Peripheral Nerve Regeneration In Rats Research Articles

Effect of vascularized jejunal conduit flap on peripheral nerve regeneration in rats.

In the literature, almost all of the nerve conduits proposed for obtaining better nerve recovery were applied as graft materials. In this study, we aimed to propose a new nerve conduit model with a flap pattern and evaluate the effect of a pedicled vascularized jejunal flap on nerve regeneration after wrapping it around a sciatic nerve. A total of 90 Wistar albino rats were randomly divided into nine groups with 10 rats in each. The first three groups constituted the control groups, whereas Groups 4-6 were the jejunum conduit (JC)-applied groups. A mucosa-resected JC (MRJC) was applied in Groups 7 and 8. Epineurial neurorrhaphy was performed in Groups 1, 4, and 7; repair with a nerve graft was applied in Groups 2, 5, and 8; and a 1-cm-long nerve defect was created in Groups 3, 6, and 9. After 2 months of follow-up, nerve regeneration was assessed by statistical analyses of the Sciatic Functional Index (SFI) and histopathological evaluation. The MRJC groups had significantly better results in terms of SFI (p = 0.005). Statistical differences in axonal degeneration, axonal density, myelination, and disorganization were found between all control groups and MRJC groups (p = 0.022, p = 0.001, p = 0.001, and p = 0.039, respectively). In this study, the feasibility of wrapping around the nerve repair zones of pedicled autologous flaps designed in a tubular fashion was observed in a small rat model. The findings must be further validated with larger animals before clinical testing.

Chitosan/PLGA-based tissue engineered nerve grafts with SKP-SC-EVs enhance sciatic nerve regeneration in dogs through miR-30b-5p-mediated regulation of axon growth

Extracellular vesicles from skin-derived precursor Schwann cells (SKP-SC-EVs) promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats. This study aimed at expanding the application of SKP-SC-EVs in nerve grafting by creating a chitosan/PLGA-based, SKP-SC-EVs-containing tissue engineered nerve graft (TENG) to bridge a 40-mm long sciatic nerve defect in dogs. SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions, supported the outgrowth and myelination of regenerated axons, and alleviated the denervation-induced atrophy of target muscles in dogs. To clarify the underlying molecular mechanism, we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons, and miR-30b-5p was the most important among others. We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK, STAT3 or CREB. Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic.

The Effect of Distraction Osteogenesis on Peripheral Nerve Regeneration in Rats: A Preliminary Study In Vivo

Distraction osteogenesis (DO) is a widely employed method for the treatment of limb discrepancies and deformity correction. This study aimed at observing the histomorphological and ultrastructural changes of peripheral nerves around the distraction area during DO and investigating the self-repair mechanism of peripheral nerves in a rat DO model. Sixty rats underwent right femoral DO surgery and were randomly separated into six groups: Control (latency, no distraction, n = 10), Group 0-week (after distraction, n = 10), Group 2-week (n = 10), Group 4-week (n = 10), Group 6-week (n = 10), and Group 8-week (n = 10) at consolidation phase. The right femur of rats in Group 0-week, Group 2-week, Group 4-week, Group 6-week, and Group 8-week was subjected to continuous osteogenesis distraction at a rate of 0.5 mm/day for 10 days. Motor nerve conduction velocity (MNCV) of the sciatic nerve, sciatic function index (SFI), histological analyses, and transmission electron microscopy were conducted to evaluate nerve function. The MNCV and SFI of Group 0-week, Group 2-week, Group 4-week, and Group 6-week were significantly lower than the Control ( P < 0.05 ). No statistical differences were found between the Control and Group 8-week in terms of MNCV and SFI ( P > 0.05 ). Injuries to nerve fibres and nodes of Ranvier were observed in the Group 0-week, whereas the nerve fibres returned to the normal arrangement in the Group 8-week and oedema of myelin disappeared, with the continuity of axons and lamellar structure of myelin being restored. Femoral DO in rats with a rate of 0.5 mm/day may cause sciatic neurapraxia, which can be self-repaired after 8 weeks of consolidation. The paraneurium around the sciatic nerve enables it to glide during the distraction phase to reduce the occurrence of injurious changes.

Benefit of Adjuvant Mesenchymal Stem Cell Transplantation to Critical-Sized Peripheral Nerve Defect Repair: A Systematic Review and Meta-Analysis of Preclinical Studies.

