Search

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

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

Alterations in anion balance potential, along with the involvement of cation-chloride cotransporters, play pivotal roles in the development of hyperalgesia after peripheral nerve injury. Chloride voltage-gated channel seven (CLCN7) is the predominant member of the CLC protein family. Investigations on CLCN7 have focused primarily on its involvement in osteosclerosis and lysosomal storage disorders; nevertheless, its contribution to neuropathic pain has not been determined. In this investigation, we noted high expression of CLCN7 in neurons situated within the spinal dorsal horns and dorsal root ganglions (DRGs). Immunofluorescence analysis revealed that CLCN7 was predominantly distributed among IB4-positive and CGRP-positive neurons. Furthermore, the expression of CLCN7 was observed to be mainly reduced in neurons within the spinal dorsal horns and in small- and medium-sized neurons located in the DRGs of spared nerve injury mice. Knockdown of CLCN7 via siRNA in the DRGs resulted in increased mechanical and thermal hyperalgesia in naïve mice. Furthermore, the excitability of cultured DRG neurons in vitro was augmented upon treatment with CLCN7 siRNA. These findings suggested that CLCN7 downregulation following SNI was crucial for the manifestation of mechanical and thermal hyperalgesia, highlighting potential targeting strategies for treating neuropathic pain. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

• CoQ10 promotes nerve regeneration by enhancing mitochondrial biogenesis. • CoQ10 improves antioxidative mechanisms led to accelerating neural tissue healing. • CoQ10 can protect against neuroinflammation in neurosensory disturbances. • Early CoQ10 supplementation enhances neuroprotection. • CoQ10 supplementation may serve as adjunctive treatment for peripheral nerve injury. 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. [Display omitted] Graphical abstract legend Coenzyme Q10 may serve as a potential therapeutic agent in preventing and mitigating neurosensory disturbances induced by peripheral nerve injury, primarily through enhancing mitochondrial biogenesis and bolstering antioxidant mechanisms. Additionally, its anti-inflammatory properties offer an appealing avenue for shielding against neuroinflammation, thereby augmenting its efficacy in treating neurosensory disorders. [ABSTRACT FROM AUTHOR]

[Display omitted] • Alzheimer's and Parkinson's: Exosomes reduce protein buildup, inflammation, apoptosis. • Head trauma: Exosomes reduce inflammation, promote neurogenesis and angiogenesis. • Nerve injury: Exosomes reduce inflammation, promote neurogenesis and angiogenesis. • Tumor: Exosomes influence cancer progression, aid diagnosis and drug delivery. • Ischemic stroke: Exosomes reduce inflammation, promote neurogenesis and angiogenesis. Neurological disorders are a diverse group of conditions that can significantly impact individuals' quality of life. The maintenance of neural microenvironment homeostasis is essential for optimal physiological cellular processes. Perturbations in this delicate balance underlie various pathological manifestations observed across various neurological disorders. Current treatments for neurological disorders face substantial challenges, primarily due to the formidable blood–brain barrier and the intricate nature of neural tissue structures. These obstacles have resulted in a paucity of effective therapies and inefficiencies in patient care. Exosomes, nanoscale vesicles that contain a complex repertoire of biomolecules, are identifiable in various bodily fluids. They hold substantial promise in numerous therapeutic interventions due to their unique attributes, including targeted drug delivery mechanisms and the ability to cross the BBB, thereby enhancing their therapeutic potential. In this review, we investigate the therapeutic potential of exosomes across a range of neurological disorders, including neurodegenerative disorders, traumatic brain injury, peripheral nerve injury, brain tumors, and stroke. Through both in vitro and in vivo studies, our findings underscore the beneficial influence of exosomes in enhancing the neural microenvironment following neurological diseases, offering promise for improved neural recovery and management in these conditions. [ABSTRACT FROM AUTHOR]

The regenerative microenvironment after peripheral nerve injury is imbalanced and difficult to rebalance, which is mainly affected by inflammation, oxidative stress, and inadequate blood supply. The difficulty in remodeling the nerve regeneration microenvironment is the main reason for slow nerve regeneration. Traditional drug treatments have certain limitations, such as difficulty in penetrating the blood-nerve barrier and lack of pleiotropic effects. Therefore, there is an urgent need to build multifunctional nerve grafts that can effectively regulate the regenerative microenvironment and promote nerve regeneration. Nitric oxide (NO), a highly effective gas transmitter with diatomic radicals, is an important regulator of axonal growth and migration, synaptic plasticity, proliferation of neural precursor cells, and neuronal survival. Moreover, NO provides potential anti-inflammation, anti-oxidation, and blood vessel promotion applications. However, excess NO may cause cell death and neuroinflammatory cell damage. The prerequisite for NO treatment of peripheral nerve injury is that it is gradually released over time. In this study, we constructed an injectable NO slow-release system with two main components, including macromolecular NO donor nanoparticles (mPEG-P(MSNO-EG) nanoparticles, NO-NPs) and a carrier for the nanoparticles, mPEG-PA-PP injectable temperature-sensitive hydrogel. Due to the multiple physiological regulation of NO and better physiological barrier penetration, the conduit effectively regulates the inflammatory response and oxidative stress of damaged peripheral nerves, promotes nerve vascularization, and nerve regeneration and docking, accelerating the nerve regeneration process. The slow regeneration speed of peripheral nerves is mainly due to the destruction of the regeneration microenvironment. Neural conduits with drug delivery capabilities have the potential to improve the microenvironment of nerve regeneration. However, traditional drugs are hindered by the blood nerve barrier and cannot effectively target the injured area. NO, an endogenous gas signaling molecule, can freely cross the blood nerve barrier and act on target cells. However, excessive NO can lead to cell apoptosis. In this study, a NO sustained-release system was constructed to regulate the microenvironment of nerve regeneration through various pathways and promote nerve regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

Biodegradable synthetic nerve conduits have become widely used for peripheral nerve injuries. Recently, bioabsorbable collagen conduits filled with collagen fibers (Renerve®) are commercially available in Japan. We investigated the clinical efficacy and safety of Renerve® conduits for digital nerve repair. We retrospectively reviewed data of patients who underwent digital nerve repair using Renerve® conduits between August 2017 and February 2022 at our hospital and were followed up for at least 12 months. Seventeen patients (20 nerves) with a median age of 46.5 years (interquartile rage: 26–48 years) were included in the analysis. We analyzed sensory nerve function recovery and residual pain or uncomfortable tingling, as well as safety outcomes. The relationship between nerve defect length and sensory function data was assessed using Spearman's rank correlation. Sensory nerve function at 12 months postoperatively was excellent in six, good in 10, and poor in four nerves, and that at the final follow-up (median period, 24 months; range, 12–30 months) was excellent in nine, good in 10, and poor in one nerve. All nerves with a defect length of <12 mm had excellent or good sensory outcomes. At 12 months postoperatively, the correlation coefficients between nerve defect length and Semmes-Weinstein monofilament test results, static two-point discrimination, and dynamic two-point discrimination were 0.35 (p = 0.131), 0.397 (p = 0.0827), and 0.451 (p = 0.0461), respectively. Residual pain or tingling sensation were observed in four nerves at the final follow-up. No postoperative complications were observed in any of the patients. This study demonstrated the clinical efficacy and safety of Renerve® conduits for digital nerve repair. Our results will be useful in clinical practice because of the scarcity of real-world data on the use of Renerve® conduits for digital nerve repair. [ABSTRACT FROM AUTHOR]

