Post-treatment with maropitant reduces oxidative stress, endoplasmic reticulum stress and neuroinflammation on peripheral nerve injury in rats.

OBJECTIVE: To determine the effective dose and therapeutic potential of maropitant using through expression of mediators of oxidative stress, inflammatory and of the unfolded protein response (UPR) (bio) markers on spinal cord using a model of neuropathic pain induced through chronic constriction injury (CCI) in rats. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: 98 male Wistar rats. METHODS: Rats were anesthetized with sevoflurane and after CCI, they were randomly assigned to the following groups that received: vehicle, 3, 6, 15, 30 e 50 mg/kg/24q of maropitant. The effect on inflammatory mediators (IL10, TNFα), oxidative stress (GPx, CAT, SOD), microglial (IBA-1) and neuronal (NeuN, TACR1) markers was evaluated though immunohistochemistry and expression levels of markers of hypoxia (HIF1α, Nrf2), antioxidant enzymes (Catalse, Sod1 and GPx1), and endoplasmic reticulum stress mediators (GRP78, CHOP and PERK) through qRT-PCR. RESULTS: Intraperitoneal injection (IP) of maropitant inhibited nociception with ID50 values of 4,1 mg/kg (5,85-19,36) in a neuropathic pain model through CCI. A dose of 30 mg/kg/24q was significantly effective in reducing mechanical allodynia 1 to 4h after treatment with nociception inhibition (145,83%). A reduction in the expression of hypoxia factors (HIF1α, Nrf2) was observed, along with an increase in antioxidant activity (CAT, SOD and GPX). Additionally, there was a reduction in inflammatory markes (IL10, TNFα), microglial (IBA-1), and neuronal markers (NeuN, TACR1). CONCLUSION AND CLINICAL RELEVANCE: These findings demonstrate that the determined dose, administered daily for seven days, had an antinociceptive effect, as well as anti-inflammatory and antioxidant activity.

Development of new nanofibrous nerve conduits by PCL-Chitosan-Hyaluronic acid containing Piracetam-Vitamin B12 for sciatic nerve: A rat model.

Peripheral nerve injury is a critical condition that can disrupt nerve functions. Despite the progress in engineering artificial nerve guidance conduits (NGCs), nerve regeneration remains challenging. Here, we developed new nanofibrous NGCs using polycaprolactone (PCL) and chitosan (CH) containing piracetam (PIR)/vitamin B12(VITB12) with an electrospinning method. The lumen of NGCs was coated by hyaluronic acid (HA) to promote regeneration in sciatic nerve injury. The NGCs were characterized via Scanning Electron Microscopy (SEM), Fourier transform infrared (FTIR), tensile, swelling, contact angle, degradation, and drug release tests. Neuronal precursor cell line (PCL12 cell) and rat mesenchymal stem cells derived from bone marrow (MSCs) were seeded on the nanofibrous conduits. After that, the biocompatibility of the NGCs was evaluated by the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, 4',6-diamidino-2-phenylindole (DAPI) staining, and SEM images. The SEM demonstrated that PCL/CH/PIR/VITB12 NGCs had nonaligned, interconnected, smooth fibers. The mechanical properties of these NGCs were similar to rat sciatic nerve. These conduits had an appropriate swelling and degradation rate. The In Vitro studies exhibited favorable biocompatibility of the PCL/CH/PIR/VITB12 NGCs towards PC12 cells and MSCs. The in vitro studies exhibited favorable biocompatibility of the PCL/CH/PIR/VIT B12 NGCs towards MSCs and PC12 cells. To analyze functional efficacy, NGCs were implanted into a 10 mm Wistar rat sciatic nerve gap and bridged the proximal and distal stump of the defect. After three months, the results of sciatic functional index (55.3 ± 1.8), hot plate latency test (5.6 ± 0.5 s), gastrocnemius muscle wet weight-loss (38.57 ± 1.6 %) and histopathological examination using hematoxylin-eosin (H&E) /toluidine blue/ Anti-Neurofilament (NF200) staining demonstrated that the produced conduit recovered motor and sensory functions and had comparable nerve regeneration compared to the autograft that can be as the gold standard to bridge the nerve gaps.

Combining PLGA microspheres loaded with Liver X receptor agonist GW3965 with a chitosan nerve conduit can promote the healing and regeneration of the wounded sciatic nerve.

