脊髓损伤后皮质脊髓束的相关研究进展

脊髓损伤导致损伤平面以下运动功能障碍,这是由于大脑向脊髓传递运动指令的下行性传导束中断所致。其中主要的传导束是支配肢体运动功能的皮质脊髓束。脊髓损伤后皮质脊髓束的再生修复或功能重塑是促进肢体运动功能恢复的解剖病理基础,本文论述了皮质脊髓束的解剖相关知识以及脊髓损伤后既往促进皮质脊髓束轴突再生修复的经典方法和国内外最新研究进展,以期对临床有一定的指导作用。     

电场诱导新生血管形成对脊髓损伤的修复作用

脊髓损伤后神经功能的恢复主要取决于神经轴突的再生。脊髓损伤后血管缺损、缺乏有效营养运输是影响轴突再生的关键因素之一,也是期待解决的问题。通过电场诱导新生血管形成,可能对脊髓损伤后的结构和功能修复有重要价值。     

干细胞移植治疗脊髓损伤

脊髓损伤是中枢神经系统的严重创伤,传统观点认为脊髓损伤是不可修复和再生的,近年来大量研究表明干细胞具有多向分化潜能,在特定的环境中对神经系统缺血、损伤、变性等原因造成的功能障碍有明显的修复作用,成为治疗脊髓损伤的新希望。     

Wnt信号通路在脊髓损伤修复中作用的实验研究进展北大核心CSCD

Wnt信号通路是参与调控神经系统发育和参与脊髓损伤修复的重要信号转导系统之一,在轴突再生、神经干细胞增殖并向神经元分化,而抑制向胶质细胞分化等方面起重要作用。脊髓损伤后,损伤部位周围多种Wnt蛋白表达。Wnt家族中的一些蛋白在脊髓损伤修复中发挥着重要作用,Wnt/β-catenin信号通路的激活更是脊髓损伤后脊髓再生的必要步骤。     

慢性脊髓损伤的病理学变化及其修复特点

目的:当前脊髓损伤慢性期患者的数量增多,慢性脊髓损伤修复治疗日益成为迫切的需要,回顾性分析慢性脊髓损伤病理学及研究的进展。资料来源:应用计算机检索Medline数据库1985-01/2005-10期间与慢性脊髓损伤有关的文章,检索词“spinalcordinjuries,chronicdisease”,并限定文章语言种类为英文,同时以相同检索词计算机检索CNKI数据库2000-01/2005-10期间的相关文章,限定文章语言种类为中文。资料选择:对资料进行初审,选择以慢性脊髓损伤修复为主要内容的文献。其中研究内容相似的,以近5年且发表在较权威杂志的优先选择。资料提炼:就检索到的400余篇文献进行筛选,以慢性脊髓损伤病理学和修复为主要内容的文献90多篇。最终选定40篇关于慢性脊髓损伤病理学和损伤修复的文献。资料综合:与急性脊髓损伤相比,由于慢性损伤期的神经纤维自身再生能力下降,损伤部位微环境不支持轴突的再生,许多能够促进急性脊髓损伤再生的治疗措施不能够诱发慢性脊髓损伤轴突的长距离再生。结论:由于慢性脊髓损伤的病理特点,其损伤修复有很大难度,当前能够实现慢性损伤脊髓纤维向损伤对侧长距离生长的方法还很少。     

Wnt信号通路在脊髓损伤修复中作用的实验研究进展

Wnt信号通路是参与调控神经系统发育和参与脊髓损伤修复的重要信号转导系统之一,在轴突再生、神经干细胞增殖并向神经元分化,而抑制向胶质细胞分化等方面起重要作用。脊髓损伤后,损伤部位周围多种Wnt蛋白表达。Wnt家族中的一些蛋白在脊髓损伤修复中发挥着重要作用,Wnt/β-catenin信号通路的激活更是脊髓损伤后脊髓再生的必要步骤。     