Critically sized nerve defects cause devastating life-long disabilities and require interposition for reconstruction. Additional local application of mesenchymal stem cells (MSCs) is considered promising to enhance peripheral nerve regeneration. To better understand the role of MSCs in peripheral nerve reconstruction, we performed a systematic review and meta-analysis of the effects of MSCs on critically sized segment nerve defects in preclinical studies. 5146 articles were screened following PRISMA guidelines using PubMed and Web of Science. A total of 27 preclinical studies (n = 722 rats) were included in the meta-analysis. The mean difference or the standardized mean difference with 95% confidence intervals for motor function, conduction velocity, and histomorphological parameters of nerve regeneration, as well as the degree of muscle atrophy, was compared in rats with critically sized defects and autologous nerve reconstruction treated with or without MSCs. The co-transplantation of MSCs increased the sciatic functional index (3.93, 95% CI 2.62 to 5.24, p < 0.00001) and nerve conduction velocity recovery (1.49, 95% CI 1.13 to 1.84, p = 0.009), decreased the atrophy of targeted muscles (gastrocnemius: 0.63, 95% CI 0.29 to 0.97 p = 0.004; triceps surae: 0.08, 95% CI 0.06 to 0.10 p = 0.71), and promoted the regeneration of injured axons (axon number: 1.10, 95% CI 0.78 to 1.42, p < 0.00001; myelin sheath thickness: 0.15, 95% CI 0.12 to 0.17, p = 0.28). Reconstruction of critically sized peripheral nerve defects is often hindered by impaired postoperative regeneration, especially in defects that require an autologous nerve graft. This meta-analysis indicates that additional application of MSC can enhance postoperative peripheral nerve regeneration in rats. Based on the promising results in vivo experiments, further studies are needed to demonstrate potential clinical benefits.

Neural grafts containing exosomes derived from Schwann cell-like cells promote peripheral nerve regeneration in rats

Schwann cell-like cells (SCLCs), differentiated from mesenchymal stem cells, have shown promising outcomes in the treatment of peripheral nerve injuries in preclinical studies. However, certain clinical obstacles limit their application. Hence, the primary aim of this study was to investigate the role of exosomes derived from SCLCs (SCLCs-exo) in peripheral nerve regeneration. SCLCs were differentiated from human amniotic mesenchymal stem cells (hAMSCs) in vitro and validated by immunofluorescence, real-time quantitative PCR and western blot analysis. Exosomes derived from hAMSCs (hAMSCs-exo) and SCLCs were isolated by ultracentrifugation and validated by nanoparticle tracking analysis, WB analysis and electron microscopy. A prefabricated nerve graft was used to deliver hAMSCs-exo or SCLCs-exo in an injured sciatic nerve rat model. The effects of hAMSCs-exo or SCLCs-exo on rat peripheral nerve injury (PNI) regeneration were determined based on the recovery of neurological function and histomorphometric variation. The effects of hAMSCs-exo or SCLCs-exo on Schwann cells were also determined via cell proliferation and migration assessment. SCLCs significantly expressed the Schwann cell markers glial fibrillary acidic protein and S100. Compared to hAMSCs-exo, SCLCs-exo significantly enhanced motor function recovery, attenuated gastrocnemius muscle atrophy and facilitated axonal regrowth, myelin formation and angiogenesis in the rat model. Furthermore, hAMSCs-exo and SCLCs-exo were efficiently absorbed by Schwann cells. However, compared to hAMSCs-exo, SCLCs-exo significantly promoted the proliferation and migration of Schwann cells. SCLCs-exo also significantly upregulated the expression of a glial cell-derived neurotrophic factor, myelin positive regulators (SRY-box transcription factor 10, early growth response protein 2 and organic cation/carnitine transporter 6) and myelin proteins (myelin basic protein and myelin protein zero) in Schwann cells. These findings suggest that SCLCs-exo can more efficiently promote PNI regeneration than hAMSCs-exo and are a potentially novel therapeutic approach for treating PNI.

