote neurite outgrowth more effectively than skin-derived Fb. Although both soluble and cell-surface factors contributed evenly to the neurite-promoting effect of nerve-derived Fb, in crush and transection injury models, Fb were not closely associated with regenerating axons, indicating that only soluble factors from Fb are available to regenerating axons. A transcriptome analysis revealed that the molecular profiles of these Fb were distinctly different and that the gene expression profiles of soluble factors that promote axonal growth are unique to each Fb. These findings indicate that Fb are molecularly and functionally different depending on their localization in nerve tissue and that Fb derived from epineurium might be involved more than was previously thought in axon regeneration after peripheral nerve injury., (© 2023 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Peripheral nerve injuries (PNIs) resulting in myelin breakdown and axonal degeneration at both the proximal and distal nerve stumps are major clinical concerns that can induce functional loss and diminished quality of life. In biomaterials science, considerable attention has been given to artificial nerve guidance conduits (NGCs), since the engineered tubular structures have the potential to supply a supportive nerve microenvironment to longitudinally align the regenerating axons for bridging the injured nerve sites. Although NGCs may become promising alternatives to nerve autografts, the fabrication approaches available to incorporate directional cues for dictating neuronal behavior and nerve reconnection have been limited to conventional micro/nano‐fabrication techniques that are complex and time‐consuming due to manual processing steps. Thus, our goal here was to develop a simple manufacturing approach for introducing topographical cues onto NGCs. To achieve this goal, we used an established mechanically actuated silk wrinkling approach to create topographically functionalized surfaces as a potential NGC material platform for guided directional alignment of neurons. We 3D‐printed thermo‐responsive shape‐memory polymer (SMP)‐based NGCs that can produce silk fibroin (SF)‐wrinkled topographies on the micro and nano‐meter length scale. Since SF is a commonly used biomaterial surface coating with excellent neuro‐compatibility, we studied the ability to develop NGCs that can autonomously actuate silk wrinkles upon heat‐induced contraction of the SMP and evaluated the effects of the topographically functionalized construct on neuronal behavior. Using an immortalized dorsal root ganglion neuronal cell line, we found that the silk‐wrinkled conduits displayed high neuronal viability and adhesion compared to uncoated conduits and tissue‐culture polystyrene controls. We also found that the wrinkled conduits enabled the neurons to elongate and align parallel to the direction of the wrinkled topography. Longer neurite extension was also observed on the wrinkled conduits compared to their respective controls. These findings demonstrate the potential for functional wrinkled protein coatings to provide directional cues in the fabrication of artificial NGCs for peripheral nerve repair. [ABSTRACT FROM AUTHOR]

Abstract: The treatment of peripheral nerve injuries remains a major problem worldwide despite the availability of a number of Food and Drug Administration (FDA) approved devices which fail to match the efficacy of autografts. Different strategies are used to improve regeneration and functional recovery using biomaterial nerve conduits. However, there is little investigation of the transcriptomic and proteomic changes which occur as a result of these interventions, particularly regarding transection injuries. This study explores differences between autograft‐mediated repair and conduit‐material‐mediated repair of peripheral nerve injuries to understand fundamental differences in their repair mechanisms at the proteomics level at the proximal, middle, and distal components in the early stages of repair. Pathway analysis demonstrates that each material selectively activates different regenerative pathways and alters different biological functions spatially throughout the biomaterial conduits. The analysis highlights some of the deficiencies in conduit‐mediated repair in comparison to autograft (e.g., recycling of myelin and cholesterol, reduction in reactive oxygen species, and higher expression of regenerative proteins). These findings thus suggest that by supplementing the expression of these proteins on the biomaterial of choice, this study can potentially attain regeneration equivalent to autograft. This approach paves the way for incorporating future biomaterial‐specific functionalities in nerve guidance conduits. [ABSTRACT FROM AUTHOR]

