外周神经损伤后再生的相关信号通路

由于神经元损伤后的自身再修复能力有限,临床上对于神经损伤一直缺乏有效的治疗手段,因此,寻找促进神经损伤后修复的药物,以及探索其相关作用机制始终是神经科学领域的研究热点.有研究表明,在外周神经组织中,神经元细胞和雪旺细胞内的信号通路对于外周神经损伤后再生有着重要作用.本文综述了雪旺细胞和神经元内与外周神经再生相关的信号通...     

Levocarnitine acetyl stimulates peripheral nerve regeneration and neuromuscular junction remodelling following sciatic nerve injury.

The effects of levocarnitine acetyl were investigated on both peripheral nerve regeneration and neuromuscular remodelling in male Sprague-Dawley rats, three months of age, following crush of their left sciatic nerve. Levocarnitine acetyl, 150 mg/kg/day in drinking water, was given from one week before to 5, 15, 20, and 60 days after nerve crush. The sciatic nerve was examined morphologically at all given times and morphometrically at 15, 20, and 60 days after the lesion. Morphology, at 5, 15, and 60 days, and morphometry, at 60 days after the nerve crush, were also performed on the neuromuscular junction in the soleus and extensor digitorum longus muscles. Five days after nerve crush, complete axonal degeneration was observed in both control and treated rats. At 15 and 20 days, recovery from injury in treated animals was better than in controls, as shown by a significantly higher increase in the number of regenerating axons. At the same times, denervated endplates were present in both groups. At 60 days, axonal regeneration restored the number of axons to normal values in all injured animals, while their size maturation was greater in treated rats than in controls. A markedly lower number of degenerating elements was found in treated animals. In the neuromuscular junctions of the soleus and extensor digitorum longus muscles, nerve terminal branch points were reduced in the lesioned rats in comparison with uninjured ones. However, morphometric analysis revealed a greater endplate complexity in treated animals in which, at 60 days after nerve crush, nerve terminal branching and sprouting index values were significantly higher than in controls. It is concluded that levocarnitine acetyl exerts a beneficial effect on nerve regeneration processes and synaptic remodelling in crush-induced neuropathies.     

Drug stimulation of the peripheral nerve regeneration

A comparative study of the effects of xymedone, riboxin, and piracetam upon the regeneration of myelinated axons and the number of surviving sensory neurons in spinal ganglia L4-L5 was studied on the model of sciatic nerve transection in rats. The three drugs decrease the number of neurons entering the posttraumatic apoptosis. Riboxin and xymedone stimulate the regeneration of myelinated axons, the latter drug being more effective and producing a 21.3 and 14.7% increase in the number of regenerated myelinated axons and a 29.3 and 37.7% increase in the relative number of sensory neurons (the transected/contralateral side ratio) in spinal ganglia L4-L5 relative to control by the 60th and 90th day upon transection, respectively.     

Effects of melatonin on peripheral nerve regeneration

In the available literature, there are thousands of studies on peripheral nerve regeneration using many nerves of several animals at different ages with various types of lesions and different methods of evaluation at certain time of follow-up. Despite many experimental data and clinical observations, there is still no ideal treatment method enhancing peripheral nerve regeneration. In clinical practice, various types of surgical nerve repair techniques do not frequently result in complete recovery due to neuroma formation, lipid peroxidative damage, ischemia and other factors. Recently, a number of neuroscientists demonstrated that pineal neurohormone melatonin (MLT) has an effect on the morphologic features of the nerve tissue, suggesting its neuroprotective, free radical scavenging, antioxidative, and analgesic effects in degenerative diseases of peripheral nerves. At present, it is widely accepted that MLT has a useful effect on axon length and sprouting after traumatic events to peripheral nerves. Our studies using various experimental injury models clearly suggest positive effects of MLT on the number of axons, thickness of myelin sheath by inhibition of collagen accumulation and neuroma formation following traumatic events to peripheral nerves, myelination of developing peripheral nerve after intrauterine ethanol exposure. Nevertheless, further experimental and randomized controlled clinical studies are vital to identify the clinical use of MLT hormone. This is an overview of recent patents and current literature in terms of the effects of MLT on peripheral nerve regeneration based on a critical analysis of electrophysiological, biochemical and light and electron microscopic findings, in addition to functional observations.     

The influence of drugs on peripheral nerve regeneration

Abstract

Currently, there are no established adjuvant drugs for the acceleration of peripheral nerve regeneration. In this paper, we reviewed the literature from the last 10 years and described the drugs proved to accelerate the functional and histological regeneration of the peripheral nerves, either after trauma or in neuropathy experimental models. The vast majority of the studies were experimental with very few small clinical studies, which indicates the need for prospective randomized studies to identify the best drugs to use as adjuvants for nerve regeneration.     