Macrophages play a crucial role in the inflammatory response following sciatic nerve injury. Studies have demonstrated that C-X-C motif chemokine (CXCL) 1 recruit macrophages by binding to C-X-C chemokine receptor (CXCR) 2 and participates in the inflammatory response of various diseases. Based on these findings, we aimed to explore the role of the CXCL1-CXCR2 axis in the repair process after peripheral nerve injury. Initially, we simulated sciatic nerve injury and observed an increased expression of CXCL1 and CXCR2 in the nerves of the injury group. Both in vivo and in vitro experiments confirmed that the heightened CXCL1 expression occurs in Schwann cells and is secreted, while the elevated CXCR2 is expressed by recruited macrophages. In addition, in vitro experiments demonstrated that the binding of CXCL1 to CXCR2 can activate the NLRP3 inflammasome and promote the production of interleukin-1 beta (IL-1β) in macrophages. However, after mice were subjected to sciatic nerve injury, the number of macrophages and the expression of inflammatory factors in the sciatic nerve were reduced following treatment with the CXCR2 inhibitor SB225002. Simultaneously, we evaluated the sciatic nerve function index, the expression of p75 neurotrophic factor receptor (p75NTR), and myelin proteins, and all of these results were improved with the use of SB225002. Thus, our results suggest that after sciatic nerve injury, the CXCL1-CXCR2 axis mediates the inflammatory response by promoting the recruitment and activation of macrophages, which is detrimental to the repair of the injured nerves. In contrast, treatment with SB225002 promotes the repair of injured sciatic nerves. [Display omitted] • Sciatic nerve injury leads to production and secretion of CXCL1 by Schwann cells. • CXCL1 recruit macrophages to the site of nerve injury by binding to CXCR2 on the surface of macrophages. • CXCL1-CXCR2 promotes IL-1β secretion by activating NLRP3 inflammasome in macrophages. • SB225005, an inhibitor of CXCR2, promotes the repair of injured nerves by inhibiting inflammation. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries (PNIs) can cause neuropathies and significantly affect the patient's quality of life. Autograft transplantation is the gold standard for conventional treatment; however, its application is limited by nerve unavailability, size mismatch, and local tissue adhesion. Tissue engineering, such as nerve guidance conduits, is an alternative and promising strategy to guide nerve regeneration for peripheral nerve repair; however, only a few conduits could reach the high repair efficiency of autografts. The healing process of PNI is frequently accompanied by not only axonal and myelination regeneration but also angiogenesis, which initializes nerve regeneration through vascular endothelial growth factor A (VEGF-A). In this study, a composite nerve conduit with a poly (lactic-co-glycolic acid) (PLGA) hollow tube as the outer layer and gelatin methacryloyl (GelMA) encapsulated with VEGF-A transfected Schwann cells (SCs) as the inner layer was established to evaluate its promising ability for peripheral nerve repair. A rat model of peripheral nerve defect was used to examine the efficiency of PLGA/GelMA-SC (VA) conduits, whereas autograft, PLGA, PLGA/GelMA, and PLGA/GelMA-SC (NC) were used as controls. VEGF-A-transfected SCs can provide a stable source for VEGF-A secretion. Furthermore, encapsulation in GelMA cannot only promote proliferation and tube formation of human umbilical vein endothelial cells but also enhance dorsal root ganglia and neuronal cell extension. Previous animal studies have demonstrated that the regenerative effects of PLGA/GelMA-SC (VA) nerve conduit were similar to those of autografts and much better than those of other conduits. These findings indicate that combination of VEGF-A-overexpressing SCs and PLGA/GelMA conduit-guided peripheral nerve repair provides a promising method that enhances angiogenesis and regeneration during nerve repair. Nerve guidance conduits shows promise for peripheral nerve repair, while achieving the repair efficiency of autografts remains a challenge. In this study, a composite nerve conduit with a PLGA hollow tube as the outer layer and gelatin methacryloyl (GelMA) encapsulated with vascular endothelial growth factor A (VEGF-A)-transfected Schwann cells (SCs) as the inner layer was established to evaluate its potential ability for peripheral nerve repair. This approach preserves growth factor bioactivity and enhances material properties. GelMA insertion promotes Schwann cell proliferation and morphology extension. Moreover, transfected SCs serve as a stable VEGF-A source and fostering angiogenesis. This study offers a method preserving growth factor efficacy and safeguarding SCs, providing a comprehensive solution for enhanced angiogenesis and nerve regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • BDNF from microglia drives neuropathic pain. • Peripheral BDNF drives chronic inflammatory pain. • BDNF does not drive pain in females. In males but not in females, brain derived neurotrophic factor (BDNF) plays an obligatory role in the onset and maintenance of neuropathic pain. Afferent terminals of injured peripheral nerves release colony stimulating factor (CSF-1) and other mediators into the dorsal horn. These transform the phenotype of dorsal horn microglia such that they express P2X4 purinoceptors. Activation of these receptors by neuron-derived ATP promotes BDNF release. This microglial-derived BDNF increases synaptic activation of excitatory dorsal horn neurons and decreases that of inhibitory neurons. It also alters the neuronal chloride gradient such the normal inhibitory effect of GABA is converted to excitation. By as yet undefined processes, this attenuated inhibition increases NMDA receptor function. BDNF also promotes the release of pro-inflammatory cytokines from astrocytes. All of these actions culminate in the increase dorsal horn excitability that underlies many forms of neuropathic pain. Peripheral nerve injury also alters excitability of structures in the thalamus, cortex and mesolimbic system that are responsible for pain perception and for the generation of co-morbidities such as anxiety and depression. The weight of evidence from male rodents suggests that this preferential modulation of excitably of supra-spinal pain processing structures also involves the action of microglial-derived BDNF. Possible mechanisms promoting the preferential release of BDNF in pain signaling structures are discussed. In females, invading T-lymphocytes increase dorsal horn excitability but it remains to be determined whether similar processes operate in supra-spinal structures. Despite its ubiquitous role in pain aetiology neither BDNF nor TrkB receptors represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) and the limitations of current treatments often result in incomplete sensory and motor function recovery, which significantly impact the patient's quality of life. While exosomes (Exo) derived from stem cells and Schwann cells have shown promise on promoting PNI repair following systemic administration or intraneural injection, achieving effective local and sustained Exo delivery holds promise to treat local PNI and remains challenging. In this study, we developed Exo-loaded decellularized porcine nerve hydrogels (DNH) for PNI repair. We successfully isolated Exo from differentiated human adipose-derived mesenchymal stem cells (hADMSC) with a Schwann cell-like phenotype (denoted as dExo). These dExo were further combined with polyethylenimine (PEI), and DNH to create polyplex hydrogels (dExo-loaded pDNH). At a PEI content of 0.1%, pDNH showed cytocompatibility for hADMSCs and supported neurite outgrowth of dorsal root ganglions. The sustained release of dExos from dExo-loaded pDNH persisted for at least 21 days both in vitro and in vivo. When applied around injured nerves in a mouse sciatic nerve crush injury model, the dExo-loaded pDNH group significantly improved sensory and motor function recovery and enhanced remyelination compared to dExo and pDNH only groups, highlighting the synergistic regenerative effects. Interestingly, we observed a negative correlation between the number of colony-stimulating factor-1 receptor (CSF-1R) positive cells and the extent of PNI regeneration at the 21-day post-surgery stage. Subsequent in vitro experiments demonstrated the potential involvement of the CSF-1/CSF-1R axis in Schwann cells and macrophage interaction, with dExo effectively downregulating CSF-1/CSF-1R signaling. Exo-loaded decellularized nerve hydrogels were fabricated by integrating exosomes, PEI, and decellularized nerve matrix for peripheral nerve repair based on improvement of remyelination and disruption of CSF-1R expression. [Display omitted] [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries are common and serious conditions. The effect of Neurotropin® (NTP), a nonprotein extract derived from the inflamed skin of rabbits inoculated with vaccinia virus, on peripheral nerve regeneration has not been fully elucidated. However, it has analgesic properties via the activation of descending pain inhibitory systems. Therefore, the current study aimed to determine the effects of NTP on peripheral nerve regeneration. We examined axonal outgrowth of dorsal root ganglion (DRG) neurons using immunocytochemistry in vitro. In addition, nerve regeneration was evaluated functionally, electrophysiologically, and histologically in a rat sciatic nerve crush injury model in vivo. Furthermore, gene expression of neurotrophic factors in the injured sciatic nerves and DRGs was evaluated. In the dorsal root ganglion neurons in vitro , NTP promoted axonal outgrowth at a concentration of 10 mNU/mL. Moreover, the systemic administration of NTP contributed to the recovery of motor and sensory function at 2 weeks, and of sensory function, nerve conduction velocity, terminal latency, and axon-remyelination 4 weeks after sciatic nerve injury. In the gene expression assessment, insulin-like growth factor 1 and vascular endothelial growth factor expressions were increased in the injured sciatic nerve 2 days postoperatively. Therefore, NTP might be effective in not only treating chronic pain but also promoting peripheral nerve regeneration after injury. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) remains a severe clinical problem with debilitating consequences. Mesenchymal stem cell (MSC)-based therapy is promising, but the problems of poor engraftment and insufficient neurotrophic effects need to be overcome. Herein, we isolated platelet-rich plasma-derived exosomes (PRP-Exos), which contain abundant bioactive molecules, and investigated their potential to increase the regenerative capacity of MSCs. We observed that PRP-Exos significantly increased MSC proliferation, viability, and mobility, decreased MSC apoptosis under stress, maintained MSC stemness, and attenuated MSC senescence. In vivo, PRP-Exo-treated MSCs (pExo-MSCs) exhibited an increased retention rate and heightened therapeutic efficacy, as indicated by increased axonal regeneration, remyelination, and recovery of neurological function in a PNI model. In vitro, pExo-MSCs coculture promoted Schwann cell proliferation and dorsal root ganglion axon growth. Moreover, the increased neurotrophic behaviour of pExo-MSCs was mediated by trophic factors, particularly glia-derived neurotrophic factor (GDNF), and PRP-Exos activated the PI3K/Akt signalling pathway in MSCs, leading to the observed phenotypes. These findings demonstrate that PRP-Exos may be novel agents for increasing the ability of MSCs to promote neural repair and regeneration in patients with PNI. [Display omitted] • PRP-Exos enhance the viability, survival, stemness, and neurotrophic paracrine properties of MSCs. • Transplantation of pExo-MSCs leads to improved functional recovery of PNI by promoting axonal regeneration and remyelination. • GDNF plays a crucial role in mediating the superior neurotrophic function of pExo-MSCs. • PRP-Exos enhance the neurotrophic properties of MSCs by activating the PI3K/Akt signalling pathway. [ABSTRACT FROM AUTHOR]

