Therapeutic roles of coenzyme Q10 in peripheral nerve injury-induced neurosensory disturbances: Mechanistic insights from injury to recovery.

Peripheral nerve injuries (PNIs) are prevalent conditions mainly resulting from systemic causes, including autoimmune diseases and diabetes mellitus, or local causes, for example, chemical injury and perioperative nerve injury, which can cause a varying level of neurosensory disturbances (NSDs). Coenzyme Q10 (CoQ10) is an essential regulator of mitochondrial respiration and oxidative metabolism. Here, we review the pathophysiology of NSDs caused by PNIs, the current understanding of CoQ10's bioactivities, and its potential therapeutic roles in nerve regeneration, based on evidence from experimental and clinical studies involving CoQ10 supplementation. In summary, CoQ10 supplementation shows promise as a neuroprotective agent, potentially enhancing treatment efficacy for NSDs by reducing oxidative stress and inflammation. Future studies should focus on well-designed clinical trials with large sample sizes, using CoQ10 formulations with proven bioavailability and varying treatment duration, to further elucidate its neuroprotective effects and to optimize nerve regeneration in PNIs-induced NSDs.

B cells drive neuropathic pain-related behaviors in mice through IgG-Fc gamma receptor signaling.

Neuroimmune interactions are essential for the development of neuropathic pain, yet the contributions of distinct immune cell populations have not been fully unraveled. Here, we demonstrate the critical role of B cells in promoting mechanical hypersensitivity (allodynia) after peripheral nerve injury in male and female mice. Depletion of B cells with a single injection of anti-CD20 monoclonal antibody at the time of injury prevented the development of allodynia. B cell-deficient (muMT) mice were similarly spared from allodynia. Nerve injury was associated with increased immunoglobulin G (IgG) accumulation in ipsilateral lumbar dorsal root ganglia (DRGs) and dorsal spinal cords. IgG was colocalized with sensory neurons and macrophages in DRGs and microglia in spinal cords. IgG also accumulated in DRG samples from human donors with chronic pain, colocalizing with a marker for macrophages and satellite glia. RNA sequencing revealed a B cell population in naive mouse and human DRGs. A B cell transcriptional signature was enriched in DRGs from human donors with neuropathic pain. Passive transfer of IgG from injured mice induced allodynia in injured muMT recipient mice. The pronociceptive effects of IgG are likely mediated through immune complexes interacting with Fc gamma receptors (FcγRs) expressed by sensory neurons, microglia, and macrophages, given that both mechanical allodynia and hyperexcitability of dissociated DRG neurons were abolished in nerve-injured FcγR-deficient mice. Consistently, the pronociceptive effects of IgG passive transfer were lost in FcγR-deficient mice. These data reveal that a B cell-IgG-FcγR axis is required for the development of neuropathic pain in mice.

Therapeutic Potential of Vitamin B Complex in Peripheral Nerve Injury Recovery: An Experimental Rat Model Study.

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.

Spared ulnar nerve injury results in increased layer III-VI excitability in the pig somatosensory cortex.

This study describes cortical recordings in a large animal nerve injury model. We investigated differences in primary somatosensory cortex (S1) hyperexcitability when stimulating injured and uninjured nerves and how different cortical layers contribute to S1 hyperexcitability after spared ulnar nerve injury. We used a multielectrode array to record single-neuron activity in the S1 of ten female Danish landrace pigs. Electrical stimulation of the injured and uninjured nerve evoked brain activity up to 3 h after injury. The peak amplitude and latency of early and late peristimulus time histogram responses were extracted for statistical analysis. Histological investigations determined the layer of the cortex in which each electrode contact was placed. Nerve injury increased the early peak amplitude compared with that of the control group. This difference was significant immediately after nerve injury when the uninjured nerve was stimulated, while it was delayed for the injured nerve. The amplitude of the early peak was increased in layers III-VI after nerve injury compared with the control. In layer III, S1 excitability was also increased compared with preinjury for the early peak. Furthermore, the late peak was significantly larger in layer III than in the other layers in the intervention and control group before and after injury. Thus, the most prominent increase in excitability occurred in layer III, which is responsible for the gain modulation of cortical output through layer V. Therefore, layer III neurons seem to have an important role in altered brain excitability after nerve injury.

[Research progress of silk-based biomaterials for peripheral nerve regeneration].