Globally, peripheral nerve injury (PNI) is a common clinical issue. Successfully repairing severe PNIs has posed a major challenge for clinicians. GW3965 is a highly selective LXR agonist, and previous studies have demonstrated its positive protective effects in both central and peripheral nerve diseases. In this work, we examined the potential reparative effects of GW3965-loaded polylactic acid co-glycolic acid microspheres in conjunction with a chitosan nerve conduit for peripheral nerve damage. The experiment revealed that GW3965 promoted Schwann cell proliferation and neurotrophic factor release in vitro. In vivo experiments conducted on rats showed that GW3965 facilitated the restoration of motor function, promoted axon and myelin regeneration in the sciatic nerve, and enhanced the microenvironment of nerve regeneration. These results offer a novel therapeutic approach for the healing of nerve damage. Overall, this work provides valuable insights and presents a promising therapeutic strategy for addressing PNI.

Electrospun Composite PLLA-PPSB Nanofiber Nerve Conduits for Peripheral Nerve Defects Repair and Regeneration.

Peripheral nerve injury (PNI) is a common clinical problem and regenerating peripheral nerve defects remain a significant challenge. Poly(polyol sebacate) (PPS) polymers are developed as promising materials for biomedical applications due to their biodegradability, biocompatibility, elastomeric properties, and ease of production. However, the application of PPS-based biomaterials in nerve tissue engineering, especially in PNI repair, is limited. In this study, PPS-based composite nanofibers poly(l-lactic acid)-poly(polycaprolactone triol-co-sebacic acid-co-N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid sodium salt) (PLLA-PPSB) are aimed to construct through electrospinning and assess their in vitro biocompatibility with Schwann cells (SCs) and in vivo repair capabilities for peripheral nerve defects. For the first time, the biocompatibility and bioactivity of PPS-based nanomaterial are examined at the molecular, cellular, and animal levels for PNI repair. Electrospun PLLA-PPSB nanofibers display favorable physicochemical properties and biocompatibility, providing an effective interface for the proliferation, glial expression, and adhesion of SCs in vitro. In vivo experiments using a 10-mm rat sciatic nerve defect model show that PLLA-PPSB nanofiber nerve conduits enhance myelin formation, axonal regeneration, angiogenesis, and functional recovery. Transcriptome analysis and biological validation indicate that PLLA-PPSB nanofibers may promote SC proliferation by activating the PI3K/Akt signaling pathway. This suggests the promising potential of PLLA-PPSB nanomaterial for PNI repair.

Therapeutic Effect of an Ursolic Acid-Based Nutraceutical on Neuronal Regeneration after Sciatic Nerve Injury.

Peripheral nerve injuries lead to severe functional impairments and long recovery times, with limited effectiveness and accessibility of current treatments. This has increased interest in natural bioactive compounds, such as ursolic acid (UA). Our study evaluated the effect of an oleolyte rich in UA from white grape pomace (WGPO) on neuronal regeneration in mice with induced sciatic nerve resection, administered concurrently with the induced damage (the WGPO group) and 10 days prior (the PRE-WGPO group). The experiment was monitored at two-time points (4 and 10 days) after injury. After 10 days, the WGPO group demonstrated a reduction in muscle atrophy, evidenced by an increased number and diameter of muscle fibers and a decreased Atrogin-1 and Murf-1 expression relative to the denervated control. It was also observed that 85.7% of neuromuscular junctions (NMJs) were fully innervated, as indicated by the colocalization of α-bungarotoxin and synaptophysin, along with the significant modulation of Oct-6 and S-100. The PRE-WGPO group showed a more beneficial effect on nerve fiber reformation, with a significant increase in myelin protein zero and 95.2% fully innervated NMJs, and a pro-hypertrophic effect in resting non-denervated muscles. Our findings suggest WGPO as a potential treatment for various conditions that require the repair of nerve and muscle injuries.

A responsive cascade drug delivery scaffold adapted to the therapeutic time window for peripheral nerve injury repair.