Background: Neurogenic erectile dysfunction (NED) caused by cavernous nerve (CN) injury is a typical complication after pelvic surgery, which lacks efficient treatments. Acetyl-L-carnitine (ALCAR) has been proven to promote nerve repair., Objectives: To investigate the effect and potential mechanism of ALCAR in the treatment of NED., Materials and Methods: Thirty-two rats were randomly divided into bilateral CN injury (BCNI) group, BCNI + lower-dose ALCAR (50 mg/kg/day) group, BCNI + higher-dose (100 mg/kg/day) group, and sham-operated group. Erectile function was assessed 14 days after daily intraperitoneal injection of ALCAR or placebo. The penile tissues were gathered for subsequent histological and molecular biological analysis. Rat Schwann cell (SC) line S16 was used to verify the mechanism of ALCAR in vitro., Results: We found that the erectile function of the rats in the BCNI group was severely impaired, which was improved considerably in both BCNI+ALCAR-LD and BCNI+ALCAR-HD groups. Also, we observed decreased smooth muscle and increased collagen content in the corpus cavernosum in the BCNI group. The expressions of fibrosis markers transforming growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and Smad 2/3 were significantly up-regulated in the BCNI group. The above changes were alleviated after the administration of lower and higher-dose ALCAR. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate pathway (cGMP) was promoted and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was inhibited in the corpus cavernosum of BCNI rats after ALCAR treatment, accompanied by increased neuronal nitric oxide synthase (nNOS) and down-regulated tyrosine hydroxylase (TH). In vitro, ALCAR promoted the migration and proliferation of SC and increased the expression of 22-kD peripheral myelin protein and nerve growth factor (NGF). Further, rats treated with ALCAR had high expression of ATF3 and S100 in the distal nerve tissues of the CN extrusion site., Discussion and Conclusion: ALCAR could promote nerve repair and regeneration, inhibit penile fibrosis, and improve penile erection by promoting the proliferation and migration of SC and the secretion of NGF. Our study confirms that ALCAR may be a potential treatment strategy for NED., (© 2022 American Society of Andrology and European Academy of Andrology.)

Peripheral nerve injuries often result in severe personal and social burden, and even with surgical treatment, patients continue to have poor clinical outcomes. Over the past two decades, electrical stimulation has been shown to promote axonal regeneration and alleviate refractory neuropathic pain. The aim of this study was to analyse this field using a bibliometric approach. Literature was searched through Web of Science Core Collection (WOSCC) for the years 2002–2023. Literature analysis included: (1) Describing publication trends in the field. (2) Exploring collaborative network relationships. (3) Finding research advances and research hotspots in the field. (4) Summarizing research trends in the field. With the number of studies in this field still increasing, a total of 693 publications were included in the analysis. This field of research is interdisciplinary in nature. Research hotspots include peripheral nerve regeneration, the treatment of neuropathic pain, materials for nerve injury repair, and the restoration of sensory function in patients with peripheral nerve injury. Correspondingly, the development of nerve conduits and systems for peripheral nerve electrical stimulation, clinical trials of peripheral nerve electrical stimulation, and tactile recovery and movement for amputees have shown significant promise as future research trends in this field. [ABSTRACT FROM AUTHOR]

Objectives: Determine if biomarkers of Alzheimer's disease and neural injury may play a role in the prediction of delirium risk. Methods: In a cohort of older adults who underwent elective surgery, delirium case‐no delirium control pairs (N = 70, or 35 matched pairs) were matched by age, sex and vascular comorbidities. Biomarkers from CSF and plasma samples collected prior to surgery, including amyloid beta (Aβ)42, Aβ40, total (t)‐Tau, phosphorylated (p)‐Tau181, neurofilament‐light (NfL), and glial fibrillary acid protein (GFAP) were measured in cerebrospinal fluid (CSF) and plasma using sandwich enzyme‐linked immunosorbent assays (ELISAs) or ultrasensitive single molecule array (Simoa) immunoassays. Results: Plasma GFAP correlated significantly with CSF GFAP and both plasma and CSF GFAP values were nearly two‐fold higher in delirium cases. The median paired difference between delirium case and control without delirium for plasma GFAP was