慢性脊髓损伤的病理学变化及其修复特点

目的：当前脊髓损伤慢性期患者的数量增多，慢性脊髓损伤修复治疗日益成为迫切的需要，回顾性分析慢性脊髓损伤病理学及研究的进展。 资料来源：应用计算机检索Medline数据库1985～01／2005—10期间与慢性脊髓损伤有关的文章，检索词“spinal cord injuries，chronic disease”，并限定文章语言种类为英文，同时以相同检索词计算机检索CNKI数据库2000-01／2005—10期间的相关文章，限定文章语言种类为中文。 资料选择：对资料进行初审，选择以慢性脊髓损伤修复为主要内容的文献。其中研究内容相似的，以近5年且发表在较权威杂志的优先选择。 资料提炼：就检索到的400余篇文献进行筛选，以慢性脊髓损伤病理学和修复为主要内容的文献90多篇。最终选定40篇关于慢性脊髓损伤病理学和损伤修复的文献。 资料综合：与急性脊髓损伤相比，由于慢性损伤期的神经纤维自身再生能力下降，损伤部位微环境不支持轴突的再生，许多能够促进急性脊髓损伤再生的治疗措施不能够诱发慢性脊髓损伤轴突的长距离再生。结论：由于慢性脊髓损伤的病理特点，其损伤修复有很大难度，当前能够实现慢性损伤脊髓纤维向损伤对侧长距离生长的方法还很少。     

从髓鞘脱失到髓鞘再生:脊髓损伤的治疗之路

髓鞘完整性是维持中枢神经系统的生理功能的重要因素,脊髓损伤后髓鞘完整性的保存和再生对于脊髓功能的恢复有关键性的作用。脊髓损伤后,郎飞氏结等结构破坏,轴索暴露,髓鞘脱失处的神经传导受阻。之后出现少突胶质细胞丢失及髓鞘溶解等进一步的损伤。本文对少突胶质细胞丢失及髓鞘溶解的主要生物学事件及机制进行综述,并探讨抑制这些过程的方法。促进内源性的髓鞘再生是脊髓损伤后修复另外一个重要方面。最近研究发现在髓鞘再生过程中,先天性免疫和自适应免疫具有多重作用,胶质疤痕也可能具有潜在的免疫调节作用。神经元活化、少突胶质细胞生成及髓鞘形成间的紧密联系提示髓鞘恢复对脊髓功能的修复有重要意义。在临床应用中,已有几种治疗方案将脊髓损伤的病理生理作为修复目标,包括基因调控、小分子治疗、免疫调节、调控胶质疤痕以及细胞移植。一些新技术也已经开始尝试用于脊髓损伤的治疗,如通过细胞编程将一种细胞转变为另一种细胞、纳米或组织工程技术等。脊髓损伤后脊髓组织的损伤情况是复杂多样的,因此在治疗中需要使用综合性的手段,在损伤后早期尽快修复少突胶质细胞和髓鞘,促进髓鞘再生,为临床应用打基础。     

嗅鞘细胞移植治疗脊髓损伤的基础与临床研究

传统观点认为中枢神经系统神经损伤后,由于内在的再生能力差和外在环境抑制,损伤轴突不能再生。但近年来的基础研究发现,脊髓损伤后,采用一些改变脊髓损伤局部环境的方法,能促使损伤神经修复、再生和恢复脊髓部分神经功能。在这些方法中,嗅鞘细胞移植被认为是治疗脊髓损伤最有前景的方法之一。基础研究和临床试验获得的初步结果均证实,它对脊髓损伤的神经功能恢复具有肯定帮助作用。嗅鞘细胞移植改变了目前脊髓损伤晚期功能恢复临床尚无有效治疗方法的现状。     

脊髓损伤动物模型的建立及其评价

脊髓损伤是一种致残率很高的疾病,建立理想的脊髓损伤动物模型对于实验研究尤为重要。脊髓损伤和再生修复机制是目前神经科学研究中的难题,脊髓损伤动物模型的建立和研究进展为突破这一难题起到了非常重要的作用。本文旨在介绍建立脊髓损伤动物模型的动物选择,以及各种脊髓损伤模型的建立方法、特点,并对常用的脊髓损伤动物模型进行评价。     

Spinal cord injury pain.

Awareness that SCI pain is common emerged during the past decade. However, there are a number of unresolved issues. There is a need for variety of experimental models to reflect diversity of SCI pains. Current classification is not as user-friendly as it should be. More attention should be given to a condition of the spinal cord below and above the SCI lesion. A consensus for what is an optimal SCI functional assessment for patients with sensory complaints and pain should be developed. Further extensive SCI pain research is needed prior to spinal cord regeneration trials in order to be able to cope with a potential for newly developed pains that may appear during incomplete spinal cord regenerative attempts.     