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI. [Display omitted] • ROS induces neuronal ferroptosis via accelerated UBA52-driven ubiquitination of Fpn. • DRGs undergo cell death within 24 h after peripheral nerve injury. • HYD inhibits Fpn degradation in DRGs by suppressing UBA52 binding to Fpn. • Immediate HYD treatment produced better outcomes than delayed HYD treatment. [ABSTRACT FROM AUTHOR]

Despite advances in the surgical management of peripheral nerve pathologies over the past several decades, it is unknown how public awareness of these procedures has changed. We hypothesize that Google searches for peripheral nerve surgery have increased over time. Google Trends was queried for search volumes of a list of 40 keywords related to the following topics in peripheral nerve surgery: spasticity, nerve injury, prosthetics, and nerve pain. Monthly relative search volume over the first 5 years of the study period (2010–2014) was compared with that of the last 5 years (2018–2022) of the study period. Search volumes for keywords "nerve injury," "nerve laceration," "peripheral nerve injury," "nerve repair," "nerve transfer", "neuroma," "neuroma pain," "nerve pain," "nerve pain surgery," and "neuroma pain surgery" all increased more than 10% points in relative search volume over the study period (P < 0.0001 for each keyword). In contrast, searches for "rhizotomy," "spasticity surgery," "targeted muscle reinnervation," "bionic arm," and "myoelectric prosthesis" either decreased or remained stable. Technical terms such as "selective neurectomy," "hyperselective neurectomy," "regenerative peripheral nerve interface," and "regenerative peripheral nerve interface surgery" did not have adequate search volume to be reported by Google Trends. The increase in Google searches related to nerve injury and pain between 2010 and 2022 may reflect increasing public recognition of these clinical entities and surgical techniques addressing them. Technical terms relating to nerve pain are infrequently searched, surgeons should use plain English terms for online discovery. Interest in spasticity and myoelectric prosthetics remains stable, indicating an opportunity for better public outreach. [ABSTRACT FROM AUTHOR]

[Display omitted] • EX527 blocked the effect of melatonin on pain-like behavior. • Melatonin increased the SIRT1 expression. • Melatonin resolved mitochondrial dysfunction by modulating the SIRT1/PGC-1α signaling. Neuropathic pain is a debilitating chronic pain condition and is refractory to the currently available treatments. Emerging evidence suggests that melatonin exerts analgesic effects in rodent models of neuropathic pain. Nevertheless, the exact underlying mechanisms of the analgesic effects of melatonin on neuropathic pain are largely unknown. Here, we observed that spinal nerve ligation (SNL) in rats L5 and L6 induced an obvious decrease in the 50% paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), indicating the induction of mechanical allodynia and the hyperalgesia, and melatonin prevented the genesis and maintenance of mechanical allodynia and the hyperalgesia. Notably, the inhibitory action of melatonin on SNL-induced mechanical allodynia and heat hypersensitivity was inhibited by a SIRT1 inhibitor (EX527). Melatonin treatment increased the expression of neuronal sirtuin1 (SIRT1) in DRGs following nerve injury. Furthermore, melatonin treatment restored the injury-dependent decrease in mitochondrial membrane potential and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and reduced the injury-dependent increase in hydrogen peroxide and 8-hydroxy-2-deoxyguanosine (8-OHdG), which was inhibited by EX527. In addition, we found that EX527 impeded the inhibitory effects of melatonin on the SNL-induced increased expression of cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β). In conclusion, the above data demonstrated that melatonin alleviated mechanical allodynia and hyperalgesia induced by peripheral nerve injury via SIRT1 activation. Melatonin resolved mitochondrial dysfunction—oxidative stress-dependent and neuroinflammation mechanisms that were driven by SIRT1 after nerve injury. [ABSTRACT FROM AUTHOR]

Although several studies have investigated models of nerve electrical injury, only a few have focused on electrical injury to peripheral nerves, which is a common and intractable problem in clinical practice. Here, we describe an experimental rat model of peripheral nerve electrical injury and its assessment. A total of 120 animals were subjected to short-term corrective electrostimulation (50 Hz, 1-s duration) applied at varying voltages (control, 65, 75, 100, 125, and 150 V) to the exposed left sciatic nerve. Behavioural testing, electrophysiological measurements, and histopathological observation of the sciatic nerve were conducted at 1-, 2-, 4-, and 8-w follow-ups. No functional defects were noted in the groups that received 65-V stimulation at any time point. Sciatic nerve functional defects were found after 2 w in animals that received 75-V stimulation, but function returned to normal after 4 w. In animals that received 100-V and 125-V stimulation, functional defects were observed at 4 w, but had partially recovered by 8 w. Conversely, animals that received 150-V stimulation did not show recovery after 8 w. We presented a model of peripheral nerve electrical injury that avoided the interference of various external factors, such as current instability, compression of the surrounding tissues, and altered blood supply. The model allowed quantitation and ranking of the nerve injury into four degrees. It facilitated effective evaluation of nerve function impairment and repair after injury. It can be used post-surgically to evaluate peripheral nerve impairment and reconstruction and enables translational interpretation of results, which may improve understanding of the mechanisms underlying the progression of peripheral nerve electrical injury. • An experimental rat model of peripheral nerve electrical injury was presented. • Sciatic nerve was exposed directly to electricity to avoid confounding factors. • The model could be quantified and allowed ranking nerve injury into four levels. • The model can evaluate peripheral nerve impairment and reconstruction. • The model helps to understand the mechanism of peripheral nerve electrical injury. [ABSTRACT FROM AUTHOR]

Peripheral glial Schwann cells switch to a repair state after nerve injury, proliferate to supply lost cell population, migrate to form regeneration tracks, and contribute to the generation of a permissive microenvironment for nerve regeneration. Exploring essential regulators of the repair responses of Schwann cells may benefit the clinical treatment for peripheral nerve injury. In the present study, we find that FOSL1, a AP-1 member that encodes transcription factor FOS Like 1, is highly expressed at the injured sites following peripheral nerve crush. Interfering FOSL1 decreases the proliferation rate and migration ability of Schwann cells, leading to impaired nerve regeneration. Mechanism investigations demonstrate that FOSL1 regulates Schwann cell proliferation and migration by directly binding to the promoter of EPH Receptor B2 (EPHB2) and promoting EPHB2 transcription. Collectively, our findings reveal the essential roles of FOSL1 in regulating the activation of Schwann cells and indicate that FOSL1 can be targeted as a novel therapeutic approach to orchestrate the regeneration and functional recovery of injured peripheral nerves. [ABSTRACT FROM AUTHOR]

• Vagus nerve stimulation paired with rehabilitation enhances somatosensory recovery. • VNS is most effective when delivered concurrently with rehabilitation. • VNS immediately before rehabilitation yields no additional benefits vs. rehab alone. • VNS immediately after rehabilitation yields no additional benefits vs. rehab alone. Chronic sensory loss is a common and undertreated consequence of many forms of neurological injury. Emerging evidence indicates that vagus nerve stimulation (VNS) delivered during tactile rehabilitation promotes recovery of somatosensation. Here, we systematically varied the timing of VNS relative to tactile rehabilitation to determine the paradigm that yields the greatest degree of somatosensory recovery after peripheral nerve injury (PNI). The medial and ulnar nerves in rats were transected, causing chronic sensory loss. Eight weeks after injury, rats were given a VNS implant followed by four weeks of tactile rehabilitation sessions consisting of repeated mechanical stimuli to the previously denervated forepaw. Rats received VNS before, during, or after tactile rehabilitation. Delivery of VNS during rehabilitative training generates robust, significant recovery compared to rehabilitative training without stimulation (56 ± 14% improvement over sham stimulation). A matched amount of VNS before training, immediately after training, or two hours after training is significantly less effective than VNS during rehabilitative training and fails to improve recovery compared to rehabilitative training alone (5 ± 10%, 4 ± 11%, and −7 ± 22% improvement over sham stimulation, respectively). These findings indicate that concurrent delivery of VNS during rehabilitative training is most effective and illustrate the importance of considering stimulation timing for clinical implementation of VNS therapy. [ABSTRACT FROM AUTHOR]