not significant (p = 0.074) but higher levels were associated with a greater risk for delirium (odds ratio 1.52, 95% confidence interval 0.85, 2.72 per standard deviation increase in plasma GFAP concentration) in this small study. No matched pair differences or associations with delirium were observed for NfL, p‐Tau 181, Aβ40 and Aβ42. Conclusions: These preliminary findings suggest that plasma GFAP, a marker of astroglial activation, may be worth further investigation as a predictive risk marker for delirium. Key points: Delirium is a common complication of hospitalization associated with poor outcomes, but the underlying pathophsysiology of this condition is poorly understoodThere is a close interrelationship between delirium and dementia, therefore CSF and blood biomarkers for Alzheimer's Disease and neural injury might be associated with deliriumWe found that plasma and CSF glial fibrillary acid protein (GFAP), a marker of reactive gliosis known to be elevated in neurodegeneration, appears to be related to delirium risk, with a nearly two‐fold greater odds of deliriumFurther larger studies are needed to understand the potential role of GFAP as a predictive risk marker for delirium [ABSTRACT FROM AUTHOR]

Background: Post-partum lower extremity motor and sensory dysfunctions occur in 0.1-9.2‰ of deliveries. While macrosomia, lithotomy position and forceps use are well-identified causes of peripheral nerve injuries, additional contributors such as patient condition and anaesthesia care may also have to be considered., Methods: We performed a case-control study nested in a cohort of 19,840 patients having neuraxial anaesthesia for childbirth. Cases were all patients who developed motor or sensory dysfunction of lower extremities in the post-partum period. These were compared, using Chi-square, Fisher's exact test, logistic regression and time series, to a random sample of controls without any neurological symptoms or injury., Results: We identified 19 (0.96‰) patients with peripheral nerve injuries of which 15 (0.76‰) were likely associated with obstetrical care. In four additional cases (0.20‰), a nerve root injury due to the Tuohy needle was suspected. Univariate risk factors were: a gestational age ≥ 41 weeks, Odds Ratio (OR) 3.8; 95% CI: 1.1-13.1, late initiation of neuraxial anaesthesia OR 8.2; 95% CI: 1.8-37.9, a repeated anaesthetic procedure OR 2.8; 95% CI: 1.0-7.8, assisted delivery with forceps OR 9.8; 95% CI: 1.2-114.1 and newborn birth weight > 3.5 kg with an OR 6.8; 95% CI: 2.0-22.5., Conclusion: Obstetrical related factors are the most prominent risk associated with peripheral nerve injuries. This study highlights however that patient and anaesthesia-related factors may also contribute to peripheral nerve injuries., (© 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Neuritin, also known as candidate plasticity gene 15 (CPG15), was first identified as one of the activity-dependent gene products in the brain. Previous studies have been reported that Neuritin induces neuritogenesis, neurite arborization, neurite outgrowth and synapse formation, which are involved in the development and functions of the central nervous system. However, the role of Neuritin in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of Neuritin steering Schwann cell dedifferentiation during Wallerian degeneration (WD) in injured peripheral nerve. Herein, using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that Neuritin vividly accelerates Schwann cell dedifferentiation. Moreover, we found that Neuritin promotes Schwann cell demyelination as well as axonal degeneration, phagocytosis, secretion capacity. In summary, we first described Neuritin acts as a positive regulator for Schwann cell dedifferentiation and WD after peripheral nerve injury., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Engineered grafts constitute an alternative to autologous transplant for repairing severe peripheral nerve injuries. However, current clinically available solutions have substantial limitations and are not suited for the repair of long nerve defects. A novel design of nerve conduit is presented here, which consists of a chitosan porous matrix embedding a 3D‐printed poly‐ε‐caprolactone mesh. These materials are selected due to their high biocompatibility, safe degradability, and ability to support the nerve regeneration process. The proposed design allows high control over geometrical features, pores morphology, compression resistance, and bending stiffness, yielding tunable and easy‐to‐manipulate grafts. The conduits are tested in chronic animal experiments, aiming to repair a 15‐mm long gap in the sciatic nerve of rats, and the results are compared with an autograft. Electrophysiological and nociception tests performed monthly during a 4‐month follow‐up show that these conduits allow a good degree of muscle functional recovery. Histological analyses show abundant cellularization in the wall and in the lumen of the conduits and regenerated axons within all rats treated with these grafts. It is suggested that the proposed conduits have the potential to repair nerves over the limiting gap length and can be proposed as strategy to overcome the limitations of autograft. [ABSTRACT FROM AUTHOR]