周围神经损伤的显微外科修复

目的 分析应用显微外科技术修复周围神经损伤的临床疗效.方法 自1997～2009年,用显微外科技术修复周围神经损伤176例197条神经,方法包括神经外膜缝合术、神经束膜缝合术、神经松解术及神经移植术.结果 术后经3～60个月随访,根据BMRC感觉、运动评价标准,其中疗效为优者84条,良者77条,优良率达81.73%.伤后24 h内修复者的优良率为93.52%,优于3个月内修复者.3个月内修复者优良率为79.31%,优于6个月后修复者.结论 应用显微外科技术对周围神经损伤的早期修复和显微镜下神经断端的精确对合可提高临床疗效.     

Axonal regeneration of fish optic nerve after injury

Since Sperry's work in the 1950s, it has been known that the central nervous system (CNS) neurons of lower vertebrates such as fish and amphibians can regenerate after axotomy, whereas the CNS neurons of mammals become apoptotic after axotomy. The goldfish optic nerve (ON) is one of the most studied animal models of CNS regeneration. Morphological changes in the goldfish retina and tectum after ON transection were first researched in the 1970s-1980s. Many biochemical studies of neurite outgrowth-promoting substances were then carried out in the 1980s-1990s. Many factors have been reported to be active substances that show increased levels during fish ON regeneration, as shown by using various protein chemistry techniques. However, there are very few molecular cloning techniques for studying ON regeneration after injury. In this review article, we summarize the neurite outgrowth-promoting factors reported by other researchers and describe our strategies for searching for ON regenerating molecules using a differential hybridization technique in the goldfish visual system. The process of goldfish ON regeneration after injury is very long. It takes about half a year from the start of axonal regrowth to complete restoration of vision. The process has been classified into three stages: early, middle and late. We screened for genes with increased expression during regeneration using axotomized goldfish retinal and tectal cDNA libraries and obtained stage-specific cDNA clones that were upregulated in the retina and tectum. We further discuss functional roles of these molecules in the regeneration processes of goldfish ON.     

神经妥乐平对周围神经损伤的治疗作用

目的 :观察神经妥乐平对周围神经损伤病人的疗效。方法 :86例周围神经损伤病人在常规治疗基础上随机分为神经妥乐平治疗组 44例 ,给神经妥乐平wk 1～ 2 ,6mL ,iv,qd或 3mL ,im ,qd ,wk3～4改为口服 ,2片 ,bid ;对照组 42例仅进行常规治疗。治疗前后观察疼痛、麻木、感觉减退、感觉过敏、乏力等指标的改善情况。结果 :神经妥乐平组的改善率分别为 87% (疼痛 )、88% (乏力 )、88% (感觉减退 )、62 % (麻木 )、5 6% (感觉过敏 )。疼痛与乏力和对照组相比 ,差异有显著意义 (P <0 .0 5 )。神经妥乐平组总有效率在治疗 4wk时为 1 0 0 % ,对照组为 69% ,2组间比较经Ridit分析差异有非常显著意义 (P <0 .0 1 )。结论 :神经妥乐平可安全、有效治疗周围神经损伤     

壳聚糖在周围神经损伤修复中的应用

壳聚糖的细胞亲和性和修复外周神经损伤等方面的研究都有新的进展。壳聚糖作为外周神经损伤修复材料有良好的研究应用价值和开发前景。此文介绍了壳聚糖在修复外周神经损伤中的研究现状。     

神经生长因子对周围神经损伤的保护作用

以小鼠化学性交感神经末梢损伤、家兔尺神经机械损伤为模型及用新生大鼠背根神经节体外无血清培养法,研究神经生长因子(NGF)对周围神经损伤及感觉神经元的保护作用。结果表明,NGF剂量依赖地提高小鼠颌下腺去甲肾上腺素残留率,提高损伤后兔C₇,T₁背根神经节的细胞数,显著促进新生大鼠背根神经节突起的生长。结果提示,NGF对周围神经损伤有明显的保护作用,并对感觉神经元有很强的神经营养作用。     

Nanofiber technology: designing the next generation of tissue engineering scaffolds

Tissue engineering is an interdisciplinary field that has attempted to utilize a variety of processing methods with synthetic and natural polymers to fabricate scaffolds for the regeneration of tissues and organs. The study of structure-function relationships in both normal and pathological tissues has been coupled with the development of biologically active substitutes or engineered materials. The fibrillar collagens, types I, II, and III, are the most abundant natural polymers in the body and are found throughout the interstitial spaces where they function to impart overall structural integrity and strength to tissues. The collagen structures, referred to as extracellular matrix (ECM), provide the cells with the appropriate biological environment for embryologic development, organogenesis, cell growth, and wound repair. In the native tissues, the structural ECM proteins range in diameter from 50 to 500 nm. In order to create scaffolds or ECM analogues, which are truly biomimicking at this scale, one must employ nanotechnology. Recent advances in nanotechnology have led to a variety of approaches for the development of engineered ECM analogues. To date, three processing techniques (self-assembly, phase separation, and electrospinning) have evolved to allow the fabrication of nanofibrous scaffolds. With these advances, the long-awaited and much anticipated construction of a truly "biomimicking" or "ideal" tissue engineered environment, or scaffold, for a variety of tissues is now highly feasible. This review will discuss the three primary technologies (with a focus on electrospinning) available to create tissue engineering scaffolds that are capable of mimicking native tissue, as well as explore the wide array of materials investigated for use in scaffolds.     