Peripheral nerve injury (PNI) is a common clinical challenge, requiring timely and orderly initiation of synergistic anti-inflammatory and reparative therapy. Although the existing cascade drug delivery system can realize sequential drug release through regulation of the chemical structure of drug carriers, it is difficult to adjust the release kinetics of each drug based on the patient's condition. Therefore, there is an urgent need to develop a cascade drug delivery system that can dynamically adjust drug release and realize personalized treatment. Herein, we developed a responsive cascade drug delivery scaffold (RCDDS) which can adapt to the therapeutic time window, in which Vitamin B12 is used in early controllable release to suppress inflammation and nerve growth factor promotes regeneration by cascade loading. The RCDDS exhibited the ability to modulate the drug release kinetics by hierarchically opening polymer chains triggered by ultrasound, enabling real-time adjustment of the anti-inflammatory and neuroregenerative therapeutic time window depending on the patient's status. In the rat sciatic nerve injury model, the RCDDS group was able to achieve neural repair effects comparable to the autograft group in terms of tissue structure and motor function recovery. The development of the RCDDS provides a useful route toward an intelligent cascade drug delivery system for personalized therapy.

Growth factors: Bioactive macromolecular drugs for peripheral nerve injury treatment - Molecular mechanisms and delivery platforms.

Bioactive macromolecular drugs known as Growth Factors (GFs), approved by the Food and Drug Administration (FDA), have found successful application in clinical practice. They hold significant promise for addressing peripheral nerve injuries (PNIs). Peripheral nerve guidance conduits (NGCs) loaded with GFs, in the context of tissue engineering, can ensure sustained and efficient release of these bioactive compounds. This, in turn, maintains a stable, long-term, and effective GF concentration essential for treating damaged peripheral nerves. Peripheral nerve regeneration is a complex process that entails the secretion of various GFs. Following PNI, GFs play a pivotal role in promoting nerve cell growth and survival, axon and myelin sheath regeneration, cell differentiation, and angiogenesis. They also regulate the regenerative microenvironment, stimulate plasticity changes post-nerve injury, and, consequently, expedite nerve structure and function repair. Both exogenous and endogenous GFs, including NGF, BDNF, NT-3, GDNF, IGF-1, bFGF, and VEGF, have been successfully loaded onto NGCs using techniques like physical adsorption, blend doping, chemical covalent binding, and engineered transfection. These approaches have effectively promoted the repair of peripheral nerves. Numerous studies have demonstrated similar tissue functional therapeutic outcomes compared to autologous nerve transplantation. This evidence underscores the substantial clinical application potential of GFs in the domain of peripheral nerve repair. In this article, we provide an overview of GFs in the context of peripheral nerve regeneration and drug delivery systems utilizing NGCs. Looking ahead, commercial materials for peripheral nerve repair hold the potential to facilitate the effective regeneration of damaged peripheral nerves and maintain the functionality of distant target organs through the sustained release of GFs.

Oxytocin mitigates peripheral nerve damage via Nrf2 and irisin pathway.

OBJECTIVE: Peripheral nerve injuries present challenges in achieving full functional restoration, necessitating effective therapeutic strategies. Oxytocin, known for its neuroprotective and anti-inflammatory properties, has shown potential in nerve recovery. This study aims to elucidate the role of oxytocin in nerve recovery via the nuclear factor erythroid 2-related factor 2 (Nrf2) and irisin pathways. MATERIALS AND METHODS: Adult male Wistar rats (n=30) were subjected to surgical dissection of sciatic nerves and divided into Control, Surgery and Saline Group, and Surgery and Oxytocin (OT) group. Electromyographic (EMG) recordings, inclined plane tests, and histological assessments were conducted to evaluate nerve function, and Nerve growth factor (NGF) immunoexpression and axonal parameters were measured. Plasma irisin levels, nerve NGF, and Nrf2 levels were quantified. RESULTS: The Surgery and Saline Group exhibited impaired EMG latency, amplitude, and inclined plane score compared to Controls, while the Surgery and OT Group demonstrated improved outcomes. Histomorphometric analysis revealed increased NGF immunoexpression, axon number, diameter, and reduced fibrosis in the Surgery and OT Group. Plasma irisin levels were higher following oxytocin administration. Additionally, nerve NGF and Nrf2 levels were elevated in the Surgery and OT Group. CONCLUSIONS: OT administration mitigated nerve injury effects, promoting functional and histological improvements. Elevated NGF and Nrf2 levels, along with increased irisin, indicated the potential interplay of these pathways in enhancing nerve recovery. The results align with OT's neuroprotective and anti-inflammatory roles, suggesting its potential as a therapeutic intervention for nerve injuries. OT's positive impact on nerve recovery is associated with its modulation of Nrf2 and irisin pathways, which collectively enhance antioxidant defense and neurotrophic support and mitigate inflammation. These findings underline OT's potential as a therapeutic agent to enhance nerve regeneration and recovery. Further research is needed to elucidate the intricate molecular mechanisms and potential clinical applications of OT in nerve injury management.

