Valproic acid protects neurons and promotes neuronal regeneration after brachial plexus avulsion

Valproic acid has been shown to exert neuroprotective effects and promote neurite outgrowth in several peripheral nerve injury models. However, whether valproic acid can exert its beneficial effect on ...     

Platelet-rich plasma promotes peripheral nerve regeneration after sciatic nerve injury

The effect of platelet-rich plasma on nerve regeneration remains controversial.In this study,we established a rabbit model of sciatic nerve small-gap defects with preserved epineurium and then filled the gaps with platelet-rich plasma.Twenty-eight rabbits were divided into the following groups(7 rabbits/group):model,low-concentrati on PRP(2.5-3.5-fold concentration of whole blood platelets),medium-concentration PRP(4.5-6.5-fold concentration of whole blood platelets),and high-concentration PRP(7...     

Retraction: Valproic acid protects neurons and promotes neuronal regeneration after brachial plexus avulsion

Concerns have been raised about the western blot bands presented in Figures 2A and 4A of this article(Li et al.,2013;doi:10.3969/j.issn.1673-5374.2013.30.006).     

Motor neuron-specific RhoA knockout delays degeneration and promotes regeneration of dendrites in spinal ventral horn after brachial plexus injury

Dendrites play irreplaceable roles in the nerve conduction pathway and are vulnerable to various insults. Peripheral axotomy of motor neurons results in the retraction of dendritic arbors, and the dendritic arbor can be re-expanded when reinnervation is allowed. RhoA is a target that regulates the cytoskeleton and promotes neuronal survival and axon regeneration. However, the role of RhoA in dendrite degeneration and regeneration is unknown. In this study, we explored the potential role of RhoA ...     

Olfactory ensheathing cell transplantation alters the expression of chondroitin sulfate proteoglycans and promotes axonal regeneration after spinal cord injury

Cell transplantation is a potential treatment for spinal cord injury. Olfactory ensheathing cells (OECs) play an active role in the repair of spinal cord injury as a result of the dual characteristics of astrocytes and Schwann cells. However, the specific mechanisms of repair remain poorly understood. In the present study, a rat model of spinal cord injury was established by transection of T10. OECs were injected into the site, 1 mm from the spinal cord stump. To a certain extent, OEC transplantation restored locomotor function in the hindlimbs of rats with spinal cord injury, but had no effect on the formation or volume of glial scars. In addition, OEC transplantation reduced the immunopositivity of chondroitin sulfate proteoglycans (neural/glial antigen 2 and neurocan) and glial fibrillary acidic protein at the injury site, and increased the immunopositivity of growth-associated protein 43 and neurofilament. These findings suggest that OEC transplantation can regulate the expression of chondroitin sulfate proteoglycans in the spinal cord, inhibit scar formation caused by the excessive proliferation of glial cells, and increase the numbers of regenerated nerve fibers, thus promoting axonal regeneration after spinal cord injury. The study was approved by the Animal Ethics Committee of the Medical College of Xi’an Jiaotong University, China (approval No. 2018-2048) on September 9, 2018.

Chinese Library Classification No. R456; R741; Q636.1     

Chondroitinase ABC promotes axonal regeneration of Clarke's neurons after spinal cord injury

We examined whether enzymatic digestion of chondroitin sulfate (CS) promoted the axonal regeneration of neurons in Clarke's nucleus (CN) into a peripheral nerve (PN) graft following injury of the spinal cord. After hemisection at T11, a segment of PN graft was implanted at the lesion site. Either vehicle, brain-derived neurotrophic factor (BDNF) or chondroitinase ABC was applied at the implantation site. The postoperative survival period was 4 weeks. Treatment with vehicle or BDNF did not promote the axonal regeneration of CN neurons into the PN graft. Application of 2.5 unit/ml chondroitinase ABC resulted in a significant increase (12.8%) in the number of regenerated CN neurons. Double labeling with Fluoro-Gold and NADPH-diaphorase histochemistry showed that the regenerated CN neurons did not express nitric oxide synthase (NOS). Our results suggest that CS is inhibitory to the regeneration of CN neurons following injury of the spinal cord.     

Electroacupuncture attenuates neuropathic pain after brachial plexus injury

Electroacupuncture has traditionally been used to treat pain, but its effect on pain following brachial plexus injury is still unknown. In this study, rat models of an avulsion injury to the left brachial plexus root(associated with upper-limb chronic neuropathic pain) were given electroacupuncture stimulation at bilateral Quchi(LI11), Hegu(LI04), Zusanli(ST36) and Yanglingquan(GB34). After electroacupuncture therapy, chronic neuropathic pain in the rats' upper limbs was significantly attenuated. Immunofluorescence staining showed that the expression of β-endorphins in the arcuate nucleus was significantly increased after therapy. Thus, experimental findings indicate that electroacupuncture can attenuate neuropathic pain after brachial plexus injury through upregulating β-endorphin expression.     