Background: Optimal functional recovery following peripheral nerve injuries (PNIs) is dependent upon early recognition and prompt referral to specialist centres for appropriate surgical intervention. Technologies which facilitate the early detection of PNI would allow faster referral rates and encourage improvements in patient outcomes. Serum Neurofilament light chain (NfL) measurements are cheaper to perform, easier to access and interpret than many conventional methods used for nerve injury diagnosis, such as electromyography and/or magnetic resonance imaging assessments, but changes in serum NfL levels following traumatic PNI have not been investigated. This pre‐clinical study aimed to determine whether serum NfL levels can: (1) detect the presence of a nerve trauma and (2) delineate between different severities of nerve trauma. Methods: A rat sciatic nerve crush and common peroneal nerve crush were implemented as controlled animal models of nerve injury. At 1‐, 3‐, 7‐ and 21‐days post‐injury, serum samples were retrieved for analysis using the SIMOA® NfL analyser kit. Nerve samples were also retrieved for histological analysis. Static sciatic index (SSI) was measured at regular time intervals following injury. Results: Significant 45‐fold and 20‐fold increases in NfL serum levels were seen 1‐day post‐injury following sciatic and common peroneal nerve injury, respectively. This corresponded with an eightfold higher volume of axons injured in the sciatic compared to the common peroneal nerve (p <.001). SSI measurements post‐injury revealed greater reduction in function in the sciatic crush group compared with the common peroneal crush group. Conclusions: NfL serum measurements represent a promising method for detecting traumatic PNI and stratifying their severity. Clinical translation of these findings could provide a powerful tool to improve the surgical management of nerve‐injured patients. [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to investigate the safety and efficacy of pregabalin versus placebo in post‐traumatic peripheral neuropathic pain (PTNP). Methods: PubMed, Cochrane Library, Web of Science, and Google Scholar were searched for relevant evidence up to January 2022. The Cochran tool was used to assess the quality of randomized clinical trials (RCTs). Data analysis was performed using Comprehensive Meta‐Analysis software. Results: Three RCTs involving 821 patients were included in the meta‐analysis. A significant difference was observed between pregabalin and placebo in terms of the pain score (the standardized mean difference [SMD] = −0.14, 95% CI: 0.28 to −0.006, p = 0.04) and sleep interference (MD = −0.25, 95% CI: −0.39 to −0.11, p = 0.00). There was also a significant difference between pregabalin and placebo regarding somnolence (risk ratio [RR] = 2.78; 95% CI: 1.64–4.71, p = 0.00), dizziness (RR = 4.13; 95% CI: 2.71–6.28, p = 0.00), and disturbance in attention (RR: 2.97; 95% CI: 1.02–8.65, p = 0.04). However, no significant difference was observed between pregabalin and placebo in terms of headache (RR = 1.20; 95% CI: 0.70–2.06, p = 0.50), fatigue (RR = 1.42; 95% CI: 0.82–2.47, p = 0.20), nausea (RR = 1.52; 95% CI: 0.88–2.62, p = 0.13), constipation (RR = 1.84; 95% CI: 0.78–4.29, p = 0.15), and discontinuation (RR = 1.52; 95% CI: 0.45–5.06, p = 0.49). Conclusion: Compared with placebo, pregabalin showed better efficacy in reducing PTNP and improving sleep interference. However, it was associated with higher adverse events. Further RCTs are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Myelin undergoes various changes after nerve injury, and c-Jun has a close relationship with Schwann cells (SCs). However, it remains unclear whether c-Jun can be involved in nerve repair by regulating ferroptosis. To explore this, we first set up a facial nerve injury model and detected the changes of ferroptosis-related proteins and c-Jun by immunofluorescence and Western blot. Then, we cultured RSC 96 and pSCs, and studied the potential regulatory relationships by a combination of experimental methods such as CCK-8, ELISA, immunofluorescence, qRT-PCR, Western blot and viral transfection. Finally, we corroborated the role of c-Jun