Comparison of the Effects of Botulinum Toxin Doses on Nerve Regeneration in Rats with Experimentally Induced Sciatic Nerve Injury.

This study was designed to compare the effects of various doses of botulinum neurotoxin A (BoNT/A) on nerve regeneration. Sixty-five six-week-old rats with sciatic nerve injury were randomly allocated to three experimental groups, a control group, and a sham group. The experimental groups received a single session of intraneural BoNT/A (3.5, 7.0, or 14 U/kg) injection immediately after nerve-crushing injury. The control group received normal intraneural saline injections after sciatic nerve injury. At three, six, and nine weeks after nerve damage, immunofluorescence staining, an ELISA, and toluidine blue staining was used to evaluate the regenerated nerves. Serial sciatic functional index analyses and electrophysiological tests were performed every week for nine weeks. A higher expression of GFAP, S100ß, GAP43, NF200, BDNF, and NGF was seen in the 3.5 U/kg and 7.0 U/kg BoNT/A groups. The average area and myelin thickness were significantly greater in the 3.5 U/kg and 7.0 U/kg BoNT/A groups. The sciatic functional index and compound muscle action potential amplitudes exhibited similar trends. These findings indicate that the 3.5 U/kg and 7.0 U/kg BoNT/A groups exhibited better nerve regeneration than the 14 U/kg BoNT/A and control group. As the 3.5 U/kg and the 7.0 U/kg BoNT/A groups exhibited no statistical difference, we recommend using 3.5 U/kg BoNT/A for its cost-effectiveness.

An injectable and adaptable hydrogen sulfide delivery system for modulating neuroregenerative microenvironment.

Peripheral nerve regeneration is a complex physiological process. Single-function nerve scaffolds often struggle to quickly adapt to the imbalanced regenerative microenvironment, leading to slow nerve regeneration and limited functional recovery. In this study, we demonstrate a "pleiotropic gas transmitter" strategy based on endogenous reactive oxygen species (ROS), which trigger the on-demand H2S release at the defect area for transected peripheral nerve injury (PNI) repair through concurrent neuroregeneration and neuroprotection processing. This H2S delivery system consists of an H2S donor (peroxyTCM) encapsulated in a ROS-responsive polymer (mPEG-PMet) and loaded into a temperature-sensitive poly (amino acid) hydrogel (mPEG-PA-PP). This multi-effect combination strategy greatly promotes the regeneration of PNI, attributed to the physiological effects of H2S. These effects include the inhibition of inflammation and oxidative stress, protection of nerve cells, promotion of angiogenesis, and the restoration of normal mitochondrial function. The adaptive release of pleiotropic messengers to modulate the tissue regeneration microenvironment offers promising peripheral nerve repair and tissue engineering opportunities.

Development of ibuprofen-loaded electrospun materials suitable for surgical implantation in peripheral nerve injury.

The development of nerve wraps for use in the repair of peripheral nerves has shown promise over recent years. A pharmacological effect to improve regeneration may be achieved by loading such materials with therapeutic agents, for example ibuprofen, a non-steroidal anti-inflammatory drug with neuroregenerative properties. In this study, four commercially available polymers (polylactic acid (PLA), polycaprolactone (PCL) and two co-polymers containing different ratios of PLA to PCL) were used to fabricate ibuprofen-loaded nerve wraps using blend electrospinning. In vitro surgical handling experiments identified a formulation containing a PLA/PCL 70/30 molar ratio co-polymer as the most suitable for in vivo implantation. In a rat model, ibuprofen released from electrospun materials significantly improved the rate of axonal growth and sensory recovery over a 21-day recovery period following a sciatic nerve crush. Furthermore, RT-qPCR analysis of nerve segments revealed that the anti-inflammatory and neurotrophic effects of ibuprofen may still be observed 21 days after implantation. This suggests that the formulation developed in this work could have potential to improve nerve regeneration in vivo.

Treatments with the specific δ-secretase inhibitor, compound 11, promote the regeneration of motor and sensory axons after peripheral nerve injury.

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

Prospects of Using Chitosan-Based Biopolymers in the Treatment of Peripheral Nerve Injuries.