Trauma to the shoulder girdle has known associations with neurological and/or vascular injury. The presentation of these can be subtle and could potentially be missed, particularly if the clinician does not maintain a high index of suspicion and clinically examine and investigate appropriately. A missed injury could be detrimental for the patient, both increasing morbidity and affecting long-term outcome. This is especially true for neurological injury, in which missing the window for effective reinnervation procedures can have a lifelong negative impact. Nerve injuries can be difficult to classify clinically in the initial stages and it is crucial to know when nerve conduction studies and imaging are useful, and when early nerve exploration is warranted. Injuries to neurological or vascular structures generally benefit from a multidisciplinary approach to achieve the best outcomes. This article describes common nerve and vascular injuries associated with shoulder girdle trauma, along with approaches to assessment, investigation and timely management. [ABSTRACT FROM AUTHOR]

• RORγ mRNA was expressed in cultured rat spinal microglia. • RORγ inverse agonist SR2211 prevented upregulation of cytokines in microglia. • Intrathecal SR2211 treatment prevented LPS-induced mechanical hypersensitivity. • Intrathecal SR2211 treatment prevented PSNL-induced mechanical hypersensitivity. • Inhibition of RORγ prevented LPS- and PSNL-induced Iba1 expression in spinal cord. Microglia are crucial in induction of central sensitization under a chronic pain state. Therefore, control of microglial activity is important to ameliorate nociceptive hypersensitivity. The nuclear receptor retinoic acid related orphan receptor γ (RORγ) contributes to the regulation of inflammation-related gene transcription in some immune cells, including T cells and macrophages. Their role and function in regulation of microglial activity and nociceptive transduction have yet to be elaborated. Treatment of cultured microglia with specific RORγ inverse agonists, SR2211 or GSK2981278, significantly suppressed lipopolysaccharide (LPS)-induced mRNA expression of pronociceptive molecules interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Intrathecal treatment of naïve male mice with LPS markedly induced mechanical hypersensitivity and upregulation of ionized calcium-biding adaptor molecule (Iba1) in the spinal dorsal horn, indicating microglial activation. In addition, intrathecal treatment with LPS significantly induced mRNA upregulation of IL-1β and IL-6 in the spinal dorsal horn. These responses were prevented by intrathecal pretreatment with SR2211. In addition, intrathecal administration of SR2211 significantly ameliorated established mechanical hypersensitivity and upregulation of Iba1 immunoreactivity in the spinal dorsal horn of male mice following peripheral sciatic nerve injury. The current findings demonstrate that blockade of RORγ in spinal microglia exerts anti-inflammatory effects, and that RORγ may be an appropriate target for the treatment of chronic pain. [ABSTRACT FROM AUTHOR]

• Allogeneic nerve grafting led to more successful recovery than end-to-end neurorrhaphy after delayed peripheral nerve repair. • High numbers of Schwann cells are needed to promote NMJ reinnervation in the target muscle. • NMJ remodeling is related to agrin-Lrp4-MuSK signaling, Dok7 and Wnt4 during innervation. • Supplemental Schwann cells are important for delayed nerve repair. Peripheral nerve injury (PNI) induces severe functional loss in extremities. Progressive denervation and atrophy occur in the muscles if the nerve repair is delayed for long periods of the time. To overcome these difficulties, detailed mechanisms should be determined for neuromuscular junction (NMJ) degeneration in target muscles after PNI and regeneration after nerve repair. We established two models of end-to-end neurorrhaphy and allogeneic nerve grafting in the chronic phase after common peroneal nerve injury in female mice (n = 100 in total). We evaluated motor function, histology, and gene expression in the target muscles during their regeneration processes and compared the models. We found that the functional recovery with allogeneic nerve grafting was superior to that with end-to-end neurorrhaphy, and the number of reinnervated NMJs and Schwann cells was increased at 12 weeks after allograft. In addition, NMJ- and Schwann cell-related molecules showed high expression in the target muscle in the allograft model. These results suggest that Schwann cell migrating from the allograft might play a crucial role in nerve regeneration in the chronic phase after PNI. The relationship between the NMJ and Schwann cells should be further investigated in the target muscle. [ABSTRACT FROM AUTHOR]

Through multiple scRNA-seq approaches, mouse DRG neurons have been classified into multiple cell types. Across studies, 17 consistent cell types can be identified, each with distinct molecular markers. Most DRG neuron clusters are equivalent in mouse and human and have various subclusters. scRNA-seq analyses revealed transcriptomic changes in DRG neuron types after peripheral nerve injury and the induction of new neuron clusters. The neural networks of different DRG neuron types provide insights into the modality selectivity of each type and into the associated pathways for processing distinct sensory modalities in the brain. Single-cell RNA sequencing (scRNA-seq) has allowed profiling cell types of the dorsal root ganglia (DRG) and their transcriptional states in physiology and chronic pain. However, the evaluation criteria used in previous studies to classify DRG neurons varied, which presents difficulties in determining the various types of DRG neurons. In this review, we aim to integrate findings from previous transcriptomic studies of the DRG. We first briefly introduce the history of DRG-neuron cell-type profiling, and discuss the advantages and disadvantages of different scRNA-seq methods. We then examine the classification of DRG neurons based on single-cell profiling under physiological and pathological conditions. Finally, we propose further studies on the somatosensory system at the molecular, cellular, and neural network levels. [ABSTRACT FROM AUTHOR]

Spinal microglia respond to peripheral nerve injury (PNI) and play a critical role in the development of neuropathic pain, a chronic pain condition resulting from a lesion or disease of the somatosensory nervous system. Spinal microglia are transcriptionally divergent and undergo temporal changes following PNI. Recent findings in mice have identified CD11c+ microglia that are necessary for the remission of PNI-induced pain-related behavior. This suggests that following PNI, the role of microglia in the course of neuropathic pain is not uniform and static but rather divergent and dynamic. CD11c+ microglia continuously repress pronociceptive signals even after the animals' pain behavior has subsided, indicating that this microglial subset is critical in determining the latent state of pain sensitization. Microglial diversity could provide important clues for developing new strategies to aid in the diagnosis and management of neuropathic pain. Microglia play pivotal roles in controlling CNS functions in diverse physiological and pathological contexts, including neuropathic pain, a chronic pain condition caused by lesions or diseases of the somatosensory nervous system. In this review article, we summarize evidence primarily from basic research on the role of microglia in the development and remission of neuropathic pain. The identification of a subset of microglia that emerged after pain development and that was necessary for remission of neuropathic pain highlights the highly divergent and dynamic nature of microglia in the course of neuropathic pain. Understanding microglial diversity in terms of gene expression, physiological states, and functional roles could lead to new strategies that aid in the diagnosis and management of neuropathic pain, and that may not have been anticipated from the viewpoint of targeting all microglia uniformly. [ABSTRACT FROM AUTHOR]