through animal experiments. Our experiments revealed that ferroptosis occurs after facial nerve injury. Erastin decreased GPX4, c-Jun proteins and GSH content, while PTGS2, NRF2, HO-1 proteins, MDA, Fe 2+ and ROS contents increased. This effect was inhibited after c-Jun overexpression but was reversed after the addition of c-Jun siRNA. Besides, we proved in vivo that c-Jun could inhibit ferroptosis and promote the recovery of facial nerve function. In conclusion, our study identified the relationship between c-Jun and ferroptosis during peripheral nerve injury repair, which provides new ideas for studying peripheral nerve injury and repair., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Peripheral nerve injury is a common clinical problem that often leads to significant functional impairment or even complete paralysis. Allograft has been proposed as a potential repair strategy for peripheral nerve injuries. Furthermore, peripheral nerve cryopreservation may result in nearly unlimited supply of grafts. However, the concentration of neurotrophic factors secreted by Schwann cells (SCs) in the local micro-environment after transplantation may not be sufficient for the survival of neuronal soma and axonal regeneration. Here, we investigated the effect of endogenous neurotrophic factors (ENTFs) on nerve regeneration in rats after the allograft of a cryopreserved sciatic nerve. ENTFs were highly expressed in the sciatic nerves pretreated for 14 days. Although the number of surviving cells in the sciatic nerves and their immunogenicity were low in the 14-day group after 4 weeks of cryopreservation, they continued to express high levels of ENTFs in vitro. At 1 week postoperation, the 14-day Allo group showed low plasma levels of interleukin-2, interferon-γ and tumour necrosis factor-alpha and low cellular immune response. At 20 weeks postoperation, nerve regeneration and functional recovery in the 14-day Allo group was similar to that in the fresh isograft group but better than that in the cryopreserved-fresh allograft and fresh allograft groups. Thus, ENTFs were induced in vitro after pretreatment of the sciatic nerve. Following cryopreservation, the sciatic nerves with high levels of ENTFs continued to express high levels of ENTFs in vitro. The immune response after allograft was weak, which promoted recipient nerve regeneration., (© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

This study aimed to investigate the therapeutic potential of human adipose‐derived mesenchymal stem cells (hADSCs) modified with recombinant adeno‐associated virus (rAAV) carrying the vascular endothelial growth factor 165 (VEGF165) gene in peripheral nerve injury (PNI). The hADSCs were categorized into blank, control (transduced with rAAV control vector), and VEGF165 (transduced with rAAV VEGF165 vector) groups. Subsequently, Schwann cell differentiation was induced, and Schwann cell markers were assessed. The sciatic nerve injury mouse model received injections of phosphate‐buffered saline (PBS group), PBS containing hADSCs (hADSCs group), rAAV control vector (control‐hADSCs group), or rAAV VEGF165 vector (VEGF165‐hADSCs group) into the nerve defect site. Motor function recovery, evaluated through the sciatic function index (SFI), and nerve regeneration, assessed via toluidine blue staining along with scrutiny of Schwann cell markers and neurotrophic factors, were conducted. Modified hADSCs exhibited enhanced Schwann cell differentiation and elevated expression of Schwann cell markers [S100 calcium‐binding protein B (S100B), NGF receptor (NGFR), and glial fibrillary acidic protein (GFAP)]. Mice in the VEGF165‐hADSCs group demonstrated improved motor function recovery compared to those in the other three groups, accompanied by increased fiber diameter, axon diameter, and myelin thickness, as well as elevated expression of Schwann cell markers (S100B, NGFR, and GFAP) and neurotrophic factors [mature brain‐derived neurotrophic factor (BDNF) and glial cell‐derived neurotrophic factor (GDNF)] in the distal nerve segment. rAAV‐VEGF165 modification enhances hADSC potential in PNI, promoting motor recovery and nerve regeneration. Elevated Schwann cell markers and neurotrophic factors underscore therapy benefits, providing insights for nerve injury strategies. [ABSTRACT FROM AUTHOR]

The article discusses the development of antibacterial fibrous patches made from alginate and Ceylon cinnamon using nozzle-pressurized spinning technology. Topics include the production of alginate fibers through a novel spinning process, the incorporation of Ceylon cinnamon to enhance antibacterial activity, and the assessment of the cytotoxicity and antibacterial effectiveness of the resulting fibrous patches.