Peripheral nerve injuries are common neurological disorders, and the available treatment options, such as conservative management and surgical repair, often yield limited results. However, there is growing interest in the potential of using chitosan-based biopolymers as a novel therapeutic approach to treating these injuries. Chitosan-based biopolymers possess unique characteristics, including biocompatibility, biodegradability, and the ability to stimulate cell proliferation, making them highly suitable for repairing nerve defects and promoting nerve regeneration and functional recovery. Furthermore, these biopolymers can be utilized in drug delivery systems to control the release of therapeutic agents and facilitate the growth of nerve cells. This comprehensive review focuses on the latest advancements in utilizing chitosan-based biopolymers for peripheral nerve regeneration. By harnessing the potential of chitosan-based biopolymers, we can pave the way for innovative treatment strategies that significantly improve the outcomes of peripheral nerve injury repair, offering renewed hope and better prospects for patients in need.

Therapeutic effects of cinnamon bark oil on sciatic nerve injury in rats.

OBJECTIVE: The aim of this study was to investigate the effects of cinnamon bark essential oil (CBO) on analgesia, motor activity, balance, and coordination in rats with sciatic nerve damage. MATERIALS AND METHODS: Rats were divided into three groups as simply randomized. The right sciatic nerve (RSN) of the Sham group was explored. Only vehicle solution was applied for 28 days. The RSN of the sciatic nerve injury (SNI) group was explored. Damage was created by unilateral clamping, and vehicle solution was applied for 28 days. The RSN of the sciatic nerve injury+cinnamon bark essential oil (SNI+CBO) group was explored. SNI was created by unilateral clamping and CBO was applied for 28 days. In the experiment study, motor activity, balance, and coordination measurements were made with rotarod and accelerod tests. A hot plate test was performed for analgesia measurements. Histopathology studies were carried out with the sciatic nerve tissues. RESULTS: In the rotarod test, there was a statistically significant difference between the SNI group and the SNI+CBO group (p<0.05). According to the accelerod test findings, there was a statistically significant difference between the SNI group with the Sham and SNI+CBO groups. In the hot plate test, there was a statistically significant difference between the SNI group with the Sham and SNI+CBO groups (p<0.05). In comparison to the Sham group and the SNI group, the SNI+CBO group was shown to have the greatest expression level of vimentin. CONCLUSIONS: We have concluded that CBO can be used as an adjuvant treatment in cases of SNI, increased pain, nociception, impaired balance, motor activity, and coordination. Our results will be supported by further studies.

Chinese herbal medicine Buyang Huanwu Decoction in treatment of peripheral nerve injury: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Peripheral nerve injuries (PNI) resulting from trauma can be severe and permanently disabling, approximately one-third of PNIs demonstrate incomplete recovery and poor functional restoration. However, despite extensive research on this aspect, complete functional recovery remains a challenge. In East Asian countries, Chinese herbal Buyang Huanwu Decoction (BHD) has been used to treat PNI for more than 200 years, and the studies of BHD to treat PNI have been increasing in recent years based on positive clinical outcomes. The purpose of this meta-analysis was to scientifically evaluate the safety and clinical efficacy of BHD in patients with PNI. METHOD: A literature search was conducted on PubMed, EMBASE, Cochrane Library, CNKI, Wanfang, VIP, and Sinomed databases for randomized controlled clinical trials that evaluated the safety and effects of BHD alone or combination treatment on PNI. RESULTS: A total of 14 studies involving 1415 participants were included in this study. Each trial did not show significant heterogeneity or publication bias. The results showed that significant improvements of the total clinical effective rate (odds ratio = 3.55; 95% confidence interval [CI] = [2.62, 4.81]; P < .0001), radial nerve function score (standardized mean difference [SMD] = 1.28; 95% CI = [1.09, 1.47]; P = .007), motor nerve conduction velocity (SMD = 1.59; 95% CI = [1.40, 1.78]; P < .0001), sensory nerve conduction velocity (SMD = 1.69; 95% CI = [1.34, 2.05]; P < .0001), and electromyography amplitude (SMD = 2.67; 95% CI = [1.27, 4.06]; P = .0002), and significantly reduce of the visual analog scale scores (SMD = -3.85; 95% CI = [-7.55, -0.15]; P = .04) in the BHD group compared with the control group. In addition, there were no serious and permanent adverse effects in the 2 groups, the difference was not significant (odds ratio = 1.00; 95% CI = [0.40, 2.50]; P = 1.00). CONCLUSION: Current evidence suggests that BHD is an effective and safe treatment for PNI and could be treated as a complementary and alternative option with few side effects compared to a single treatment with neurotrophic drugs or electrical stimulation. However, considering the low methodological quality of the included studies, further rigorous studies are required.