人组织激肽释放酶对周围神经系统损伤后的修复效应

目的:评价人组织激肽释放酶(HTK)促进周围神经系统损伤后的修复作用.方法:取30只体重180～200 g的雄性SD大鼠,随机分成3组:假手术组、HTK组(17.5×10~(-3) PNAU/kg)、对照组,每组各10只.术前第0天和术后第1、第3、第5、第7、第9、第11、第13天测定坐骨神经功能指数(SFI)以及静止坐骨神经指数(SSI),术后第14天测定坐骨神经干动作电位传导速度(NCV).结果:SFI、SSI值在假手术组手术前后未见明显改变.HTK组和对照组中,术后第1天SFI、SSI均为-100左右.以后发现HTK组的SFI、SSI恢复的情况要优于对照组,从第5天开始两组SFI、SSI值有统计学差异(P<0.05).术后第14天HTK组的NCV值要高于对照组,两组间有统计学差异(P<0.05).结论:HTK具有促进周围神经系统损伤后的修复作用.     

明胶管修复周围神经缺损的实验研究

目的　了解明胶管 (gelatinconduit)在修复外周神经缺损中的作用。方法　用明胶制成长1.0cm、内径 1.0mm的导管 ,套接修复大鼠右侧坐骨神经缺损 6.0mm ,左侧从同样规格的硅胶管套接作对照 ,于术后 3月进行电生理学、免疫组织化学、辣根过氧化物酶 (HRP)示踪等检查。结果　明胶管内有较多的再生神经纤维。明胶管套接侧胫前肌肌湿重、有髓神经纤维直径方面优于硅酮管 (P <0 .0 5 ) ,明胶管变薄无异物反应及炎症反应、无粘连。辣根过氧化物酶示踪证实在相应的背根神经节找到阳性的神经元。结论　作为一种新材料 ,明胶管能有效桥接坐骨神经缺损     

Oxidized galectin-1 is an essential factor for peripheral nerve regeneration

Although many factors have been implicated in the regenerative response of peripheral axons to nerve injury, the signals that prompt neurons to extend processes in peripheral nerves after axotomy are not well-understood. As shown in the first chapter, oxidized recombinant human galectin-1 (rhGAL-1/Ox), which lacks lectin activity, promotes initial axonal growth in an in vitro peripheral nerve regeneration model at low concentrations (pg/ml). At a similarly low concentration, rhGAL-1/Ox has also been shown to be effective in enhancing axonal regeneration using in vivo experiments. Moreover, the application of functional anti-rhGAL-1 antibody strongly inhibited axonal regeneration in vivo as well as in vitro. Since galectin-1 (GAL-1) is expressed in the regenerating sciatic nerves as well as in both sensory and motoneurons, these results indicate that GAL-1, which is secreted into the extracellular space, is subsequently oxidized and then may regulate initial repair after axotomy. This possibility was confirmed by Western blot analysis, which revealed that both reduced and oxidized forms of GAL-1 are present in culture media of DRG neurons and immortalized adult mouse Schwann cells (IMS32). Externalized GAL-1/Ox has been found to stimulate macrophages to secrete an axonal regeneration-promoting factor. From these results, we propose that axonal regeneration occurs in axotomized peripheral nerves as a result of cytosolic reduced GAL-1 being released from Schwann cells and injured axons, which then becomes oxidized in the extracellular space. GAL-1/Ox in the extracellular space stimulates macrophages to secrete a factor that promotes axonal growth and Schwann cell migration, thus enhancing peripheral nerve regeneration and functional recovery. These results suggest that rhGAL-1/Ox may be a novel factor for functional restoration of injured peripheral nerves.     