Introduction: Posterior femoral cutaneous nerve (PFCN) neuropathy is an uncommon, potentially under‐recognized cause of low back, buttock, perineal, and posterior and lateral thigh pain and numbness. Most PFCN injuries are caused by intramuscular injections; however, this is the first reported case of a PFCN injury of hamstring pathology due to tendonitis caused by long‐distance running. Case Report: A middle‐aged man presented with right lower buttock pain, which started 2 weeks after running a marathon. The pain was located medial and superior to the ischia tuberosity and extended distally to the right scrotum with no testicular pain. The pain progressed such that he was unable to sit down for over a year. An initial MRI showed right hamstring tendonitis. Consults with sports medicine and hip orthopedics provided no clear diagnosis. He failed to improve with NSAIDs, physical therapy, massage, PRP injection, two Ganglion of Impar Nerve blocks, and trial of Pregabalin. The diagnosis was confirmed with temporary relief following a PFCN block. He was then advised to have the nerve resected because of the failure of nonsurgical treatment. Discussion: After excluding the more common etiologies of buttock pain and sitting intolerance, practitioners should consider the rarer condition of the impingement of the PFCN in runners. [ABSTRACT FROM AUTHOR]

Background and Purpose: Chronic pain is a devastating problem affecting one in five individuals around the globe, with neuropathic pain the most debilitating and poorly treated type of chronic pain. Advances in transcriptomics have contributed to cataloguing diverse cellular pathways and transcriptomic alterations in response to peripheral nerve injury but have focused on phenomenology and classifying transcriptomic responses. Experimental approach: To identifying new types of pain‐relieving agents, we compared transcriptional reprogramming changes in the dorsal spinal cord after peripheral nerve injury cross‐sex and cross‐species, and imputed commonalities, as well as differences in cellular pathways and gene regulation. Key Results: We identified 93 transcripts in the dorsal horn that were increased by peripheral nerve injury in male and female mice and rats. Following gene ontology and transcription factor analyses, we constructed a pain interactome for the proteins encoded by the differentially expressed genes, discovering new, conserved signalling nodes. We investigated the interactome with the Drug‐Gene database to predict FDA‐approved medications that may modulate key nodes within the network. The top hit from the analysis was fostamatinib, the molecular target of which is the non‐receptor spleen associated tyrosine kinase (Syk), which our analysis had identified as a key node in the interactome. We found that intrathecally administrating the active metabolite of fostamatinib, R406 and another Syk inhibitor P505‐15, significantly reversed pain hypersensitivity in both sexes. Conclusions and Implications: Thus, we have identified and shown the efficacy of an agent that could not have been previously predicted to have analgesic properties. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries can occur at any time during the peri-operative period. The long-term disability that results may have serious consequences for a patient. The incidence of peri-operative nerve injuries can be reduced by anaesthetists being aware of their causes and pathophysiology. This review article aims to explain the incidence, pathophysiology and medicolegal implications of peri-operative nerve injury and provides suggestions as to how they may best be avoided.