Objective: To describe the research progress of silk-based biomaterials in peripheral nerve repair and provide useful ideals to accelerate the regeneration of large-size peripheral nerve injury. Methods: The relative documents about silk-based biomaterials used in peripheral nerve regeneration were reviewed and the different strategies that could accelerate peripheral nerve regeneration through building bioactive microenvironment with silk fibroin were discussed. Results: Many silk fibroin tissue engineered nerve conduits have been developed to provide multiple biomimetic microstructures, and different microstructures have different mechanisms of promoting nerve repair. Biomimetic porous structures favor the nutrient exchange at wound sites and inhibit the invasion of scar tissue. The aligned structures can induce the directional growth of nerve tissue, while the multiple channels promote the axon elongation. When the fillers are introduced to the conduits, better growth, migration, and differentiation of nerve cells can be achieved. Besides biomimetic structures, different nerve growth factors and bioactive drugs can be loaded on silk carriers and released slowly at nerve wounds, providing suitable biochemical cues. Both the biomimetic structures and the loaded bioactive ingredients optimize the niches of peripheral nerves, resulting in quicker and better nerve repair. With silk biomaterials as a platform, fusing multiple ways to achieve the multidimensional regulation of nerve microenvironments is becoming a critical strategy in repairing large-size peripheral nerve injury. Conclusion: Silk-based biomaterials are useful platforms to achieve the design of biomimetic hierarchical microstructures and the co-loading of various bioactive ingredients. Silk fibroin nerve conduits provide suitable microenvironment to accelerate functional recovery of peripheral nerves. Different optimizing strategies are available for silk fibroin biomaterials to favor the nerve regeneration, which would satisfy the needs of various nerve tissue repair. Bioactive silk conduits have promising future in large-size peripheral nerve regeneration.

Muscle-resident mesenchymal progenitors sense and repair peripheral nerve injury via the GDNF-BDNF axis.

Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors Ret and Gfra1 can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses Bdnf. FAP-specific inactivation of Bdnf (Prrx1Cre; Bdnffl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced Bdnf expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs' response to peripheral nerve injury.

Comparison of Neural Recovery Effects of Botulinum Toxin Based on Administration Timing in Sciatic Nerve-Injured Rats.

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 S100ß (S100ß), 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.

Evaluation of Rehabilitation Techniques for Traumatic Ulnar Nerve Injuries After Surgical Repair: A Systematic Review.

BACKGROUND: Traumatic ulnar nerve injuries often result in significant loss of motor and sensory function, negatively impacting patients' quality of life. Physical rehabilitation is crucial for recovery, but standardized treatment protocols are lacking. This study aims to systematically review rehabilitation techniques to identify future research direction and improve existing protocols for ulnar nerve injury patients. METHODS: PubMed, Embase, CINAHL, Cochrane CENTRAL, Web of Science, and Scopus were queried from inception until July 31, 2023. Articles containing axonotmesis or neurotmesis injuries of the ulnar nerve were included. Reviews, opinions, editorials, technical reports without clinical outcomes, conference abstracts, non-English text, nonhuman studies, and studies without adult patients were excluded. Three independent reviewers performed screening and data extraction using Covidence, and risk of bias assessments utilizing Cochrane and JBI tools. Because of article heterogeneity, a narrative review was conducted. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database, registration number CRD42023442016. RESULTS: This systematic review included one randomized controlled trial and four observational studies (103 patients), which exhibited differences in study quality. Overall, motor and sensory outcomes improved after rehabilitation. Rehabilitation techniques varied widely, and early sensory reeducation appeared to improve sensory function. Only two studies included patient-reported outcomes. CONCLUSIONS: Diverse rehabilitation techniques are used to address ulnar nerve injuries. The low number of included studies, differences in study quality, and small sample size underscore the need for larger and more inclusive studies to improve functional recovery after ulnar nerve injuries. Future research should consider the impact of patient and injury characteristics to develop comprehensive treatment guidelines for these patients.

[Peripheral nerves' function recovery by intratissual electric stimulation]. / Vosstanovlenie funktsii perifericheskikh nervov vnutritkanevoi elektrostimulyatsiei.