• The expression of Sox2ot is increased after peripheral nerve injury. • Overexpression of Sox2ot promotes Schwann cells migration and proliferation. • Sox2ot regulates the expression of Cthrc1 through competitive adsorption of miR-9 in Schwann cells. • Sox2ot provides a new direction for the treatment of peripheral nerve injury. The effects of traditional treatments for peripheral nerve injury (PNI) are not ideal, which has prompted the identification of new therapeutic strategies. As unique glial cells in the peripheral nervous system, Schwann cells (SCs) play an important role in the repair of PNI. Recent studies have demonstrated that long noncoding RNAs (lncRNAs) are involved in the regulation of nerve repair after PNI. In this study, we used microarray technology to detect mRNA and lncRNA expression profiles at different time points after PNI and identified lncRNA Sox2ot-miR-9-Cthrc1 as a competitive endogenous RNA (ceRNA) for further investigation. Expression of lncRNA Sox2ot was increased after PNI, and overexpression of Sox2ot promoted SCs migration and proliferation. Mechanistic analyses confirmed that Sox2ot can regulate the expression of Cthrc1 through competitive adsorption of miR-9 in SCs, ultimately affecting SCs migration and proliferation. Our findings reveal the key role of lncRNA Sox2ot in nerve regeneration and provide a new direction for PNI treatment. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries remain a major medical problem worldwide and are associated with multiple causes, including gunshot wounds (GSWs), which are the second most common cause of brachial plexus injuries in peacetime and the main, or only, cause reported in wartime studies. The ulnar nerve (UN) is one of the most affected nerves. Peripheral nerve trauma may cause intense neuropathic pain, which is very difficult to control. Particularly UN gunshot injuries may impact individual daily life, as injuries to this nerve result in both sensory and motor deficits within the hand. We evaluated the improvement of neuropathic pain after surgical treatment in a consecutive series of 20 patients with UN injury due to GSWs. This single-center, retrospective, consecutive case series included 20 patients with UN injuries due to GSWs, who presented with excruciating neuropathic pain and underwent surgical treatment between 2005 and 2017. Of injuries, 13 occurred in the right upper limb (65%); 12 patients had a high UN injury (60%). Regarding associated injuries, 8 patients had bone injuries (40%), and 4 patients had arterial injuries (20%). A neuroma in continuity was detected in 8 cases (40%), and 4 patients (20%) had shrapnel lodged within the UN. All patients had severe neuropathic pain and functional deficit, with a mean visual analog scale score of 8.45 ± 1.4 and a mean reduction of 6.95 points 12 months after surgery; 10 patients (50%) had a British Medical Research Council score ≥M3. Surgery is an effective treatment for neuropathic pain from GSWs. Early isolated external neurolysis is associated with better pain management and functional outcomes postoperatively. [ABSTRACT FROM AUTHOR]

The rat sciatic nerve (SN) is the most frequently used model in experimental research on peripheral nerve injuries. Within the broad range of evaluation methods to determine the experimental outcome, recovery of behavior represents the major criterion to assess functional regeneration. The grasping test indicates when recovery begins and its improvement with time. However, lesions of the SN have yet remained unstudied with this method. Therefore, rats received a SN resection and were divided into experimental groups: 1) control with lesion only, 2) nerve bridge, and 3) autograft. During weekly sessions, the grasping test measured the grip strength, and the locomotor behavior was assessed in the open field. Finally, the nerves were prepared for electrophysiology and histomorphometry. Autograft recovered grasping after 7 weeks with the strongest improvement afterwards. Nerve tube allowed grasping by week 12. Control animals did not recover. In the open field, no differences were observed between the groups. Recordings were possible only in the autograft group, which could be explained by higher number of regenerated fibers. This study indicates that grasping data correspond with physiological and anatomical findings. We conclude that the grasping test is a valid method to evaluate functional recovery after SN resection in rats. • When investigating sciatic nerve lesion: grip strength measurement allows for precise analysis of the time course of functional recovery. • When investigating sciatic nerve lesion:grasping test seems to be more reliable than locomotor activity in the open field. • When investigating sciatic nerve lesion: grip strength is associated with electrophysiological findings. • When investigating sciatic nerve lesion: grip strength appears to correlate with histomorphometry. [ABSTRACT FROM AUTHOR]

Patients with peripheral nerve injuries would highly likely suffer from chronic neuropathic pain even after surgical intervention. The primary reasons for this involve sustained neuroinflammatory and dysfunctional changes in the nervous system after the nerve injury. We previously reported an injectable boronic ester-based hydrogel with inherent antioxidative and nerve protective properties. Herein, we first explored the anti-neuroinflammatory effects of Curcumin on primary sensory neurons and activated macrophages in vitro. Next, we incorporated thiolated Curcumin-Pluronic F-127 micelles (Cur-M) into our boronic ester-based hydrogel to develop an injectable hydrogel that serves as sustained curcumin release system (Gel-Cur-M). By orthotopically injecting the Gel-Cur-M to sciatic nerves of mice with chronic constriction injuries, we found that the bioactive components could remain on the nerves for at least 21 days. In addition, the Gel-Cur-M exhibited superior functions compared to Gel and Cur-M alone, which includes ameliorating hyperalgesia while simultaneously improving locomotor and muscular functions after the nerve injury. This could stem from in situ anti-inflammation, antioxidation, and nerve protection. Furthermore, the Gel-Cur-M also showed extended beneficial effects for preventing the overexpression of TRPV1 as well as microglial activation in the lumbar dorsal root ganglion and spinal cord, respectively, which also contributed to its analgesic effects. The underlying mechanism may involve the suppression of CC chemokine ligand-2 and colony-stimulating factor-1 in the injured sensory neurons. Overall, this study suggests that orthotopic injection of the Gel-Cur-M is a promising therapeutic strategy that especially benefits patients with peripheral neuropathy who require surgical interventions. [Display omitted] • An injectable, boronic ester-based hydrogel controls a sustained release of Cur. • The Cur hydrogel has antioxidant, anti-inflammatory and neuroprotective effects. • The Cur hydrogel helps pain relief and functional recovery following PNIs. [ABSTRACT FROM AUTHOR]

Ziconotide (ZIC) is an N-type calcium channel antagonist for treating severe chronic pain that is intolerable, or responds poorly to the administration of other drugs, such as intrathecal morphine and systemic analgesics. As it can only work in the brain and cerebrospinal fluid, intrathecal injection is the only administration route for ZIC. In this study, borneol (BOR)-modified liposomes (LIPs) were fused with exosomes from mesenchymal stem cells (MSCs) and loaded with ZIC to prepare microneedles (MNs) to improve the efficiency of ZIC across the blood-brain barrier. To evaluate local analgesic effects of MNs, the sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of peripheral nerve injury, diabetes-induced neuropathy pain, chemotherapy-induced pain, and ultraviolet-B (UV-B) radiation-induced neurogenic inflammatory pain. BOR-modified LIPs loaded with ZIC were spherical or nearly spherical, with a particle size of about 95 nm and a Zeta potential of −7.8 mV. After fusion with MSC exosomes, the particle sizes of LIPs increased to 175 nm, and their Zeta potential increased to −3.8 mV. The nano-MNs constructed based on BOR-modified LIPs had good mechanical properties and could effectively penetrate the skin to release drugs. The results of analgesic experiments showed that ZIC had a significant analgesic effect in different pain models. In conclusion, the BOR-modified LIP membrane-fused exosome MNs constructed in this study for delivering ZIC provide a safe and effective administration for chronic pain treatment, as well as great potential for clinical application of ZIC. [Display omitted] • To provide a transdermal delivery system for the delivery of ziconotide. • ZIC@MSCEXO/LIP-BOR can improve the ability of crossing the BBB effectively. • ZIC@MSCEXO/LIP-BOR have the characteristics of liposomes and exosomes. • Various pain models were established to evaluate the analgesic effect. • MN#ZIC@MSCEXO/LIP-BOR has high biocompatibility and analgesic effect. [ABSTRACT FROM AUTHOR]

Repair of peripheral nerve crush injury remains a major clinical challenge. Currently, oral or intravenous neurotrophic drugs are the main treatment for peripheral nerve crush injury; however, this repair process is slow, and the final effect may be uncertain. The current study aimed at developing an injectable hydrogel with vascular endothelial growth factor (VEGF)-mimetic peptide (QK)-encapsulated nanoliposomes (QK-NLs@Gel) for sustainable drug release that creates an appropriate microenvironment for nerve regeneration. The QK-encapsulated nanoliposomes (QK-NLs) could facilitate the proliferation, migration, and tube formation capacities of human umbilical vein endothelial cells through the VEGF signaling pathway. The QK-NLs@Gel hydrogel encapsulated with QK-NLs showed enhanced physical properties and appropriate biocompatibility in vitro. Thereafter, the QK-NLs@Gel hydrogel was directly injected into the site of peripheral nerve crush injury in a rat model, where it enhanced revascularization and promoted the M2-polarization of the macrophages, thus providing an optimized microenvironment for nerve regeneration. At four weeks post-surgery, the QK-NLs@Gel injected rats exhibited enhanced axon regeneration, remyelination, and better functional recovery in comparison with other groups in vivo. Overall, these findings demonstrate that the composite hydrogel could promote a multicellular pro-regenerative microenvironment at the peripheral nerve injury site, thus revealing great potential for peripheral nerve restoration. Peripheral nerve injury (PNI) is a leading public health issue, and how to delivery beneficial drugs to injured sites efficiently is still a big challenge. In the current study, an injectable hydrogel with VEGF-mimetic peptide (QK)-encapsulated nanoliposomes (QK-NLs@Gel) was first developed and used to repair a rat crush injury model. Our results showed that QK-NLs promoted the proliferation, migration, and angiogenesis of HUVEC via VEGF signaling pathway in vitro. Furthermore, when injected to the crushed sites in vivo , the QK-NLs@Gel hydrogel could accelerate nerve repair through enhanced revascularization and M2-polarization of macrophages. These results collectively demonstrate that injection of QK-NLs@Gel hydrogel could create an appropriate microenvironment for peripheral nerve regeneration. This strategy is effective, economical, and convenient for clinical applications. [Display omitted] [ABSTRACT FROM AUTHOR]