Nogo及其受体在脊髓损伤修复中的作用机制

成体哺乳动物中枢神经系统(CNS)髓磷脂可影响神经的可塑性并抑制神经纤维的再生。Nogo-A被认为是中枢神经系统中抑制轴突生长最关键的一种髓磷脂抑制分子。在脊髓损伤(SCI)动物模型中,抑制Nogo-A的活性可明显促进轴突再生及功能改善。Nogo-A及其信号转导机制的研究日益成为SCI修复过程中的研究热点;Nogo-A及其信号转导分子特别是Nogo-66受体(NgR)、p75神经营养素受体(p75NTR)和LINGO-1成为损伤后促进轴突再生、抑制生长锥塌陷的主要治疗靶点。抑制Nogo-A及其受体NgR/p75NTR/LINGO-1可能有助于SCI的修复,促进患者功能的恢复。     

Current and future therapeutic strategies for functional repair of spinal cord injury

Spinal cord injury (SCI) is one of the major disabilities dealt with in clinical rehabilitation settings and is multifactorial in that the patients suffer from motor and sensory impairments as well as many other complications throughout their lifetimes. Many clinical trials have been documented during the last two decades to restore damaged spinal cords. However, only a few pharmacological therapies used in clinical settings which still have only limited effects on the regeneration and functional recovery. This review presents recent clinical trials and recent advances in the development of strategies to restore locomotion after SCI. Several approaches toward functional recovery in SCI succeeded in acute and subacute phases in animal models.However, effective strategies against chronic phase of SCI have not been established yet. The strategy aiming to inhibit single molecule sometimes shows controversial results. In SCI, a lot of players participate in motor and sensory dysfunctions. Therefore, sufficient functional recovery may be achieved by regulating multiple targets. Regrowth of tracts connecting the brain and spinal cord, and axonal sprouting of propriospinal interneurons are fundamentally important for neuronal network working. In addition, remyelination, protection of neuronal death, inhibition of inflammation, and upregulation of beneficial influence of astrocytes are also quite crucial to supporting the axonal refining. Combination of several strategies might be useful as practical therapy. Several compounds such as a Sema3A inhibitor, estrogen, withanoside IV and their relating compounds or other neurotrophic factor-mimicking agents may be candidates for useful SCI therapeutic drugs since those have multi-effects on damaged spinal cord.     

Neural regeneration therapy after spinal cord injury induces unique brain functional reorganizations in rhesus monkeys

PurposeSpinal cord injury (SCI) destroys the sensorimotor pathway and induces brain plasticity. However, the effect of treatment-induced spinal cord tissue regeneration on brain functional reorganization remains unclear. This study was designed to investigate the large-scale functional interactions in the brains of adult female Rhesus monkeys with injured and regenerated thoracic spinal cord.Materials and methodsResting-state functional magnetic resonance imaging (fMRI) combined with Granger Causality analysis (GCA) and motor behaviour analysis were used to assess the causal interaction between sensorimotor cortices, and calculate the relationship between causal interaction and hindlimb stepping in nine Rhesus monkeys undergoing lesion-induced spontaneous recovery (injured, n = 4) and neurotrophin-3/chitosan transplantation-induced regeneration (NT3-chitosan, n = 5) after SCI.ResultsThe results showed that the injured and NT3-chitosan-treated animals had distinct spatiotemporal features of brain functional reorganization. The spontaneous recovery followed the model of “early intra-hemispheric reorganization dominant, late inter-hemispheric reorganization dominant”, whereas regenerative therapy animals showed the opposite trend. Although the variation degree of information flow intensity was consistent, the tendency and the relationship between local neuronal activity properties and coupling strength were different between the two groups. In addition, the injured and NT3-chitosan-treated animals had similar motor adjustments but various relationship modes between motor performance and information flow intensity.ConclusionsOur findings show that brain functional reorganization induced by regeneration therapy differed from spontaneous recovery after SCI. The influence of unique changes in brain plasticity on the therapeutic effects of future regeneration therapy strategies should be considered.

Key messages

• Neural regeneration elicited a unique spatiotemporal mode of brain functional reorganization in the spinal cord injured monkeys, and that regeneration does not simply reverse the process of brain plasticity induced by spinal cord injury (SCI).
• Independent “properties of local activity – intensity of information flow” relationships between the injured and treated animals indicating that spontaneous recovery and regenerative therapy exerted different effects on the reorganization of the motor network after SCI.
• A specific information flow from the left thalamus to the right insular can serve as an indicator to reflect a heterogeneous “information flow – motor performance” relationship between injured and treated animals at similar motor adjustments.