An intratissual electrical stimulation, accompanied by irritation of their central neurons, is used to recover the function of damaged peripheral nerves. Treatment results exceeded those with the use of cutaneous electrical stimulation, which is confirmed by comparative results of trial animal experiments. The time and quality of peripheral nerves' function recovery in comparison of intratissual and cutaneous electrical stimulation methods remain unknown. OBJECTIVE: To evaluate the time and quality of peripheral nerves' functions recovery after their suturing and conducting two different methods of electrical stimulation, namely intratissual and cutaneous, in projection of central neurons of damaged spinal nerves in the postoperative period. MATERIAL AND METHODS: The basic technical parameters of the method of peripheral nerves' functions recovery in the postoperative period were ptacticed. Postoperative rehabilitation treatment was performed in 77 patients with traumatic peripheral nerves' injuries at the level of the forearm: in 42 with intratissual electrical stimulation, in 35 - using cutaneous one with similar characteristics of electrical current and concomitant pharmacological therapy. The follow-up duration was 2 years. RESULTS: A significant (in 4-6 times) reduction in time of treatment and a greater improvement in qualitative indicators when using intratissual electrical stimulation compared to the use of cutaneous stimulation were obtained. The effectiveness of the restorative therapy was dependent on the number of procedures, and a complete recovery of the damaged peripheral nerves' functions was observed after three courses of intratissual electrical stimulation. CONCLUSION: The time and degree of recovery of peripheral nerves' functions depends on the functional activity of their central neurons at the level of the spinal cord. The activation of these neurons by low-frequency electrical current allows to activate their trophic function. Thus, the cutaneous electrical stimulation does not cause the necessary level of irritation of the neurons due to the fact that the skin is a barrier to electrical current, which reduces its impact in 200-500 times. The intratissual electrical stimulation allows to solve the problem by supplying the needle-electrode much closer to the «target¼. The proposed method of intratissual electrical stimulation has shown its advantage over cutaneous electrical stimulation, significantly reducing the duration of the restorative treatment and increasing its qualitative indicators.

Upper Extremity Ballistic Nerve Injury: A Scoping Review and Algorithm for Management.

¼ Gunshot injuries to the upper extremity (UE) have high likelihood for causing peripheral nerve injury secondary to the high density of vital structures. Roughly one-fourth of patients sustaining a gunshot wound (GSW) to the UE incur a nerve injury. Of these nerve injuries, just over half are neurapraxic. In cases of surgical exploration of UE nerve injuries, nearly one-third demonstrate a transected or discontinuous nerve.¼ Existing literature regarding surgical management of nerve injuries secondary to GSWs comes from both military and civilian injuries. Outcomes are inconsistently reported, and indications are heterogeneous; however, reasonable results can be obtained with nerve reconstruction.¼ Our proposed management algorithm hinges on 4 treatment questions: if there is a nerve deficit present on examination, if there is a concomitant injury in the extremity (i.e., fracture or vascular insult), whether the injured nerve would be in the operative field of the concomitant injury, and whether there was an identified nerve lesion encountered at the time of surgery by another surgeon?¼ Early exploration rather than continued expectant management may offer improved recovery from GSW nerve injuries in particular situations. When an UE nerve deficit is present, establishing follow-up after the initial GSW encounter and early referral to a peripheral nerve surgeon are pivotal.

Diffusion Tensor Imaging: Techniques and Applications for Peripheral Nerve Injury.

ABSTRACT: Peripheral nerve injuries (PNIs) represent a complex clinical challenge, necessitating precise diagnostic approaches for optimal management. Traditional diagnostic methods often fall short in accurately assessing nerve recovery as these methods rely on the completion of nerve reinnervation, which can prolong a patient's treatment. Diffusion tensor imaging (DTI), a noninvasive magnetic resonance imaging (MRI) technique, has emerged as a promising tool in this context. DTI offers unique advantages including the ability to quantify nerve recovery and provide in vivo visualizations of neuronal architecture. Therefore, this review aims to examine and outline DTI techniques and its utility in detecting distal nerve regeneration in both preclinical and clinical settings for peripheral nerve injury.

In-Vivo MRI in Rodents: A Protocol for Optimal Animal Positioning.