Acute nerve injuries in the hand are common. Mechanisms of injury vary and include sharp transection, direct and indirect blunt trauma resulting in contusions and traction injuries respectively, ischaemic and compression injuries and chemical, thermal or electrical injury. Sharp, penetrating injuries are the most common, with patients typically presenting after a laceration with glass or a knife. Both blunt and sharp injuries can be associated with bony injuries as well as injury to the vascular and tendinous structures. The management principles of nerve injuries in the hand follow those of nerve injuries elsewhere, however the distal nature of the injuries often means that some treatment strategies are less applicable. In this article we will discuss the basic structure of nerves as well as the anatomy of the peripheral nerves in the hand, followed by the treatment strategies that can be employed to address acute nerve injuries in the hand. [ABSTRACT FROM AUTHOR]

Activation of autophagy in Schwann cells (SCs) has emerged as a powerful trigger for peripheral nerve injury (PNI) repair. Lithium ion (Li+) is a classical autophagy activator that plays an important role in promoting axonal extension and remyelination. However, the therapeutic window of existing lithium drugs is extremely narrow, and the adverse side effects, especially nephrotoxicity, severely limit their therapeutic value. Herein, Li+-doped carbonized polymer dots (Li-CPDs) was synthesized for the first time to change the pharmacokinetics of Li+ from occupying epithelial sodium channels to lipid raft-mediated endocytosis. The in-vivo results confirmed that Li-CPDs could accelerate the removal of myelin debris and promote nerve regeneration via activating autophagy of SCs. Moreover, Li-CPDs exhibited almost no renal toxicity compared to that of raw lithium drugs. Thus, Li-CPDs could serve as a promising Li+-based nanomedicine for PNI regeneration with improved biosafety. Regardless of the fact that lithium drugs have been used in treatment of mental illness such as manic depression, the systemic side effects and renal metabolic toxicity still seriously restrict their clinical application. Since Li+ and Na+ compete for ion channels of cell membrane, the cell entry efficiency is extremely low and easily affected by body fluctuations, which seems to be an unsolvable problem. Herein, we rationally exploited the endocytotic features of CPDs to develop Li-CPDs. The Li-CPDs improved the entry pathway, greatly reduced nephrotoxicity, and inherited the biological function of Li+ to activate autophagy for promoting peripheral nerve regeneration. Due to the BBB-crossing property of Li-CPDs, it also showed application prospects in future research on central nervous system diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

The purpose of the study is to examine presentation, injury patterns, and clinical course, for COVID-19-related peripheral nerve injury following mechanical ventilation. A multicenter retrospective study of patients with COVID-19 complicated by acute respiratory distress syndrome (ARDS) that required mechanical ventilation was undertaken. Patient records were reviewed for intensive care unit and intubation characteristics, prone or lateral decubitus positioning, and the onset of neuropathy diagnosis. Between September 2020 and January 2022, 11 patients were diagnosed with peripheral neuropathy, including 9 with brachial plexopathy following COVID-19 infection. Each patient developed ARDS requiring mechanical ventilation for a median of 39 days. Six patients (54.5%) underwent prone positioning and 1 lateral decubitus. Neuropathies involved 5 brachial pan-plexopathies, 2 incomplete brachial plexopathies, 2 lower trunk plexopathies, 1 radial neuropathy, and 1 bilateral ulnar neuropathy. At a mean follow-up of 10.2 months, patients with brachial pan-plexopathies demonstrated signs of reinnervation proximally, and 1 resolved to a radial mononeuropathy; however, the majority have demonstrated minimal clinical improvements. Our series demonstrates that peripheral neuropathies and especially brachial plexopathies have occurred following mechanical ventilation for ARDS-related COVID-19 infections. Contrary to prior COVID-19 studies, only 54.5% of these patients underwent prone positioning. Aside from a traumatic disturbance of prone positioning, the increased incidence of neuropathy may involve an atraumatic effect of COVID-19 via direct invasion of nerves, autoantibody targeting of nervous tissue, or hypercoagulation-induced microthrombotic angiopathy. [ABSTRACT FROM AUTHOR]

Developing nerve conduits with biological cues is a promising approach for repairing peripheral nerve injuries. Although most biological cues incorporated into conduits generally exert their biological functions at the surface, they could not be released into the on-demand regeneration sites under physiological conditions. Herein, we firstly report a bio-orthogonally functionalized chitosan scaffold with esterase-activatable release for peripheral nerve regeneration. In this study, biological cues are not only selectively conjugated into nerve conduits by bio-orthogonal reaction, but also precisely released in on-demand regeneration sites via esterase-activatable cleavage for peripheral nerve repair. Moreover, this nerve scaffold with esterase-activatable release could promote Schwann cells proliferation. In a rat sciatic nerve defect model, the bio-orthogonally functionalized scaffold with esterase-activatable release significantly increased sciatic nerve function recovery and improved target muscles weight. This strategy of incorporating esterase-activatable bioactive cues into peripheral nerve conduits offers great potential in preclinical studies. [ABSTRACT FROM AUTHOR]

Peripheral nerve injuries (PNI) lead to alterations in the Agrin-LRP4-MuSK pathway. This results in disaggregation of AChRs and change from epsilon (mature, innervated) to gamma (immature, denervated) subunit. Tubulization technique has been shown to be effective for PNI repair and it also allows the use of adjuvants, such as fibrin biopolymer (FB). This study evaluated the effect of the association of tubulization with FB after PNI on AChRs and associated proteins. Fifty-two adults male Wistar rats were used, distributed in 4 experimental groups: Sham Control (S), Denervated Control (D); Tubulization (TB) and Tubulization + Fibrin Biopolymer (TB+FB). Catwalk was performed every 15 days. Ninety days after surgery the right soleus muscles and ischiatic nerves were submitted to the following analyses: (a) morphological and morphometric analysis of AChRs by confocal microscopy; (b) morphological and morphometric analysis of the ischiatic nerve; (c) protein quantification of AChRs: alpha, gama, and epsilon, of Schwann cells, agrin, LRP4, MuSK, rapsyn, MMP3, MyoD, myogenin, MURF1 and atrogin-1. The main results were about the NMJs that in the TB+FB group presented morphological and morphometric approximation (compactness index; area of the AChRs and motor plate) to the S group. In addition, there were also an increase of S100 and AChRε protein expression and a decrease of MyoD. These positive association resulted in AChRs stabilization that potentiate the neuromuscular regeneration, which strengthens the use of TB for severe injuries repair and the beneficial effect of FB, along with tubulization technique. [ABSTRACT FROM AUTHOR]