硫酸软骨素酶ABC(ch ABC)对大鼠坐骨神经损伤后神经再生功能的实验研究

目的观察硫酸软骨素酶ABC(chABC)对坐骨神经再生功能的影响。方法将72只SD大白鼠双侧坐骨神经切断造成0.8 cm缺损,用甲壳素导管桥接神经缺损后随机分为3组,每组24只。A组(实验组):管内注入聚乳酸-聚乙醇酸—chABC缓释微球(chABC-PLGA);B组(赋形剂组):管内注入聚乳酸-聚乙醇酸微球;C组(空白对照组):管内注入等渗盐水。术后4周、8周取材作神经电生理、神经组织学观察。结果术后4周、8周组织学观察见有再生神经通过再生室,其间有新生血管;神经电生理检查A组再生神经传导速度优于B、C组,差异有统计学意义(P<0.05),B、C组再生神经传导速度差别无统计学意义,组间比较(P>0.0167)组间多重比较行Bonferroni法检验,取校正α=0.0167)。S-100免疫组织化学及Loyez氏神经染色法显示:A组神经纤维数多于B、C组,差异有统计学意义(P<0.05),B、C组再生神经纤维数差别无统计学意义,组间比较(P>0.0167)。结论硫酸软骨素酶ABC(chABC)具有促进周围神经再生的作用。     

Three-dimensional bioprinting collagen/silk fibroin scaffold combined with neural stem cells promotes nerve regeneration after spinal cord injury

Many studies have shown that bio-scaffolds have important value for promoting axonal regeneration of injured spinal cord.Indeed,cell transplantation and bio-scaffold implantation are considered to be effective methods for neural regeneration.This study was designed to fabricate a type of three-dimensional collagen/silk fibroin scaffold (3D-CF) with cavities that simulate the anatomy of normal spinal cord.This scaffold allows cell growth in vitro and in vivo.To observe the effects of combined transplantation of neural stem cells (NSCs) and 3D-CF on the repair of spinal cord injury.Forty Sprague-Dawley rats were divided into four groups: sham (only laminectomy was performed),spinal cord injury (transection injury of T10 spinal cord without any transplantation),3D-CF (3D scaffold was transplanted into the local injured cavity),and 3D-CF + NSCs (3D scaffold co-cultured with NSCs was transplanted into the local injured cavity.Neuroelectrophysiology,imaging,hematoxylin-eosin staining,argentaffin staining,immunofluorescence staining,and western blot assay were performed.Apart from the sham group,neurological scores were significantly higher in the 3D-CF + NSCs group compared with other groups.Moreover,latency of the 3D-CF + NSCs group was significantly reduced,while the amplitude was significantly increased in motor evoked potential tests.The results of magnetic resonance imaging and diffusion tensor imaging showed that both spinal cord continuity and the filling of injury cavity were the best in the 3D-CF + NSCs group.Moreover,regenerative axons were abundant and glial scarring was reduced in the 3D-CF + NSCs group compared with other groups.These results confirm that implantation of 3D-CF combined with NSCs can promote the repair of injured spinal cord.This study was approved by the Institutional Animal Care and Use Committee of People’s Armed Police Force Medical Center in 2017 (approval No.2017-0007.2).     

Electrical stimulation combined with exercise increase axonal regeneration after peripheral nerve injury

Although injured peripheral axons are able to regenerate, functional recovery is usually poor after nerve transection. In this study we aim to elucidate the role of neuronal activity, induced by nerve electrical stimulation and by exercise, in promoting axonal regeneration and modulating plasticity in the spinal cord after nerve injury. Four groups of adult rats were subjected to sciatic nerve transection and suture repair. Two groups received electrical stimulation (3 V, 0.1 ms at 20 Hz) for 1 h, immediately after injury (ESa) or during 4 weeks (1 h daily; ESc). A third group (ES+TR) received 1 h electrical stimulation and was submitted to treadmill running during 4 weeks (5 m/min, 2 h daily). A fourth group performed only exercise (TR), whereas an untreated group served as control (C). Nerve conduction, H reflex and algesimetry tests were performed at 1, 3, 5, 7 and 9 weeks after surgery, to assess muscle reinnervation and changes in excitability of spinal cord circuitry. Histological analysis was made at the end of the follow-up. Groups that received acute ES and/or were forced to exercise in the treadmill showed higher levels of muscle reinnervation and increased numbers of regenerated myelinated axons when compared to control animals or animals that received chronic ES. Combining ESa with treadmill training significantly improved muscle reinnervation during the initial phase. The facilitation of the monosynaptic H reflex in the injured limb was reduced in all treated groups, suggesting that the maintenance of activity helps to prevent the development of hyperreflexia.     