转化生长因子β_1抗体促进大鼠周围神经再生的实验研究

目的评价局部应用外源性转化生长因子β1(TGF-β1)抗体对端端吻合神经远端再生的影响。方法选用雄性SD大鼠48只,随机分为2组,TGF-β1组和生理盐水对照组各24只;行坐骨神经切断吻合术,切口分别注入TGF-β1抗体和生理盐水各30μL;术后4,12周取材进行大体观察及电生理、超微结构和病理学染色检测。结果12周时神经电生理检查,4,12周行MESSION染色、电镜等方面均显示实验组神经再生均优于对照组。结论TGF-β1抗体对大鼠神经再生有明显促进作用。     

神经妥乐平促进周围神经再生作用的临床研究

目的探讨神经妥乐平(Neurotropin,NT)对损伤神经的促再生作用及疗效。方法对前臂及小腿切割伤病人46例(60根神经)根据入院时间随机分成2组并进行比较,维生素(A)组:神经缝合术后维生素B12500μg,1次/d;维生素B120mg,3次/d;维生素B620mg,3次/d肌肉注射;神经妥采平(B)组:神经缝合术后NT6ml静脉滴注,1次/d。术后随访4～12个月(平均7个月)进行电生理检测,并测定其神经运动电位、感觉电位的潜伏期和波幅。结果在恢复的神经中,各神经感觉电位潜伏期与波幅、运动电位潜伏期与波幅A组均优于B组(P<0.05,P<0.01)。结论NT对周围神经损伤后有促进其恢复的作用。     

Comparison of five different rat models of peripheral nerve injury

Described here is a comparison of five peripheral sciatic nerve injury models in rats which all result in various degrees of neuropathic pain symptoms. They are the chronic constriction injury (CCI), the spinal nerve ligation (SNL), the partial sciatic ligation (PSL), the tibial and sural transection (TST), and the complete sciatic transection (CST) model. Behavioral testing was performed on these models over a 56-day period under strict experimental conditions to minimise variability between the surgical models and to allow for an accurate evaluation of the sensory deficits produced by each model. Overall, all five models of neuropathic pain produced signs of allodynia and hyperalgesia to various stimuli. However, the duration and magnitude of the evoked responses varied considerably between the different models.     

睫状神经营养因子对周围神经损伤后功能恢复的影响

目的：研究睫状神经营养因子（ＣＮＴＦ）对受损周围神经功能恢复的影响。方法：将８０只大鼠左侧坐骨神经切断后行神经外膜吻合,随机分为两组。实验组腹腔内注入基因重组人ＣＮＴＦ,对照组注入等量生理盐水（ＮＳ）。术后行坐骨神经功能指数（ＳＦＩ）测定、电生理检测、轴突图像分析及霍乱毒素－辣根过氧化物酶（ＣＢ－ＨＲＰ）逆行追踪。结果：ＣＮＴＦ组ＳＦＩ恢复率、各项电生理及轴突图像分析指标、ＣＢ－ＨＲＰ标记的脊髓前     

不同时间修复周围神经损伤后神经生长因子含量的变化

目的观察在不同时期修复受损兔坐骨神经后,其局部神经生长因子(NGF)含量的变化及修复效果。方法新西兰大白兔24只,切断双侧坐骨神经,分为4组,每组6只。Ⅰ组为第5天进行神经修复组,Ⅱ组为第15天神经修复组,Ⅲ组为第25天神经修复组,Ⅳ组为即时神经修复组。修复后1周,各组随机抽取3只,取修复神经段的远端,进行神经生长因子(NGF)免疫组织化学检测,并进行灰度值分析;修复后2个月各组进行苏木素-伊红(HE)染色、透射电镜及轴突计数等检测。结果即时修复组与第5天神经修复组NGF含量分别高于其他2组(P<0.05),这2组间进行比较差异无统计学意义,第25天神经修复组含量最低,与其他组比较差异有统计学意义(P<0.05)。结论 5d内修复受损神经的局部NGF含量最高,其修复效果最佳。     

Altered hippocampal long-term potentiation after peripheral nerve injury in mice

It has been clinically reported that patients with chronic pain often have accompanying cognitive deficiency, which hampers efficient medical treatment. In the present study, we investigated whether hippocampal synaptic plasticity, which has been considered to be a cellular model of learning and memory, could be influenced by chronic pain conditions using a murine model of neuropathic pain prepared by partial ligation of the sciatic nerve (the Seltzer model). In slices obtained from neuropathic animals, tetanus-induced long-term potentiation of CA1 hippocampal synaptic transmission was impaired, whereas long-term depression induced by low-frequency stimulation was similar in neuropathic and sham-treated (control) animals. Bath application of the beta-adrenoceptor agonist isoproterenol or the beta-adrenoceptor antagonist propranolol diminished the difference of synaptic plasticity between neuropathic and control mice. In the presence of isoproterenol, long-term potentiation was successfully induced in neuropathic mice. By contrast, long-term potentiation in sham-treated mice was impaired by propranolol which did not alter the already impaired long-term potentiation after peripheral nerve injury. These results suggest that beta-adrenergic functions are changed in chronic pain conditions, which may underlie the deficiency of long-term potentiation.