To provide useful information for selecting the most appropriate peripheral nerve injury model for different research purposes in nerve injury and repair studies, and to compare nerve regeneration capacity and characteristics between them. Sixty adult SD rats were randomly divided into two groups and underwent crush injury alone (group A, n = 30) or transection injury followed by surgical repair (group B, n = 30) of the right hind paw. Each group was subjected to the CatWalk test, gastrocnemius muscle evaluation, pain threshold measurement, electrophysiological examination, retrograde neuronal labeling, and quantification of nerve regeneration before and 7, 14, 21, and 28 days after injury. Gait analysis showed that the recovery speed in group A was significantly faster than that in group B at 14 days. At 21 days, the compound muscle action potential of the gastrocnemius muscle in group A was significantly higher than that in group B, and the number of labeled motor neurons in group B was lower than that in group A. The number of new myelin sheaths and the g-ratio were higher in group A than in group B. There was a 7-day time difference in the regeneration rate between the two injury groups. The regeneration of nerve fibers was rapid after crush nerve injury, whereas the transection injury was relatively slow, which provides some ideas for the selection of clinical research models. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI), typically caused by traumatic accidents or medical events, is currently one of the most common diseases that leads to limb disability. After PNI, tetrodotoxin-resistant voltage-gated sodium channel Nav1.8 is upregulated at the lesion site. Our earlier study suggested that ropivacaine promotes axon regrowth by regulating Nav1.8-mediated macrophage signaling. Nevertheless, the mechanism of ropivacaine in regulation of Nav1.8 expression remains incompletely understood. Kinesin family 5b (KIF5b) was reported to mediate the Nav1.8 axonal transport from dorsal root ganglia (DRGs) to lesion site. Herein, we investigated whether ropivacaine promotes axon regeneration through inhibition of KIF5b-mediated Nav1.8 transport. Reduced levels of KIF5b and Nav1.8 in DRGs coincide with their increase at the lesion site. Nav1.8 mRNA was significantly increased at the lesion site but not in DRGs. Surprisingly, ropivacaine reversed the alterations of Nav1.8 and KIF5b protein expression without affecting Nav1.8 mRNA level. Due to KIF5b overexpression in DRGs, Nav1.8 protein level was significantly decreased in DRGs and increased at the lesion site. We also found KIF5b overexpression significantly impaired behavioral functions, reduced the recovery index of compound muscle action potential (CMAP) amplitude, inhibited axonal regrowth, slowed M1 macrophage infiltration and shift to M2 phenotype, and delayed myelin debris clearance. Notably, all aforementioned results caused by KIF5b overexpression were alleviated by ropivacaine. Furthermore, we demonstrated that inhibition of Nav1.8 transport by A-803467 produced mitigating effects on the impairment of regenerative capacity induced by KIF5b overexpression similar to ropivacaine. These results suggest that ropivacaine promotes axonal regeneration at least partially by inhibiting KIF5b-mediated Nav1.8 forward transport. [Display omitted] • Ropivacaine promoted histologic and functional recovery after sciatic nerve injury. • Nav1.8 forward transport was mediated by KIF5b after sciatic nerve injury. • Ropivacaine promoted axon regeneration by inhibiting KIF5b-mediated Nav1.8 transport. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury is a serious medical condition, but the limited availability of autologous grafts often delays timely treatment for many patients. The implantation of functional hydrogels with good biocompatibility provides an effective solution to this challenge. In this study, a novel chitosan derivative, choline functionalized catechol carboxymethyl chitosan (CF-Catechol-CMCS), was synthesized by modifying carboxymethyl chitosan (CMCS) with choline functionalized (CF) molecule and catechol. CF-Catechol-CMCS, sodium alginate (SA), and pyrrole monomer (Py) were then combined, crosslinked with Fe3+ and Ca2+, and polymerized in situ to form polypyrrole (PPy), resulting in the CF-Catechol-CMCS/SA/PPy hydrogel. This hydrogel exhibits excellent thermal stability, with a maximum thermal degradation temperature of 580 °C. By adjusting the ratio of PPy to CF-Catechol-CMCS/SA in the hydrogel, its degradation properties, swelling behavior, mechanical properties, and electrical conductivity can be fine-tuned. Specifically, when the mass ratio of PPy to CF-Catechol-CMCS/SA is 8:10, the hydrogel achieves optimal conductivity within a safe range (1.82 × 10−3 S·cm−1). By controlling the mass ratio of CF-Catechol-CMCS to SA in the hydrogel, the acetylcholine concentration can be regulated. When the CF-Catechol-CMCS:SA ratio is 2:1, the measured Sciatic Function Index (SFI) value is −34.54, indicating that the CF-Catechol-CMCS/SA/PPy hydrogel has excellent nerve repair potential. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury occurs in a relatively large proportion of trauma patients, in whom it generally results in severe functional impairment and permanent disability. At present, however, there are no effective treatments available. Studies have shown that Schwann cells play an indispensable role in removing myelin debris and guiding axonal regeneration, and transplantation using autologous Schwann cells has shown good efficacy for patients with peripheral nerve injury. In recent years, Schwann cell autologous transplantation therapy has become an area of intensive research and is anticipated to provide a new strategy for the clinical treatment of peripheral nerve injury. In this article, we review the rationale for selecting Schwann cell autotransplantation therapy and the latest progress in key aspects of cell transplantation and clinical efficacy, and also summarize the future directions of research on this therapy. All of the above provide a strong basis for the further improvement and clinical promotion of this therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

To investigate the prevalence of upper limb peripheral nerve injuries (PNI) in adult patients admitted to the intensive care unit (ICU) with acute respiratory distress syndrome (ARDS) undergoing prone positioning. This systematic review with meta-analysis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. Four electronic databases including PubMed, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), The Cochrane Library, and EMBASE were searched from inception to January 2024. The quality of the included studies was evaluated according to the Joanna Briggs Institute Critical Appraisal Tools. A proportion meta-analysis was conducted to examine the combined prevalence of upper limb PNI among patients requiring prone positioning. A total of 8 studies (511 patients) were pooled in the quantitative analysis. All studies had a low or moderate risk of bias in methodological quality. The overall proportion of patients with upper limb PNI was 13% (95%CI: 5% to 29%), with large between-study heterogeneity (I2 = 84.6%, P<0.001). Both ulnar neuropathy and brachial plexopathy were described in 4 studies. During the COVID-19 pandemic, prone positioning has been used extensively. Different approaches among ICU teams and selective reporting by untrained staff may be a factor in interpreting the large variability between studies and the 13% proportion of patients with upper limb PNI found in the present meta-analysis. Therefore, it is paramount to stress the importance of patient assessment both after discharge from the ICU and during subsequent follow-up evaluations. Specialized training is essential to ensure safe prone positioning, with careful consideration given to arms and head placement to mitigate potential nerve injuries. Therefore, healthcare protocols should incorporate preventive strategies, with patient assessments conducted by expert multidisciplinary teams. [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) causes motor and sensory defects, has strong impact on life quality and still has no effective therapy. Glycyrrhizic acid (GA) is one of the most widely used in traditional Chinese prescriptions and as a flavoring additive in the food industry; the aims of the study were to investigate the effects of GA during sciatic nerve regeneration in a mouse model of sciatic nerve crush injury. We established peripheral nerve crush model and investigated the effects of GA. We further studied the potential mechanism of action of GA by Western blotting, fluorescence immunohistochemistry, and PCR analysis. GA improves the sensory and motor functions of crushed nerve by preventing Schwann cell loss, axonal loss and promoting remyelination of sciatic nerve. Affected by GA, the inflammatory response in the distal part of the sciatic nerve was reduced. Finally, the neuroprotective properties of GA may be regulated by the nuclear factor (NF)‐κB pathway. Our data suggest that GA can effectively alleviate PNI, and the mechanism involves mediating inflammatory response by suppressing NF-κB pathway activation. Thus, GA may represent a potential therapeutic intervention for nerve crush injury. [ABSTRACT FROM AUTHOR]

Efficient repair of peripheral nerve injuries (PNI) poses a significant challenge in neurosurgery. Wireless charging systems developed from piezoelectric materials, which can convert various forms of exogenous or endogenous mechanical signal into electrical stimulation, are highly regarded in the field of nerve regeneration. However, the potential mobility restrictions of patients with PNI and the attenuation of mechanical signal in deep tissues make it difficult to generate optimal electrical stimulation for inducing nerve regeneration, thereby limiting their clinical applications. Here, we developed a dual-oriented fibrous scaffold with excellent magneto-electric conversion performance to provide stable and controllable wireless electrical stimulation for PNI repair. The oriented arrangement of cobalt ferrite (CoFe 2 O 4 , CFO) fibrous fillers combined with the aligned orientation of polyvinylidene fluoride (PVDF) fibers improves the magneto-electric conversion performance of the scaffolds, resulting in the generation of approximately 150 mV under a low-frequency alternating magnetic field (150 Oe, 1000 Hz). Gait analysis demonstrated that stable electrical stimulation resulted in significant motor function recovery in rats when using the scaffold wrapped around Gelatin Methacryloyl (GelMA) hydrogel with neural stem cells (NSCs) under an AC magnetic field. Further, single-cell transcriptomics and histological studies confirmed that the scaffold modulates immune activity, promotes nerve growth factor expression, accelerates stem cell differentiation into neurons, and aids tissue regeneration. This study presents a novel wireless charging magnetoelectric (ME) scaffold, contributing to address critical gap in therapeutic strategies for PNI. [Display omitted] [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) can cause nerve demyelination, neuronal apoptosis, axonal atrophy, inflammatory infiltration, glial scar formation, and other pathologies that can lead to sensory and motor dysfunction and seriously affect the psychosomatic health of patients. There is currently no effective treatment method, so exploring a promising treatment method is of great significance. Several studies have revealed the therapeutic roles of Schwann cells (SCs) and their exosomes in nerve injury repair. Exosomes are extracellular nanovesicles secreted by cells that act as key molecules in intercellular communication. Progress has been made in understanding the role of exosomes derived from SCs (SC-EXOs) in peripheral nerve regeneration, including the promotion of axonal regeneration and myelin formation, anti-inflammation, vascular regeneration, neuroprotection, and neuroregulation. Therefore, in this paper, we summarize the functional characteristics of SC-EXOs and discuss their potential therapeutic effects on PNI repair as well as some existing problems and future challenges. [Display omitted] [ABSTRACT FROM AUTHOR]