Phrenic and intercostal nerves with rhythmic discharge can promote early nerve regeneration after brachial plexus repair in rats

Exogenous discharge can positively promote nerve repair. We, therefore, hypothesized that endogenous discharges may have similar effects. The phrenic nerve and intercostal nerve, controlled by the respiratory center, can emit regular nerve impulses; therefore these endogenous automatically discharging nerves might promote nerve regeneration. Action potential discharge patterns were examined in the diaphragm, external intercostal and latissimus dorsi muscles of rats. The phrenic and intercostal nerves showed rhythmic clusters of discharge, which were consistent with breathing frequency. From the first to the third intercostal nerves, spontaneous discharge amplitude was gradually increased. There was no obvious rhythmic discharge in the thoracodorsal nerve. Four animal groups were performed in rats as the musculocutaneous nerve cut and repaired was bland control. The other three groups were followed by a side-to-side anastomosis with the phrenic nerve, intercostal nerve and thoracodorsal nerve. Compound muscle action potentials in the biceps muscle innervated by the musculocutaneous nerve were recorded with electrodes. The tetanic forces of ipsilateral and contralateral biceps muscles were detected by a force displacement transducer. Wet muscle weight recovery rate was measured and pathological changes were observed using hematoxylin-eosin staining. The number of nerve fibers was observed using toluidine blue staining and changes in nerve ultrastructure were observed using transmission electron microscopy. The compound muscle action potential amplitude was significantly higher at 1 month after surgery in phrenic and intercostal nerve groups compared with the thoracodorsal nerve and blank control groups. The recovery rate of tetanic tension and wet weight of the right biceps were significantly lower at 2 months after surgery in the phrenic nerve, intercostal nerve, and thoracodorsal nerve groups compared with the negative control group. The number of myelinated axons distal to the coaptation site of the musculocutaneous nerve at 1 month after surgery was significantly higher in phrenic and intercostal nerve groups than in thoracodorsal nerve and negative control groups. These results indicate that endogenous autonomic discharge from phrenic and intercostal nerves can promote nerve regeneration in early stages after brachial plexus injury.     

硫酸软骨素酶ABC对脑损伤后胶质瘢痕影响的实验研究

目的 探讨硫酸软骨素酶ABC(chABC)对脑损伤后胶质瘢痕组织的影响.方法 38只Wistar大鼠按随机数字表法分成5组:正常对照组(n=2)、模型组(n=9)、1.0 U/mL chABC治疗组(n=9)、2.5 U/mL chABC治疗组(n=9)、5.0 U/mL chABC治疗组(n=9),后4组采用自由落体撞击法制作大鼠脑损伤模型,造模后即刻在后3组大鼠局部脑皮层下1 mm处注射不同浓度chABC 2μL,正常对照组不做任何处理.造模后1、2、4周取脑组织标本行HE染色,分别应用免疫组化染色和Western blotting检测硫酸软骨素多聚蛋白糖(CSPGs)的表达.结果 HE染色显示损伤后2周模型组大鼠脑皮层大量星形胶质细胞聚集,不同浓度chABC治疗组损伤部位的星形胶质细胞聚集较模型组减少,以5.0U/mL chABC治疗组明显.免疫组化染色显示模型组,1.0、2.5、5.0U/mL chABC 治疗组损伤后2周大鼠脑组织CSPGs分泌均较正常对照组增加,差异有统计学意义(P＜0.05);与模型组比较,5.0 U/mL chABC治疗组大鼠脑组织CSPGs分泌减少,差异有统计学意义(P＜0.05).Western blotting检测显示造模后1、2、4周不同浓度chABC治疗组CSPGs表达均较模型组低,差异有统计学意义(P＜0.05);模型组和2.5、5.0 U/mL chABC治疗组大鼠脑组织中CSPGs的表达在造模后1、2、4周逐渐降低,差异有统计学意义(P<0.05).结论 chABC能降解胶质瘢痕中主要抑制分子CSPGs,改善脑损伤后局部轴突再生的抑制性微环境,且高浓度(5.0U/mL)chABC表现最明显.