Peripheral nerve regeneration in rats using nerve graft in a vein conduit pre-filled with platelet-rich fibrin (PRF)

Treatment of peripheral nerve injury is not always satisfactory. To improve results, specific adjuvant methods have been used, such as platelet-rich fibrin (PRF) and vein conduits. The goal of this study was to assess whether use of PRF and vein conduits after nerve suture improves nerve regeneration as measured by a functional score and histomorphometry analysis. Ten isogenic spontaneously hypertensive rats were randomly assigned to 4 experimental procedures: 1) Sham group (n = 10); 2) Nerve graft (NG) group (n = 10); 3) Nerve graft covered with a vein conduit (NGVC) (n = 10); and 4) Nerve graft covered with a vein conduit pre-filled with PRF (NGVCP) (n = 10). Nerve repair results were evaluated on: sciatic functional index (SFI) at 0, 30, 60 and 90 days; morphometric and morphologic analysis of the distal nerve; and histological analysis of Fluoro-Gold® stained motor neurons in the anterior horn of the spinal cord. Compared to the Sham control group, the NGVC and NGVCP groups exhibited lower SFI on all measures. The NGVC group showed improvement in SFI at day 90, which was significant compared to the NG group. Fiber and axon diameters were comparable in the NGVC and NGVCP groups, which were both significantly lower than in the Sham and NG groups. Significant improvement was expected with PRF, but in fact the release of factors from this substance was not as effective as hoped.

Evaluation of peripheral nerve regeneration in Murphy Roths Large mouse strain following transection injury.

Aim: Murphy Roths Large (MRL/MpJ) mice have demonstrated the ability to heal with minimal or no scar formation in several tissue types. In order to identify a novel animal model, this study sought to evaluate whether this attribute applies to peripheral nerve regeneration. Materials & methods: This was a two-phase study. 6-week-old male mice were divided into two interventional groups: nerve repair and nerve graft. The MRL/MpJ was compared with the C57BL/6J strain for evaluation of both functional and histological outcomes. Results: MRL/MpJ strain demonstrated superior axon myelination and less scar formation, however functional outcomes did not show significant difference between strains. Conclusion: Superior histological outcomes did not translate into superior peripheral nerve regeneration in MRL/MpJ strain.

Localized delivery of brain-derived neurotrophic factor from PLGA microspheres promotes peripheral nerve regeneration in rats

BackgroundRepair of peripheral nerve defect presents a considerable challenge for reconstructive surgeons. The aim of this study is to develop a brain-derived neurotrophic factor (BDNF) from poly(D,L-lactide-co-glycolide) (PLGA) microspheres for the treatment of the peripheral nerve defect.MethodBDNF microspheres were prepared by using an oil-in-water emulsification-solvent evaporation method. The morphology, particle size, encapsulation efficiency, drug loading and sustained release performance of microspheres was observed and calculated. Adipose mesenchymal stem cells (ADSCs) were isolated and expanded. ADSCs were divided into four groups: control, BDNF, blank microsphere and BDNF microsphere groups. Cell count kit-8 (CCK-8) assays were used to assess cell proliferation. Cell migration was determined by Transwell assays. Twenty-eight male Sprague–Dawley rats underwent transection damage model on the right sciatic nerve. The wet weight ratio of the gastrocnemius muscle was calculated by comparing the weight of the gastrocnemius muscle from the operated side to that of the normal side. Neuroelectrophysiological testing was performed to assess nerve function recovery. Nerve regeneration was evaluated by histological analysis and immunohistochemical staining.ResultsThe microspheres were spherical and had uniform size (46.38 ± 1.00 μm), high encapsulation efficiency and high loading capacity. In vitro release studies showed that BDNF-loaded microspheres had good sustained release characteristics. The duration of BDNF release was extended to more than 50 days. BDNF or BDNF microsphere promote the proliferation and migration of ADSCs than control group (P < 0.05). Compared with control group, BDNF significantly decreased the nerve conduction velocity (NCV) and compound amplitude (AMP) (P < 0.05). The nerve fibers in the BDNF microsphere group were closely arranged and uniformly distributed than control group.ConclusionBDNF/PLGA sustained-release microsphere could promote the migration of ADSCs and promoted neural differentiation of ADSCs. Moreover, BDNF/PLGA sustained-release microsphere ameliorated nerve conduction velocity and prevented neuralgic amyotrophy.

Polydopamine-modified chitin conduits with sustained release of bioactive peptides enhance peripheral nerve regeneration in rats.