ABSTRACT: Magnetic resonance imaging (MRI) is a potentially powerful novel peripheral nerve diagnosis technique. To determine its validity, in-vivo preclinical studies are necessary. However, when using a rodent model, positioning rats and achieving high-resolution images can be challenging. We present a short report that outlines an optimal protocol for positioning rats for in-vivo MRI acquisition. Female Sprague-Dawley rats with sciatic nerve injury were induced into anesthesia using 4% isoflurane in oxygen and maintained at 1.5%. Rats were placed into a plexiglass cradle in a right lateral recumbent position, and a surface coil was placed over the left leg. Respiration rate and body temperature were monitored throughout the scan. Our protocol was successful as rats were able to undergo MRI scanning safely and efficiently. There were no adverse reactions, and clear images of the left sciatic nerve were obtained. Animal positioning took 30 minutes, and 5 different acquisitions were obtained in 2 hours. The total time from anesthesia induction to recovery was under 3 hours. Given the increasing interest in MRI diagnostic techniques, we hope this report aids other researchers studying peripheral nerve injury imaging in rat models.

An analysis of differential gene expression in peripheral nerve and muscle utilizing RNA sequencing after polyethylene glycol nerve fusion in a rat sciatic nerve injury model.

Application of polyethylene glycol (PEG) to a peripheral nerve injury at the time of primary neurorrhaphy is thought to prevent Wallerian degeneration via direct axolemma fusion. The molecular mechanisms of nerve fusion and recovery are unclear. Our study tested the hypothesis that PEG alters gene expression in neural and muscular environments as part of its restorative properties. Lewis rats underwent unilateral sciatic nerve transection with immediate primary repair. Subjects were randomly assigned to receive either PEG treatment or standard repair at the time of neurorrhaphy. Samples of sciatic nerve distal to the injury and tibialis muscle at the site of innervation were harvested at 24 hours and 4 weeks postoperatively. Total RNA sequencing and subsequent bioinformatics analyses were used to identify significant differences in differentially expressed genes (DEGs) and their related biological pathways (p<0.05) in PEG-treated subjects compared to non-PEG controls. No significant DEGs were identified in PEG-treated sciatic nerve compared to controls after 24 hours, but 1,480 DEGs were identified in PEG-treated tibialis compared to controls. At 4 weeks, 918 DEGs were identified in PEG-treated sciatic nerve, whereas only 3 DEGs remained in PEG-treated tibialis compared to controls. DEGs in sciatic were mostly upregulated (79%) and enriched in pathways present during nervous system development and growth, whereas DEGs in muscle were mostly downregulated (77%) and related to inflammation and tissue repair. Our findings indicate that PEG application during primary neurorrhaphy leads to significant differential gene regulation in the neural and muscular environment that is associated with improved functional recovery in animals treated with PEG compared to sham non-PEG controls. A detailed understanding of key molecules underlying PEG function in recovery after peripheral nerve repair may facilitate amplification of PEG effects through systemic or focal treatments at the time of neurotmesis.

Collagen protein-chitosan nerve conduits with neuroepithelial stem cells promote peripheral nerve regeneration.

The peripheral nervous system consists of ganglia, nerve trunks, plexuses, and nerve endings, that transmit afferent and efferent information. Regeneration after a peripheral nerve damage is sluggish and imperfect. Peripheral nerve injury frequently causes partial or complete loss of motor and sensory function, physical impairment, and neuropathic pain, all of which have a negative impact on patients' quality of life. Because the mechanism of peripheral nerve injury and healing is still unclear, the therapeutic efficacy is limited. As peripheral nerve injury research has processed, an increasing number of studies have revealed that biological scaffolds work in tandem with progenitor cells to repair peripheral nerve injury. Here, we fabricated collagen chitosan nerve conduit bioscaffolds together with collagen and then filled neuroepithelial stem cells (NESCs). Scanning electron microscopy showed that the NESCs grew well on the scaffold surface. Compared to the control group, the NESCs group contained more cells with bigger diameters and myelinated structures around the axons. Our findings indicated that a combination of chitosan-collagen bioscaffold and neural stem cell transplantation can facilitate the functional restoration of peripheral nerve tissue, with promising future applications and research implications.

Knowledge, attitudes, and practices of healthcare professionals toward rehabilitation of peripheral nerve injury.

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.

A potential treatment for erectile dysfunction: Effect of platelet-rich plasma administration on axon and collagen regeneration in cavernous nerve injury.