Abstract：

Objective To explore the effect of chondroitin sulfate enzyme ABC (chABC) on glial scar in rat models of brain traumatic injury (TBI). Methods Thirty-eight Wistar rats were randomly divided into 5 groups, including normal control group (n=2), model group (rat models of TBI,n=9), 1.0 U/mL chABC treatment group (n=9), 2.5 U/ml chABC treatment group (n=9) and 5.0 U/ml chABC treatment group (n=9). After performing TBI by free falling in the later 4 groups, rats of the model group were given no treatment, while those of the other 3 groups were administrated with different concentrations of chABC by local injection respectively. One, 2 and 4 w after TBI, HE staining was performed on the brain tissues of these rat models;and immunohistochemical assay and Western blotting were employed to evaluate the secreting of chondroitin sulfate proteoglycans (CSPGs) and the therapeutic effect of chABC on glial scar. Data were statistically analyzed using t-test. Results Pathological test revealed the scars in the treatment groups were significantly fewer than those in the model group 2 w after TBI, with 5.0 U/mL chABC treatment group enjoying the fewest level (P<0.05). Immunohistochemical assay showed that the secreting of CSPGs in the treatment groups and model group was significantly increased than that in normal control group 2 w after TBI (P<0.05);the 5.0 U/ml chABC treatment group showed an obvious reduction of CSPGs secreting as compared with the model group (P<0.05). Western blotting indicated that the treatment groups showed an obvious reduction of CSPGs secreting as compared with the model group 1, 2 and 4 w after TBI (P<0.05);an obvious gradual reduction of CSPGs secreting in the model group, 2.5 and 5.0 U/ml chABC treatment groups was noted 1, 2 and 4 w after TBI (P<0.05). Conclusion ChABC could degrade the glial scar by degrading the CSPGs molecules and improve the microenvironment of local axonal regeneration after TBI;In this experiment, the highest concentration of chABC (5U/ml) shows the best effect on removing the glial scar.     

Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve graft bridge

Chondroitin sulfate proteoglycans (CSPG) within the glial scar formed after central nervous system (CNS) injury are thought to play a crucial role in regenerative failure. We previously showed that delivery of the CSPG-digesting enzyme chondroitinase ABC (ChABC) via an osmotic minipump allowed axonal regeneration and functional recovery in a peripheral nerve graft (PNG)-bridging model. In this study, we sought to overcome the technical limitations associated with minipumps by microinjecting ChABC directly into the distal lesion site in the PN bridging model. Microinjection of ChABC immediately rostral and caudal to an injury site resulted in extensive CSPG digestion. We also demonstrate that this delivery technique is relatively atraumatic and does not result in a noticeable inflammatory response. Importantly, microinjections of ChABC into the lesion site permitted more regenerating axons to exit a PNG and reenter spinal cord tissue than saline injections. These results are similar to our previous findings when ChABC was delivered via a minipump and suggest that microinjecting ChABC is an effective method of delivering the potentially therapeutic enzyme directly to an injury site.     

Scaffoldless tissue-engineered nerve conduit promotes peripheral nerve regeneration and functional recovery after tibial nerve injury in rats

Damage to peripheral nerve tissue may cause loss of function in both the nerve and the targeted muscles it innervates. This study compared the repair capability of engineered nerve conduit (ENC), engineered fibroblast conduit (EFC), and autograft in a 10-mm tibial nerve gap. ENCs were fabricated utilizing primary fibroblasts and the nerve cells of rats on embryonic day 15 (E15). EFCs were fabricated utilizing primary fi-broblasts only. Following a 12-week recovery, nerve repair was assessed by measuring contractile properties in the medial gastrocnemius muscle, distal motor nerve conduction velocity in the lateral gastrocnemius, and histology of muscle and nerve. The autografts, ENCs and EFCs reestablished 96%, 87% and 84% of native distal motor nerve conduction velocity in the lateral gastrocnemius, 100%, 44% and 44% of native specific force of medical gastrocnemius, and 63%, 61% and 67% of native medial gastrocnemius mass, re-spectively. Histology of the repaired nerve revealed large axons in the autograft, larger but fewer axons in the ENC repair, and many smaller axons in the EFC repair. Muscle histology revealed similar muscle fiber cross-sectional areas among autograft, ENC and EFC repairs. In conclusion, both ENCs and EFCs promot-ed nerve regeneration in a 10-mm tibial nerve gap repair, suggesting that the E15 rat nerve cells may not be necessary for nerve regeneration, and EFC alone can suffice for peripheral nerve injury repair.     