The introduction of neurotrophic factors into injured peripheral nerve sites is beneficial to peripheral nerve regeneration. However, neurotrophic factors are rapidly degraded in vivo and obstruct axonal regeneration when used at a supraphysiological dose, which limits their clinical benefits. Bioactive mimetic peptides have been developed to be used in place of neurotrophic factors because they have a similar mode of action to the original growth factors and can activate the equivalent receptors but have simplified sequences and structures. In this study, we created polydopamine-modified chitin conduits loaded with brain-derived neurotrophic factor mimetic peptides and vascular endothelial growth factor mimetic peptides (Chi/PDA-Ps). We found that the Chi/PDA-Ps conduits were less cytotoxic in vitro than chitin conduits alone and provided sustained release of functional peptides. In this study, we evaluated the biocompatibility of the Chi/PDA-Ps conduits. Brain-derived neurotrophic factor mimetic peptide and vascular endothelial growth factor mimetic peptide synergistically promoted proliferation of Schwann cells and secretion of neurotrophic factors by Schwann cells and attachment and migration of endothelial cells in vitro. The Chi/PDA-Ps conduits were used to bridge a 2 mm gap between the nerve stumps in rat models of sciatic nerve injury. We found that the application of Chi/PDA-Ps conduits could improve the motor function of rats and reduce gastrocnemius atrophy. The electrophysiological results and the microstructure of regenerative nerves showed that the nerve conduction function and remyelination was further restored. These findings suggest that the Chi/PDA-Ps conduits have great potential in peripheral nerve injury repair.

Sustained release of exosomes loaded into polydopamine-modified chitin conduits promotes peripheral nerve regeneration in rats.

Exosomes derived from mesenchymal stem cells are of therapeutic interest because of their important role in intracellular communication and biological regulation. On the basis of previously studied nerve conduits, we designed a polydopamine-modified chitin conduit loaded with mesenchymal stem cell-derived exosomes that release the exosomes in a sustained and stable manner. In vitro experiments revealed that rat mesenchymal stem cell-derived exosomes enhanced Schwann cell proliferation and secretion of neurotrophic and growth factors, increased the expression of Jun and Sox2 genes, decreased the expression of Mbp and Krox20 genes in Schwann cells, and reprogrammed Schwann cells to a repair phenotype. Furthermore, mesenchymal stem cell-derived exosomes promoted neurite growth of dorsal root ganglia. The polydopamine-modified chitin conduits loaded with mesenchymal stem cell-derived exosomes were used to bridge 2 mm rat sciatic nerve defects. Sustained release of exosomes greatly accelerated nerve healing and improved nerve function. These findings confirm that sustained release of mesenchymal stem cell-derived exosomes loaded into polydopamine-modified chitin conduits promotes the functional recovery of injured peripheral nerves.

Effect of Nimodipine and Botulinum Toxin A on Peripheral Nerve Regeneration in Rats: A Pilot Study

BackgroundPeripheral nerve damage is a frequent problem, with an estimated 2.8%-5.0% of trauma admissions involving peripheral nerve injury. End-to-end, tension-free microsurgical repair (neurorrhaphy) is the current gold standard treatment for complete transection (neurotmesis). While neurorrhaphy reapproximates the nerve, it does not address the complex molecular regenerative process. Evidence suggests that botulinum toxin A (BTX) and nimodipine (NDP) may improve functional recovery, but mechanisms of action remain unknown. MethodsThis research investigates BTX and NDP for their novel capacity to improve neural regeneration in the setting of neurorrhaphy using a Lewis rat tibial nerve neurotmesis model. In a triple-masked, placebo-controlled, randomized study design, we compared functional (rotarod, horizontal ladder walk), electrophysiological (conduction velocity, duration), and stereological (axon count, density) outcomes of rats treated with: NDP+saline injection, BTX+NDP, Saline+placebo, and BTX+placebo. Additional controls included sham surgery +/- BTX. ResultsNDP+saline outperformed other treatment groups in the ladder walk. This group had the fewest deep slips (15.07% versus 30.77% in BTX+NDP, P = 0.122), and the most correct steps (70.53% versus 55.58% in BTX+NDP, P = 0.149) in functional testing. NDP+saline also had the fastest nerve conduction velocity (0.811m/s versus 0.598m/s in BTX+NDP, P = 0.126) among treatment groups. BTX+NDP had the highest axon count (10,012.36 versus 7,738.18 in NDP+Saline, P = 0.009). ConclusionThis study is the first to test NDP with BTX in a multimodal assessment of nerve recovery following neurotmesis and neurorrhaphy. NDP outperformed BTX+NDP functionally. Future work will focus on nimodipine in an effort to improve nerve recovery in trauma patients.

Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats

Peripheral nerve regeneration using nerve conduits has been less effective than autogenous nerve grafts. To overcome this hurdle, we developed a tissue-engineered nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres, for the first time, which accelerated nerve regeneration in mice. We previously demonstrated the long-term efficacy and safety outcomes of this hybrid nerve conduit for mouse peripheral nerve regeneration. In this study, we investigated the therapeutic potential of nerve conduits coated with human iPSC (hiPSC)-derived neurospheres in rat sciatic nerve defects, as a translational preclinical study. The hiPSC-derived quaternary neurospheres containing neural stem/progenitor cells were three-dimensionally cultured within the nerve conduit (poly l-lactide and polycaprolactone copolymer) for 14 days. Complete 5-mm defects were created as a small size peripheral nerve defect in sciatic nerves of athymic nude rats and reconstructed with nerve conduit alone (control group), nerve conduits coated with hiPSC-derived neurospheres (iPS group), and autogenous nerve grafts (autograft group) (n = 8 per group). The survival of the iPSC-derived neurospheres was continuously tracked using in vivo imaging. At 12 weeks postoperatively, motor and sensory function and histological nerve regeneration were evaluated. Before implantation, the hiPSC-derived quaternary neurospheres that three-dimensional coated the nerve conduit were differentiated into Schwann-like cells. The transplanted hiPSC-derived neurospheres survived for at least 56 days after implantation. The iPS group showed non-significance higher sensory regeneration than the autograft group. Although there was no actual motor functional nerve regeneration in the three groups: control, iPS, and autograft groups, the motor function in the iPS group recovered significantly better than that in the control group, but it did not recover to the same level as that in the autograft group. Histologically, the iPS group demonstrated significantly higher axon numbers and areas, and lower G-ratio values than the control group, whereas the autograft group demonstrated the highest axon numbers and areas and the lowest G-ratio values. Nerve conduit three-dimensionally coated with hiPSC-derived neurospheres promoted axonal regeneration and functional recovery in repairing rat sciatic nerve small size defects. Transplantation of hiPSC-derived neurospheres with nerve conduits is a promising clinical iPSC-based cell therapy for the treatment of peripheral nerve defects.

Nerve guidance conduit promoted peripheral nerve regeneration in rats.

Nerve growth factor (NGF) is important for peripheral nerve regeneration. However, its short half-life and rapid diffusion in body fluids limit its clinical efficacy. Collagen has favorable biocompatibility and biodegradability, and weak immunogenicity. Because it possesses an NGF binding domain, we cross-linked heparin to collagen tubes to construct nerve guidance conduits for delivering NGF. The conduits were implanted to bridge a facial nerve defect in rats. Histological and functional analyses were performed to assess the effect of the nerve guidance conduit on facial nerve regeneration. Heparin enhanced the binding of NGF to collagen while retaining its bioactivity. Also, the nerve guidance conduit significantly promoted axonal growth and Schwan cell proliferation at 12weeks after surgery. The nerve regeneration and functional recovery outcomes using the nerve guidance conduit were similar to those of autologous nerve grafting. Therefore, the nerve guidance conduit may promote safer nerve regeneration.

Peripheral nerve regeneration in rats by chitosan/alginate hydrogel composited with Berberine and Naringin nanoparticles: in vitro and in vivo study

In the current study, we prepared chitosan (Cs)/Alginate (Alg) hydrogel containing Berberine (Ber)-loaded Cs nanoparticles (NPs) and Naringin (Nar)-loaded Cs NPs as the promising biomaterials for peripheral nerve regeneration. The Ber- and Ner-loaded NPs were synthesized via the ion gelation method and incorporated into Cs/Alg hydrogel. The characterizations of NPs showed that Ber-loaded NPs have an average size of 594 nm with the encapsulation efficacy (EE) of 51.6 ± 7.4%, and Nar-loaded NPs have an average size of 636 nm with EE of 47.1 ± 5.8%. The pore size of Cs/Alg hydrogel and Cs/Alg/Ber/Nar hydrogel were 22 ± 11 and 32 ± 13 μm, respectively. It was observed that the swelling and weight loss value of the prepared hydrogels were suitable for nerve regeneration. The compression strength of Cs/Alg hydrogel and Cs/Alg/Ber/Nar hydrogel were 39.7 ± 4.7 kPa and 32.08 ± 6.8 kPa. The releasing measurement showed a burst release at the first days following a sustained release of up to about 90% for 24 days. The in vitro studies illustrated that the hydrogels were hemo- and biocompatible with the significant proliferative effect on PC12 cells. The animal studies showed that the treatment using the hydrogels significantly promoted nerve regeneration. Treatment of the damaged nerve using Cs/Alg/Ber/Nar hydrogel resulted in the sensory function recovery (hot plate latency of 4.66 ± 0.57 s), the motor function recovery (sciatic index function of −14.6 ± 3.7) and anatomical healing (the gastrocnemius muscle cross-sectional area of 2509 ± 142 μm2). In conclusion, the results indicate that the prepared hydrogels possess promising characteristics and significantly enhanced sensory and motor functional recovery, as well as anatomical healing.