Recent studies highlighted the role of platelet-rich plasma (PRP) in progenitor cell homing, migration, and nerve cell regeneration while also inhibiting fibrosis and apoptosis in cavernous nerve injury (CNI). The aim of this study was to investigate the effect of PRP administration on axon and collagen regeneration in CNI. A true experimental study using a post-test-only control group design was conducted. Twenty-five male Wistar rats (Rattus norvegicus), weighing 200-300 grams, were divided into five groups: two control groups (sham procedure and negative control), and three experimental groups receiving local PRP, intraperitoneal PRP, and a combination of local and intraperitoneal PRP. The cavernous nerve was injured with a hemostasis clamp for one minute before 200 µL of 200 PRP was injected locally, intraperitoneally, or both, depending on the group. After four weeks, the rats were euthanized, tissue segments (2 mm) from each cavernous nerve and mid-penis were collected and analyzed for collagen density, axon diameter, and number of myelinated axons. Our study found that collagen growth was slower in CNI group without PRP (sham procedure) compared to all PRP groups (local, intraperitoneal, and combination). The intraperitoneal PRP group had the highest collagen density at 5.62 µm; however, no significant difference was observed in collagen density among all groups (p=0.056). Similar axon diameter was found across the groups, with no statistically significant difference observed (p=0.856). In the number of myelinated axons, a significant difference was found among all groups with significantly more axons in local PRP and combined local and intraperitoneal PRP groups compared to others (p=0.026). In conclusion, PRP administration improved the number of myelinated axons in CNI, suggesting PRP role in CNI regeneration and the potential for an innovative approach to treating erectile dysfunction associated with CNI.

MFG-E8 Ameliorates Nerve Injury-Induced Neuropathic Pain by Regulating Microglial Polarization and Neuroinflammation via Integrin ß3/SOCS3/STAT3 Pathway in Mice.

Spinal microglial polarization plays a crucial role in the pathological processes of neuropathic pain following peripheral nerve injury. Accumulating evidence suggests that milk fat globule epidermal growth factor-8 (MFG-E8) exhibits anti-inflammatory effect and regulates microglial polarization through the integrin ß3 receptor. However, the impact of MFG-E8 on microglial polarization in the context of neuropathic pain has not yet been investigated. In this study, we evaluated the effect of MFG-E8 on pain hypersensitivity and spinal microglial polarization following spared nerve injury (SNI) of the sciatic nerve in mice. We determined the molecular mechanisms underlying the effects of MFG-E8 on pain hypersensitivity and spinal microglial polarization using pain behavior assessment, western blot (WB) analysis, immunofluorescence (IF) staining, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and small interfering RNA (siRNA) transfection. Our findings indicate that SNI significantly increased the levels of MFG-E8 and integrin ß3 expressed in microglia within the spinal cord of mice. Additionally, we observed that intrathecal injection of recombinant human MFG-E8 (rhMFG-E8) alleviated SNI induced-mechanical allodynia and thermal hyperalgesia. Furthermore, the results suggested that rhMFG-E8 facilitated M2 microglial polarization and ameliorated neuroinflammation via integrin ß3/SOCS3/STAT3 pathway in the spinal cord of mice with SNI. Importantly, these effects were negated by integrin ß3 siRNA, or SOCS3 siRNA. These results demonstrate that MFG-E8 ameliorates peripheral nerve injury induced-mechanical allodynia and thermal hyperalgesia by driving M2 microglial polarization and mitigating neuroinflammation mediated by integrin ß3/SOCS3/STAT3 pathway in the spinal cord of mice. MFG-E8 may serve as a promising target for the treatment of neuropathic pain.

Effects of N-acetylcysteine on sciatic nerve healing: A histopathological, functional, and biochemical study of the rat sciatic nerve.