Corrigendum: Three-dimensional bioprinting collagen/silk fibroin scaffold combined with neural stem cells promotes nerve regeneration after spinal cord injury

doi:10.4103/1673-5374.280332 In the article titled“Three-dimensional bioprinting collagen/silk fibroin scaffold combined with neural stem cells promotes nerve regeneration after spinal cord injury”published on pages 959–968,Issue 5,Volume 15 of Neural Regeneration Research,(Jiang et al.,2020)the“author affiliations”are written incorrectly.The correct“author affiliations”are:“Ji-Peng Jiang1,#,Xiao-Yin Liu1,2,#,Fei Zhao1,#,Xiang Zhu3,Xiao-Yin Li1,Xue-Gang Niu4,Zi-Tong Yao1,Chen Dai1,Hui-You Xu1,Ke Ma1,Xu-Yi Chen1,*,Sai Zhang1,*1 Tianjin Key Laboratory of Neurotrauma Repair,Institute of Traumatic Brain Injury and Neuroscience,Center for Neurology and Neurosurgery of Chinese People’s Armed Police Force(PAP)Characteristic Medical Center,Tianjin,China;2 Tianjin Medical University,Tianjin,China;3 Department of Neurology,Luoyang First Hospital of Traditional Chinese Medicine,Luoyang,Henan Province,China;4 Department of Neurosurgery,Fourth Central Hospital of Tianjin,Tianjin,China.”     

Kindlin-1 enhances axon growth on inhibitory chondroitin sulfate proteoglycans and promotes sensory axon regeneration

Growing and regenerating axons need to interact with the molecules in the extracellular matrix as they traverse through their environment. An important group of receptors that serve this function is the integrin superfamily of cell surface receptors, which are evolutionarily conserved αβ heterodimeric transmembrane proteins. The function of integrins is controlled by regulating the affinity for ligands (also called "integrin activation"). Previous results have shown that CNS inhibitory molecules inactivate axonal integrins, while enhancing integrin activation can promote axon growth from neurons cultured on inhibitory substrates. We tested two related molecules, kindlin-1 and kindlin-2 (Fermitin family members 1 and 2), that can activate β1, β2, and β3 integrins, for their effects on integrin signaling and integrin-mediated axon growth in rat sensory neurons. We determined that kindlin-2, but not kindlin-1, is endogenously expressed in the nervous system. Knocking down kindlin-2 levels in cultured sensory neurons impaired their ability to extend axons, but this was partially rescued by kindlin-1 expression. Overexpression of kindlin-1, but not kindlin-2, in cultured neurons increased axon growth on an inhibitory aggrecan substrate. This was found to be associated with enhanced integrin activation and signaling within the axons. Additionally, in an in vivo rat dorsal root injury model, transduction of dorsal root ganglion neurons to express kindlin-1 promoted axon regeneration across the dorsal root entry zone and into the spinal cord. These animals demonstrated improved recovery of thermal sensation following injury. Our results therefore suggest that kindlin-1 is a potential tool for improving axon regeneration after nervous system lesions.     

Recombinant human fibroblast growth factor-2 promotes nerve regeneration and functional recovery after mental nerve crush injury

Several studies have shown that fibroblast growth factor-2(FGF2) can directly affect axon regeneration after peripheral nerve damage. In this study, we performed sensory tests and histological analyses to study the effect of recombinant human FGF-2(rh FGF2) treatment on damaged mental nerves. The mental nerves of 6-week-old male Sprague-Dawley rats were crush-injured for 1 minute and then treated with 10 or 50 μg/m L rh FGF2 or PBS in crush injury area with a mini Osmotic pump. Sensory test using von Frey filaments at 1 week revealed the presence of sensory degeneration based on decreased gap score and increased difference score. However, at 2 weeks, the gap score and difference score were significantly rebounded in the mental nerve crush group treated with 10 μg/m L rh FGF2. Interestingly, treatment with 10 μg/m L rh FGF had a more obviously positive effect on the gap score than treatment with 50 μg/m L rh FGF2. In addition, retrograde neuronal tracing with Dil revealed a significant increase in nerve regeneration in the trigeminal ganglion at 2 and 4 weeks in the rh FGF2 groups(10 μg/m L and 50 μg/m L) than in the PBS group. The 10 μg/m L rh FGF2 group also showed an obviously robust regeneration in axon density in the mental nerve at 4 weeks. Our results demonstrate that 10 μg/m L rh FGF induces mental nerve regeneration and sensory recovery after mental nerve crush injury.