• Evaluate the potential anti-allodynic effects of photobiomodulation therapy (PBMT) using two protocols, prevent and reversal. • PBMT could offer a non-invasive and potentially effective approach for managing neuropathic pain. • Inclusion of both sexes in the study design underscores the importance of understanding sex-specific responses in pain research and treatment. • PBMT exerts its therapeutic effects and optimizing treatment protocols to enhance its clinical applicability in managing neuropathic pain. Pathological nociception arising from peripheral nerve injury impacts quality of life. Current therapeutics are generally ineffective. However, photobiomodulation therapy (PBMT) has shown promise in addressing this issue. We aimed to assess the potential anti-allodynic effects of 2 p.m. protocols, each applied transcutaneously over the peripheral nerve injury. In addition to evaluating nociceptive behavior, we also conducted morphological analysis using electron microscopy (EM) to investigate potential ultrastructural changes at the cellular level. We sought to determine, using the chronic constriction injury (CCI) model, whether our parameters could alleviate established allodynia and/or dampen allodynia development. Adult male and female rats with CCI or sham were treated with PBMT (850-nm wavelength) for 2 min, 3 times a week over three or four weeks across three studies, where PBMT began either before or after CCI. Allodynia was assessed prior to surgery and across weeks and, at the conclusion of the third study, sciatic nerve was processed for EM and histomorphometrically evaluated. The results showed that PBMT before versus after CCI injury yielded similar behaviors, effectively decreasing allodynia. Interestingly, these positive effects of PBMT do not appear to be accounted by protection of the sciatic injury site, based on EM. CCI reliably decreased axon size and the number of myelinated axons present in both PBMT and control groups. While PBMT reduced the number of C-fibers in CCI samples, no improvement in any measure was observed in response to PBMT. [Display omitted] [ABSTRACT FROM AUTHOR]

Peripheral nerve injury (PNI) poses a significant public health issue, often leading to muscle atrophy and persistent neuropathic pain, which can drastically impact the quality of life for patients. Electrical stimulation represents an effective and non-pharmacological treatment to promote nerve regeneration. Yet, the postoperative application of electrical stimulation remains a challenge. Here, we propose a fully biodegradable, self-powered nerve guidance conduit (NGC) based on dissolvable zinc-molybdenum batteries. The conduit can offer topographic guidance for nerve regeneration and deliver sustained electrical cues between both ends of a transected nerve stump, extending beyond the surgical window. Schwann cell proliferation and adenosine triphosphate (ATP) production are enhanced by the introduction of the zinc-molybdenum batteries. In rodent models with 10-mm sciatic nerve damage, the device effectively enhances nerve regeneration and motor function recovery. This study offers innovative strategies for creating biodegradable and electroactive devices that hold important promise to optimize therapeutic outcomes for nerve regeneration. • We develop a fully biodegradable and self-powered NGC for PNI, which offers topographic guidance and continuous electric cues. • Zn-Mo battery shows desirable biocompatibility and functionality to promote Schwann cell proliferation and ATP production. • The self-powered NGC facilitates neurite regrowth, myelination, and motor function restoration in sciatic nerve defects. • The study offers novel strategies for biodegradable and electroactive devices, promising advances in electronic medicine. [ABSTRACT FROM AUTHOR]

[Display omitted] • Dopamine methacrylate-conjugated exosomes (mExo) are synthesized to achieve mitochondrial targeting. • Difunctional dextran-based hydrogel patch with mExo immobilization is developed by boronic ester bonding integration. • Hydrogel patch provides neuroprotection and neurotherapy through ROS scavenging and mitochondrial dysfunction targeting. • The two-pronged approach of neuroprotection and neurotherapy enhances the treatment of diabetic PNI. Peripheral nerve injury (PNI) is a common clinical complication of diabetes, however, lacks effective clinical treatment due to complex pathological microenvironment. Considering both biomimetic remodeling and pathological reversal, we proposed a boronic ester bonding integrated strategy to develop dextran-based hydrogel patch with dopamine methacrylate-conjugated exosomes (mExo) immobilization. Aldehyde/phenylboronic acid difunctional dextran was synthesized to establish hydrogel skeleton and provide self-adhesion and ROS/glucose modulation capacities for neuroprotection. Meanwhile, mExo as therapeutic factors were immobilized into hydrogels via boronic ester bonding and released in pathologic response to target mitochondrial dysfunction and achieve neurotherapy. Through in vitro assays, the composite hydrogel patch was shown to reduce oxidative stress by ROS scavenging, thereby protecting the mitochondrial morphological and functional homeostasis of healthy RSC96 cells. Indeed, the sustained released exosome conjugates regulated bioenergy metabolism and alleviated mitochondrial dysfunction in hyperglycemia damaged RSC96 cells by the up-regulated expression of E-cadherin and AMPK proteins. In vivo experiments proved that through correcting diabetic pathology and targeted treatment of damaged mitochondria, the hydrogel patch inhibited neuronal apoptosis and finally promoted axon regeneration, remyelination and motor function recovery after PNI in diabetic rats. The synergistic "two-pronged" strategy of biomimetic remodeling and pathological reversal opens a promising opportunity for non-invasive treatment of diabetic PNI. [ABSTRACT FROM AUTHOR]

Introduction: Proinflammatory cytokines released from nerve endings and surrounding injured tissue after nerve damage can prolong the inflammation process, delay nerve healing or result in poor quality nerve healing. In this case, due to the loss of function in the muscles innervated by the damaged nerve, the patient may have neurological and functional difficulties which may reduce the patient's quality of life and create an economic burden. Although the attempts of many pharmacological agents to heal crush injury of peripheral nerves have been recorded in literature, a drug that can provide adequate recovery of the crushed nerve and can be applied in daily life has not been defined as yet. This study aimed to assess the effects of calcium dobesilate on sciatic nerve crush injury in a rat model.Methods: A total of 26 male Wistar albino rats were separated into four groups as follows: CONTROL group (healthy subjects, n=6); SHAM group (crush injury was created, n=6); MP group (after created crush injury, methylprednisolone was administered, n=7); and CAD group (after created crush injury, calcium dobesilate was administered, n=7). A crush injury was created, then the electrophysiological findings and sciatic nerve functional index (SFI) were recorded before euthanasia. After the euthanasia of all the rats, samples of the crushed nerve and gastrocnemius muscle were evaluated histopathologically, immunohistochemically, and biochemically.Results: Both pharmacological agents were histopathologically effective in axon regeneration and repair. Calcium dobesilate did not preserve total muscle mass but was seen to prevent atrophy microscopically. Immunohistochemistry and biochemistry results showed that calcium dobesilate and methylprednisolone had anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-autophagic activity in the crushed sciatic nerve. Neither calcium dobesilate nor methylprednisolone improved the nerve conductance level. SFI values obtained on day 30 from the CAD group were numerically closer to the values of the healthy animals but not at a statistically significant level.Conclusion: The study results demonstrated that calcium dobesilate could suppress inflammatory processes and provide histopathological and functional improvements in the injured nerve in rats. Therefore, further clinical studies are recommended to investigate in detail the therapeutic effects of calcium dobesilate on peripheral nerve crush injury. [ABSTRACT FROM AUTHOR]

Introduction: Peripheral nerve injury due to animal bite is a rare phenomenon. Most animal bites are from dogs. Monkey bites constitute a common risk, second only to dog bites, among travelers. Peripheral nerve injuries may occur due to a combination of monkey's strong jaws and sharp long teeth penetrating deep into the soft tissues. Such injuries are associated with increased perineural fibrosis. Human amniotic membrane (HAM) wrap around the nerve repair site reduces fibrotic response, prevents adhesions and scar formation thereby improving outcome. We report a case of "High Radial nerve palsy due to monkey bite, treated by neurorrhaphy with HAM wrap".Method: A 3-year old boy presented with wrist drop, and inability to extend the fingers and thumb of his right dominant hand, following a monkey bite over the distal arm. The diagnosis of high radial nerve injury was corroborated by high frequency ultrasound and electrodiagnostic studies. On exploration the radial nerve was found to be transected. An end to end repair was performed, with HAM wrap around the neurorrhaphy.Results: Wrist dorsiflexion recovered at 2.5 months followed by active finger and thumb extension at 4 months with no infection or immune rejection.Conclusion: Nerve regeneration in our patient occurred at a faster rate as compared to the conventional 1 mm/day. This could be attributed to decreased perineural fibrosis, improved neurotropism due to the HAM wrap and neuronal plasticity in young brain in addition, the patient being a small child having better regenerative ability in comparison to an adult. [ABSTRACT FROM AUTHOR]