Background Aim Study Design Results Relevance to Clinical Practice Prone positioning improves oxygenation in adults with acute respiratory distress syndrome (ARDS) and has been extensively applied in intensive care units (ICU) during the COVID‐19 pandemic. Although some complications due to the manoeuvre are well known, brachial plexus injury after prone positioning is reported as a rare complication and the phenomenon could be either very rare or underestimated.This study aimed to evaluate the effect of swimmer position during prone ventilation on the onset of brachial plexus injury in patients admitted to ICU for ARDS. The study will also evaluate the safety of prolonged prone positioning collecting data on any adverse events occurred.A prospective, observational cohort study will be conducted in a tertiary level ICU in the metropolitan area of Milano (Italy) specialized in advanced treatment of patients with ARDS. This observational study will report clinical data on the electromyography (EMG) and the muscle strength assessment, including comorbidities and cardio‐respiratory status. A baseline EMG will be performed within 2 h from the first pronation manoeuvre and immediately at the end of each pronation cycle. The functional assessment of patients will be also performed at the end of ICU stay and at hospital discharge.The primary outcome is to estimate the prevalence of brachial plexus injury in patients with ARDS placed in the swimmer position during prone ventilation. Secondary outcomes will also include the safety of the manoeuvre by evaluation of all adverse events classified as skin or ocular damage, loss of tube and vascular access and new pressure ulcers.The findings of this study will contribute to understand the possible benefits/harms of prone ventilation performed using swimmer position. Eventually, this will call for the development of specific and tailored rehabilitation programs for patients with upper limb injuries during ICU stay, including also timely follow‐up upon ICU‐discharge. [ABSTRACT FROM AUTHOR]

Background: Apoptosis is an important pathologic mechanism of erectile dysfunction after radical prostatectomy. Studies have shown that programmed cell death factor 4 is connected to the modulation of apoptosis in many cells. However, the programmed cell death factor 4 function in the cavernous nerve injury erectile dysfunction is unclear., Objective: This investigation aimed to explore the programmed cell death factor 4 function in erectile dysfunction in rats with bilateral cavernous nerve crush., Materials and Methods: The experiment used 30 male Sprague Dawley rats (18 months old) that were screened for normal erectile function by the apomorphine test. Ten rats were randomized into Sham and bilateral cavernous nerve crush groups to detect changes in programmed cell death factor 4 expression. The remaining 20 rats were distributed at random to four groups: the Sham group treated by sham surgery, the phosphate-buffered saline group, the lentivirus containing negative control short hairpin RNA group, and the lentivirus containing short hairpin RNA targeting programmed cell death factor 4 group underwent bilateral cavernous nerve crush and were afterward administered intracavernous injections of phosphate-buffered saline, lentivirus containing negative control short hairpin RNA, or lentivirus containing short hairpin RNA targeting programmed cell death factor 4. Electrical stimulation of the cavernous nerve was conducted 2 weeks later for penile erectile function assessment. The cavernous tissue was collected for histological analysis and western blotting., Results: The apoptosis level in rat corpus cavernosum was elevated, and programmed cell death factor 4 expression was increased after bilateral cavernous nerve crush. Knockdown of programmed cell death factor 4 significantly improved erectile function in bilateral cavernous nerve crush rats. Furthermore, lentivirus containing short hairpin RNA targeting programmed cell death factor 4 treatment raised smooth muscle content and attenuated cavernous fibrosis and apoptotic levels. Additionally, programmed cell death factor 4 was found to mediate the PI3K/AKT pathway., Discussion and Conclusion: Elevated programmed cell death factor 4 expression may be an important pathogenetic mechanism for erectile dysfunction after bilateral cavernous nerve crush, and the knockdown of programmed cell death factor 4 enhanced erectile function in 18-month-old rats after cavernous nerve damage. The potential mechanism may be the stimulation of the PI3K/AKT pathway to attenuate the cavernous apoptosis level., (© 2024 American Society of Andrology and European Academy of Andrology.)