     

Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms

Spinal cord injury (SCI) often leads to persistent functional deficits due to loss of neurons and glia and to limited axonal regeneration after injury. Here we report that transplantation of human dental pulp stem cells into the completely transected adult rat spinal cord resulted in marked recovery of hind limb locomotor functions. Transplantation of human bone marrow stromal cells or skin-derived fibroblasts led to substantially less recovery of locomotor function. The human dental pulp stem cells exhibited three major neuroregenerative activities. First, they inhibited the SCI-induced apoptosis of neurons, astrocytes, and oligodendrocytes, which improved the preservation of neuronal filaments and myelin sheaths. Second, they promoted the regeneration of transected axons by directly inhibiting multiple axon growth inhibitors, including chondroitin sulfate proteoglycan and myelin-associated glycoprotein, via paracrine mechanisms. Last, they replaced lost cells by differentiating into mature oligodendrocytes under the extreme conditions of SCI. Our data demonstrate that tooth-derived stem cells may provide therapeutic benefits for treating SCI through both cell-autonomous and paracrine neuroregenerative activities.     

急性大鼠脊髓损伤Allen's法模型的改良及电生理评价

目的建立一种更实用、标准、可靠的急性大鼠脊髓撞击损伤模型,为脊髓损伤(spinal cord injury,SCI)的进一步研究奠定基础。方法将36只成年雌性Wistar大鼠随机分成三组,每组12只。脊髓损伤(SCI)组:用自制改良的Allen’s撞击器,以60gcm致伤力损伤大鼠T10胸椎对应脊髓。假手术组:只打开椎板,暴露脊髓,不造成SCI。正常对照组:正常大鼠,不做任何处理。各组定期行为学观察(BBB评分),术后30天进行组织学观察和神经电生理检测。结果 HE染色:假手术组与正常对照组基本一致的。SCI组可见灰、白质组织结构不完整,损伤区可见大片坏死灶、细胞肿胀。BBB评分:假手术组术后1周功能恢复接近正常。SCI组术后第2周开始恢复,到第3周基本停止,最终BBB评分未超过6分,两组比较有明显差异。神经电生理(SEP,MEP)检测:SCI组可以明显看到SEP与MEP的峰-峰值急剧降低,且潜伏期明显延长,差异显著(P0.01)。结论改良后的急性大鼠脊髓损伤模型制作法操作简便、重复性好,是较为理想的方法。     

Reconstructing neural circuits using transplanted neural stem cells in the injured spinal cord

Traumatic spinal cord injury is one of the most common causes of disability in young adults. Restoring independent ambulation in such patients is considered one of the biggest challenges in regenerative medicine because repair of spinal cord injury involves the complex processes of axonal regeneration, remyelination, and formation of new synaptic connections. In this issue of the JCI, Abematsu et al. report their attempts to rise to this challenge, showing in a mouse model of severe spinal cord injury that spinal neuronal circuits can be restored by neural stem cell transplantation, leading to impressive functional recovery in the hind limbs. Traumatic brain and spinal cord injury (SCI) is one of the most common causes of disability in young adults and poses a huge social and economical burden (1). The impact of nonpenetrating, blunt (contusive) trauma to the spinal cord causes abrupt discontinuation of axonal projections. There is also release of neurotoxic compounds and inflammatory mediators that add to neuronal and oligodendroglial cell death during the first hours and days after injury. This is followed by secondary processes of loss of myelin, degeneration of axons, and formation of a glial scar that inhibits spontaneous regeneration. Currently, there is no proven reparative treatment for SCI. Restoring independent ambulation in paraplegic trauma victims is considered one of the biggest challenges in regenerative medicine. This would require the development of approaches to achieve effective transmission of electrical impulses through the lesion. To this end, it is necessary to induce robust regeneration of severed axons, their covering with myelin sheaths — a process termed remyelination — and formation of new synaptic connections. With this notion in mind, studies of neural stem cell transplantation have been performed in experimental models of SCI during the last decade and have demonstrated increased growth of severed host axons and improved remyelination (2). In this issue of the JCI, Abematsu et al. (3) show that transplanting neural stem cells epigenetically directed to differentiate into neurons can promote the reconstruction of spinal neuronal circuits, leading to impressive functional recovery in mouse hind limbs following SCI.     