OBJECTIVES: This study aims to evaluate the histopathological, biochemical, and functional effects of N-acetylcysteine (NAC), which has antioxidant, anti-inflammatory, and cytoprotective activity, on nerve regeneration in rats with sciatic nerve crush (axonotmesis) injury. MATERIALS AND METHODS: This study used 16 male Wistar rats, which were divided into treatment and control groups. A standard axonotmesis-type surgical injury was induced in the left sciatic nerves of all rats. The treatment group was given 300 mg/kg of intraperitoneal NAC once a day, whereas the control group received an equal volume of saline solution. After conducting gait analyses, the sciatic functional index (SFI) was used for functional assessment. After gait analysis, all animals were euthanized. Blood samples were examined biochemically. The left sciatic nerves and left triceps surae muscles were examined histopathologically. RESULTS: Histopathologically, the thickness of the perineurium, axonal degeneration, axonolysis, edema, inflammation, muscle atrophy, and muscle degeneration were all significantly lower in the treatment group (p<0.05). Functionally, SFI-1, SFI-2, and SFI-3 were significantly higher in the treatment group (p<0.05). Biochemically, while the native thiol level and native thiol/total thiol ratio were significantly higher in the treatment group (p<0.003), the disulfide/total thiol ratio was significantly higher in the control group (p<0.005). Significant correlations were found between six of the seven gait parameters and the histopathological findings (p<0.05). CONCLUSION: Our study results suggest that NAC may contribute positively to the histopathological and functional recovery of sciatic nerve injury in rats. Furthermore, NAC may have an antioxidant effect on thiol-disulfide homeostasis at a biochemical level. We believe that NAC has a stimulatory effect on healing following nerve injuries.

A systematic review of clinical and laboratory studies comparing vascularised versus non-vascularised nerve grafts in peripheral nerve reconstruction.

BACKGROUND: Peripheral nerve injuries (PNIs) are common, with complex defects posing a significant reconstructive challenge. Although vascularised (VNGs) and non-vascularised nerve grafts (NVNGs) are established treatment options, there is no comprehensive summary of the evidence supporting their clinical, electrophysiological, and histological outcomes. This review aims to systematically evaluate the clinical and laboratory literature comparing VNGs and NVNGs to inform future clinical practice and research. METHODS: This review was prospectively registered and reported according to PRISMA guidelines. PubMed, EMBASE, SCOPUS, and the Cochrane Register were systematically searched. Studies comparing VNGs and NVNGs in PNIs were included. Meta-analyses were performed for outcomes reported in ≥3 laboratory studies. Functional outcomes were synthesised by vote-counting based on direction of effect for clinical studies. Risk-of-bias was assessed using RoB2, ROBINS-I, and SYRCLE, and the certainty of evidence was evaluated using GRADE. RESULTS: Seven clinical and 34 laboratory studies were included. Of the clinical comparisons, 90% and 56% identified an effect on recovery of sensibility (p = 0.01) and motor function (p = 0.05), respectively, that favoured VNGs. Nine (of 13) separate meta-analyses of laboratory studies demonstrated reduced muscular atrophy, superior axonal regeneration, and remyelination in VNGs. VNGs eliminated the 3-day interval of ischaemia otherwise sustained by NVNGs. Overall, the quality of evidence was low. CONCLUSION: This systematic review indicates that VNGs may offer some advantages over NVNGs in PNI reconstruction. However, due to the low quality of evidence, significant statistical heterogeneity, and clinical diversity of the included studies, these conclusions should be interpreted with caution. Further high-quality clinical trials are necessary to validate these findings.

Transcriptional reprogramming post-peripheral nerve injury: A systematic review.

Neuropathic pain is characterised by periodic or continuous hyperalgesia, numbness, or allodynia, and results from insults to the somatosensory nervous system. Peripheral nerve injury induces transcriptional reprogramming in peripheral sensory neurons, contributing to increased spinal nociceptive input and the development of neuropathic pain. Effective treatment for neuropathic pain remains an unmet medical need as current therapeutics offer limited effectiveness and have undesirable effects. Understanding transcriptional changes in peripheral nerve injury-induced neuropathy might offer a path for novel analgesics. Our literature search identified 65 papers exploring transcriptomic changes post-peripheral nerve injury, many of which were conducted in animal models. We scrutinize their transcriptional changes data and conduct gene ontology enrichment analysis to reveal their common functional profile. Focusing on genes involved in 'sensory perception of pain' (GO:0019233), we identified transcriptional changes for different ion channels, receptors, and neurotransmitters, shedding light on its role in nociception. Examining peripheral sensory neurons subtype-specific transcriptional reprograming and regeneration-associated genes, we delved into downstream regulation of hypersensitivity. Identifying the temporal program of transcription regulatory mechanisms might help develop better therapeutics to target them effectively and selectively, thus preventing the development of neuropathic pain without affecting other physiological functions.