Conserved transcriptional programming across sex and species after peripheral nerve injury predicts treatments for neuropathic pain.

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

Electroactive scaffolds of biodegradable polyurethane/polydopamine-functionalized graphene oxide regulating the inflammatory response and revitalizing the axonal growth cone for peripheral nerve regeneration.

Long-gap peripheral nerve injury remains a major challenge in regenerative medicine and results in permanent sensory and motor dysfunction. Nerve guidance scaffolds (NGSs) are known as a promising alternative to autologous nerve grafting. The latter, the current "gold standard" in clinical practice, is frequently constrained by the limited availability of sources and the inevitable damage to the donor area. Given the electrophysiological properties of nerves, electroactive biomaterials are being intensively investigated in nerve tissue engineering. In this study, we engineered a conductive NGS compounded of biodegradable waterborne polyurethane (WPU) and polydopamine-reduced graphene oxide (pGO) for repairing impaired peripheral nerves. The incorporation of pGO at the optimal concentration (3 wt%) promoted in vitro spreading of Schwann cells (SCs) with high expression of the proliferation marker S100 protein. In an in vivo study of sciatic nerve transection injury, WPU/pGO NGSs were found to regulate the immune microenvironment by activating macrophage M2 polarization and upregulate growth-associated protein 43 (GAP43) to facilitate axonal elongation. Histological and motor function analysis demonstrated that WPU/pGO NGSs had a neuroprosthetic effect close to that of an autograft, which significantly promoted the regeneration of myelinated axons, reduced gastrocnemius atrophy, and enhanced hindlimb motor function. These findings together suggested that electroactive WPU/pGO NGSs may represent a safe and effective strategy to manage large nerve defects.

Natural polysaccharides and their derivatives as potential medical materials and drug delivery systems for the treatment of peripheral nerve injuries.

Peripheral nerve repair following injury is one of the most serious problems in neurosurgery. Clinical outcomes are often unsatisfactory and associated with a huge socioeconomic burden. Several studies have revealed the great potential of biodegradable polysaccharides for improving nerve regeneration. We review here the promising therapeutic strategies involving different types of polysaccharides and their bio-active composites for promoting nerve regeneration. Within this context, polysaccharide materials widely used for nerve repair in different forms are highlighted, including nerve guidance conduits, hydrogels, nanofibers and films. While nerve guidance conduits and hydrogels were used as main structural scaffolds, the other forms including nanofibers and films were generally used as additional supporting materials. We also discuss the issues of ease of therapeutic implementation, drug release properties and therapeutic outcomes, together with potential future directions of research.

The Effect of Acetyl-L-Carnitine (ALCAR) on Peripheral Nerve Regeneration in Animal Models: A Systematic Review.

Peripheral neuropathies caused by the peripheral nervous system (PNS) damage can occur due to trauma and other disorders. They present as altered sensation, weakness, autonomic symptoms, and debilitating pain syndrome with a wide range of clinical signs. Acetyl-L-Carnitine (ALCAR) is a biological compound with essential roles in mitochondrial oxidative metabolism and anti-oxidant effects that protects mitochondria from oxidative damage and inhibits apoptosis caused by mitochondrial damage. This study is a systematic review and meta-analysis of the effects of ALCAR on peripheral nerve injuries. This review examines studies on treating traumatic peripheral neuropathies in which ALCAR is administered to rats with sciatic nerve injury with an appropriate control group. The articles were divided based on the mode of ALCAR administration. If one method was used in more than one article, their results were entered in the "Revman5.4" software and were meta-analyzed. Studies were selected from 1994 to 2018 on rats with varying physical injuries to their sciatic nerves. In one study, ALCAR was provided to rats in their drinking water, while in other studies, ALCAR was injected intra-peritoneally. Different mechanisms of ALCAR actions have been suggested in this study, but the underpinnings of the neuroprotective effects of ALCAR are still unclear. Further studies are mandatory to clarify the actual mechanisms of the neuroprotective activity of ALCAR. Based on the results of existing studies, ALCAR effectively increases the tolerance threshold of thermal and mechanical stimuli, reduces latency, and reduces apoptosis; finally, adjusting the dose and duration of administration may increase the dose and duration axon diameter.