Basic concepts of activity-based interventions for improved recovery of motor function after spinal cord injury

Roy RR, Harkema SJ, Edgerton VR. Basic concepts of activity-based interventions for improved recovery of motor function after spinal cord injury. Spinal cord injury (SCI) is a devastating condition that affects a large number of individuals. Historically, the recovery process after an SCI has been slow and with limited success. Recently, a number of advances have been made in the strategies used for rehabilitation, resulting in marked improved recovery, even after a complete SCI. Several rehabilitative interventions, that is, assisted motor training, spinal cord epidural stimulation, and/or administration of pharmacologic agents, alone or in combination, have produced remarkable recovery in motor function in both humans and animals. The success with each of these interventions appears to be related to the fact that the spinal cord is smart, in that it can use ensembles of sensory information to generate appropriate motor responses without input from supraspinal centers, a property commonly referred to as central pattern generation. This ability of the spinal cord reflects a level of automaticity, that is, the ability of the neural circuitry of the spinal cord to interpret complex sensory information and to make appropriate decisions to generate successful postural and locomotor tasks. Herein, we provide a brief review of some of the neurophysiologic rationale for the success of these interventions.     

Potential of olfactory ensheathing cells for cell-based therapy in spinal cord injury

Contusive spinal cord injury (SCI) results in a complex lesion that includes cellular and axonal loss, microglia and macrophage activation, and demyelination. These changes result in permanent neurological deficits in people with SCI and in high financial costs to society. Unlike the peripheral nervous system (PNS), in which axonal regeneration can occur, axonal regeneration in the central nervous system (CNS) is extremely limited. This limited regeneration is thought to result from a lack of a permissive environment and from active inhibitory molecules that are present in the CNS but minimal in the PNS. Currently, cell transplantation approaches are among several experimental strategies being investigated for the treatment of SCI. In the olfactory system, a specialized glial cell called the olfactory ensheathing cell (OEC) has been shown to improve functional outcome when transplanted into rodents with SCI, and clinical studies transplanting OECs into patients with SCI are ongoing in China, Portugal, and other sites. Yet, a number of controversial issues related to OEC biology and transplantation must be addressed to understand the rationale and expectations for OEC cell therapy approaches in SCI. This review provides information on these issues for spinal cord medicine clinicians.     

嗅鞘细胞移植改善晚期脊髓损伤患者神经功能的近期效应

背景:既往认为中枢神经无再生能力。但近年来研究发现,脊髓损伤后,改变局部环境,损伤的神经轴突可以有再生能力并能恢复部分神经功能。目的:探讨胚嗅鞘细胞移植治疗晚期脊髓损伤患者是否安全、可行和有效恢复神经功能。设计:自身前后对照观察。单位:北京西山医院神经疾病研究治疗中心、首都医科大学附属北京朝阳医院神经外二科和解放军海军总医院神经外二科。对象:选择2001-11/2003-02首都医科大学附属北京朝阳医院神经外二科和海军总医院神经外二科治疗的晚期脊髓损伤患者171例。其中完全性损伤147例,不全性损伤24例。伤后时间:0.5～18年。治疗过程经有关医疗伦理委员会讨论同意,细胞捐献者自愿同意,被治疗者知情同意。方法:①取胚胎嗅球,消化成单个嗅鞘细胞后培养12～17d。②将胚胎嗅鞘细胞移植到患者脊髓损伤部位的上下处。③所有患者在胚胎嗅鞘细胞移植手术前和手术后2～8周按美国脊髓损伤学会(ASIA)评分标准评价。主要观察指标:①嗅鞘细胞移植术后患者脊髓功能恢复情况。②不良事件及副反应。结果:171例患者全部进入结果分析。①嗅鞘细胞移植术后患者脊髓功能恢复情况:171例均有部分神经功能快速恢复,其中运动功能评分由术前34.5±20.3提高到42.0±20.0(P<0.001),轻触觉评分由术前47.2±24.0提高到61.8±23.0(P<0.001),痛觉评分由术前48.6±23.5提高到64.0±22.8(P<0.001)。②不良事件及副反应:1例术区感染导致脊髓损害表现早期加重;2例严重肺部感染,1例丘脑出血,此3例患者最终因严重呼吸、循环衰竭而死亡。结论:嗅鞘细胞移植能快速促进晚期脊髓损伤患者恢复部分神经功能,但作用机制尚需进一步观察。