Peripheral nerve injury often leads to the loss of neurological functions due to the slow regeneration rate and inefficient functional reconstruction. Current clinical treatments using nerve guidance conduits (NGCs) still face challenges in providing a biomimetic microenvironment to promote nerve repair. Herein, decellularized extracellular matrix (dECM) is obtained from porcine Achilles tendon and crosslinked with 3‐amino‐4‐methoxybenzoic acid grafted gelatin (PAMB‐G) to obtain conductive hydrogels. Then, a novel nerve guidance conduit is developed by assembling poly(vinyl alcohol) (PVA) conduit and conductive ECM@PAMB‐G hydrogel. This bioengineered ECM@PAMB‐G/PVA conduit demonstrated excellent cytocompatibility, electrical conductivity, mechanical properties, and biodegradability. In vitro experiments confirmed that the ECM@PAMB‐G hydrogel significantly promotes the proliferation and migration of PC12 cells and primary Schwann cells, as well as the growth of dorsal root ganglion (DRG) axons. Furthermore, in vivo studies in a rat sciatic nerve model exhibited improvements in axonal regeneration, Schwann cell migration, myelin sheath formation, and functional recovery mediated by the ECM@PAMB‐G/PVA conduit. This work demonstrates the synergistic effects of extracellular matrix and electrical cues in enhancing peripheral nerve regeneration. The ECM@PAMB‐G/PVA nerve guidance conduit shows potential as an alternative to autografts for supporting peripheral nerve reconstruction. [ABSTRACT FROM AUTHOR]

Electroactive materials are increasingly recognized for their efficacy in promoting the repair of peripheral nerve injury. However, the mechanism by which electroactive materials promote peripheral nerve regeneration by modulating the immune microenvironment remains incompletely explored. In this study, a PVDF/PLCL/PEDOT artificial peripheral nerve conduit with dual electroactivity by integrating piezoelectric properties and electrical conductivity is constructed. The electroactive conduit exhibited excellent spontaneous electrical and conductive properties, superior suture resistance and anti‐twisting properties. Detailed in vitro cell experiments and in vivo animal experiments are conducted, revealing that the electroactive nerve conduit can effectively promote rat sciatic nerve regeneration while facilitating reconstruction of both nerve conduction function and motor function. Furthermore, the underlying mechanism in depth is investigated and found that the electroactive material can regulate the immune microenvironment by activating the PI3K/AKT‐Nrf2 signaling pathway, thereby promoting macrophage polarization toward M2 anti‐inflammatory phenotype. This subsequently facilitated Schwann cell recruitment and myelin formation through mediation of the macrophage paracrine system. Importantly, blocking immune signaling pathways diminished the effectiveness of the electroactive nerve conduit in promoting nerve repair. The work elucidated how electroactive materials modulate immune microenvironment to positively impact peripheral nerve repair, highlighting the critical role of immune modulation in peripheral nerve repair. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are debilitating, and current clinical management is limited to surgical intervention, which often leads to poor functional outcomes. Development of pharmacological interventions aimed at enhancing regeneration may improve this. One potential pharmacological target is the P2X purinergic receptor 7 (P2X7R) expressed in Schwann cells, which is known to play a role during the development of the peripheral nerves. Herein, we analysed differences in regeneration between genetically engineered P2X7 knockout mice and wild-type controls, using in vivo and ex vivo models of peripheral nerve regeneration. We have found that the speed of axonal regeneration is unaltered in P2X7 knockout mice, nevertheless regenerated P2X7 knockout nerves are morphologically different to wild-type nerves following transection and immediate repair. Indeed, the detailed morphometric analysis at 4 and 8 weeks after injury showed evidence of delayed remyelination in P2X7 knockout mice, compared to the wild-type controls. Furthermore, the Wallerian degeneration phase was unaltered between the two experimental groups. We also analysed gene expression changes in the dorsal root ganglia neurones as a result of the peripheral nerve injury, and found changes in pathways related to pain, inflammation and cell death. We conclude that P2X7 receptors in Schwann cells may be a putative pharmacological target to control cell fate following injury, thus enhancing nerve re-myelination., (© 2020 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)