Ultrasound therapy with optimal intensity facilitates peripheral nerve regeneration in rats through suppression of pro-inflammatory and nerve growth inhibitor gene expression.

BackgroundTherapeutic ultrasound (US) is a promising physical therapy modality for peripheral nerve regeneration. However, it is necessary to identify the most effective US parameters and clarify the underlying mechanisms before its clinical application. The intensity of US is one of the most important parameters. However, the optimum intensity for the promotion of peripheral nerve regeneration has yet to be determined.ObjectivesTo identify the optimum intensity of US necessary for the promotion of peripheral nerve regeneration after crush injuries in rats and to clarify the underlying mechanisms of US by mRNA expression analysis.MethodsWe inflicted sciatic nerve crush injuries on adult Lewis rats and performed ultrasound irradiation using 4 different US intensities: 0 (sham stimulation), 30, 140, and 250 mW/cm2 with frequency (5 days/week) and duration (5 min/day). We evaluated peripheral nerve regeneration by quantitative real-time PCR one week after injury. Histomorphometric analyses and motor function analysis were evaluated 3 weeks after injury.ResultsUS stimulation enhanced re-myelination as well as sprouting of axons, especially at an intensity of 140 mW/cm2. mRNA expression revealed that US suppressed the expression of the inflammatory cytokines TNF and IL-6 and the axonal growth inhibitors SEMA3A and GSK3β.ConclusionsAn intensity of 140 mW/cm2 was optimal to support regeneration of the sciatic nerve after a crush injury in rats by, in part, the suppression of pro-inflammatory and nerve growth inhibitor gene expression.

Extracellular Vesicles Derived From Olfactory Ensheathing Cells Promote Peripheral Nerve Regeneration in Rats.

Accumulating evidence showed that extracellular vesicles (EVs) and their cargoes are important information mediators in the nervous system and have been proposed to play an important role in regulating regeneration. Moreover, many studies reported that olfactory ensheathing cells (OECs) conditioned medium is capable of promoting nerve regeneration and functional recovery. However, the role of EVs derived from OECs in axonal regeneration has not been clear. Thereby, the present study was designed to firstly isolate EVs from OECs culture supernatants, and then investigated their role in enhancing axonal regeneration after sciatic nerve injury. In vitro studies showed that OECs-EVs promoted axonal growth of dorsal root ganglion (DRG), which is dose-dependent and relies on their integrity. In vivo studies further demonstrated that nerve conduit containing OECs-EVs significantly enhanced axonal regeneration, myelination of regenerated axons and neurologically functional recovery in rats with sciatic nerve injury. In conclusion, our results, for the first time, demonstrated that OECs-EVs are capable of promoting nerve regeneration and functional recovery after peripheral nerve injuries in rats.

The Cofilin/Limk1 Pathway Controls the Growth Rate of Both Developing and Regenerating Motor Axons

Regenerating axons often have to grow considerable distances to reestablish circuits, making functional recovery a lengthy process. One solution to this problem would be to co-opt the "temporal" guidance mechanisms that control the rate of axon growth during development to accelerate the rate at which nerves regenerate in adults. We have previously found that the loss of Limk1, a negative regulator of cofilin, accelerates the rate of spinal commissural axon growth. Here, we use mouse models to show that spinal motor axon outgrowth is similarly promoted by the loss of Limk1, suggesting that temporal guidance mechanisms are widely used during development. Furthermore, we find that the regulation of cofilin activity is an acute response to nerve injury in the peripheral nervous system. Within hours of a sciatic nerve injury, the level of phosphorylated cofilin dramatically increases at the lesion site, in a Limk1-dependent manner. This response may be a major constraint on the rate of peripheral nerve regeneration. Proof-of-principle experiments show that elevating cofilin activity, through the loss of Limk1, results in faster sciatic nerve growth, and improved recovery of some sensory and motor function.SIGNIFICANCE STATEMENT The studies shed light on an endogenous, shared mechanism that controls the rate at which developing and regenerating axons grow. An understanding of these mechanisms is key for developing therapies to reduce painful recovery times for nerve-injury patients, by accelerating the rate at which damaged nerves reconnect with their synaptic targets.

Effect of Local and Systemic Dimethylsulfoxide on Peripheral Nerve Repair: A Controlled Randomized Experimental Study

Introduction We investigated the possible beneficial effect of dimethylsulfoxide (DMSO) on peripheral nerve repair in rats. Methods: Seventy rats were divided into four groups: control, sham, DMSO-L, and DMSO-IP. Except in the control group, nerve repair was done at the right sciatic nerve. DMSO was administered locally and intraperitoneally for 12 weeks to the DMSO-L and DMSO-IP groups, respectively. No therapeutic agent was administered to the other groups. Nerve regeneration was assessed by behavioral, electrophysiological, histopathological, and immunohistochemical tests. Results: With the exception of S-100 protein expression, all results indicate that DMSO has a beneficial effect on peripheral nerve regeneration. Functional nerve recovery was notably more evident in the DMSO-L than in the DMSO-IP group. Under macroscopic examination, nerve scores of the regeneration area in the DMSO-L group was also better than in the others. Discussion: We believe that DMSO can improve peripheral nerve regeneration in rats.

Nicotine exerts neuroprotective effects by attenuating local inflammatory cytokine production following crush injury to rat sciatic nerves.

Recent studies have demonstrated that nicotine exhibited anti-inflammatory and neuroprotective properties by interacting with the alpha 7 nicotinic acetylcholine receptor (α7nAChR). However, the role of nicotine in regeneration during peripheral nerve injury has not been elucidated. The aim of this study was to investigate whether nicotine down-regulated production of proinflammatory cytokines and promoted peripheral nerve regeneration in rats. Rats challenged with sciatic nerve crush injury were treated with nicotine (1.5 mg/kg), three times per day. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL-1β), pinch test results, growth-associated protein 43 (GAP-43) expression, morphometric analyses, and the sciatic functional indexes were determined in sciatic nerves. Treatment with nicotine decreased local levels of TNF-α and IL-1β, and increased the expression of GAP-43. Nicotine also improved nerve regeneration and functional recovery. The overall protective effects of nicotine were reversed by concomitant treatment with α7nACHR antagonist methyllycaconitine, indicating that nicotine exerted its specific anti-inflammatory and neuroprotective effects through the α7nAChR. These findings show that nicotine administration can provide a potential therapeutic pathway for the treatment of peripheral nerve injury, by a direct protective effect through the α7nAChR-mediated cholinergic anti-inflammatory pathway.

The Effects of Chicken Embryo Brain Extract on Sciatic Nerve Regeneration of Male Rat; An Experimental Study

Objective:To determine the effects of chicken embryo brain extract (BE) on transects sciatic nerve in male rats. Methods:Thirty adult male Sprague-Dawley rats weighing 200 to 250 g, were randomized into three groups treated with (1) sham surgery, (2) normal saline (NS), and (3) brain extract (BE). The BE was taken from incubating chick embryos at day 8. The sciatic nerve was exposed and sharply transected at the mid thigh level. Immediate epineurial repair was then performed. The BE treated animals were given 400 µl/kg of the chick embryo BE intraperitoneal, once daily, for 2 weeks. All animals were evaluated by sciatic functional index (SFI), electrophysiology, histology, and immunohistochemistry at days 28, 90 after surgery. Results:The mean SFI difference between BE and NS groups at days 28, 60 and 90 after surgery was statistically significant (p=0.086). The mean number of myelinated fibers in the BE group was significantly greater than that of the NS group on days 28 and 90 after surgery (p=0.034). At days 28 and 90 after surgery, the mean nerve conduction velocity (NCV) in the BE group was significantly faster than that of the NS group (p=0.041). Conclusion: These results indicate for the first time that chick embryo brain extract can enhance peripheral nerve regeneration in rat.