硫化氢与脊髓损伤治疗

脊髓损伤(spinal cord injury,SCI)是一种由于脊髓外部损伤或内部病变引起的暂时性或永久性的功能损伤,其症状包括肌肉功能损伤、自主运动功能减退或丧失等。目前,流行病学调查发现,我国SCI患病率较高,具有较高的社会和医疗负担。因此,合理引导SCI病人进行治疗和康复尤为重要。硫化氢（hydrogen sulfide,H2S）是一种重要的神经信号分子,近年来H2S对SCI康复的作用机制逐渐成为研究热点,例如一些国内外研究团队对SCI后缺血-再灌注损伤（ischemia reperfusion injury,I/R injury）、降低SCI后氧化应激及抗炎作用等机制,以及SCI康复临床治疗研究均取得了一定的成果。本文通过H2S对SCI康复的机制研究和临床治疗发展进行综述,旨在为后续研究及临床应用提供参考。     

硫化氢与脊髓损伤治疗

脊髓损伤(spinal cord injury,SCI)是一种由于脊髓外部损伤或内部病变引起的暂时性或永久性的功能损伤,其症状包括肌肉功能损伤、自主运动功能减退或丧失等。目前,流行病学调查发现,我国SCI患病率较高,具有较高的社会和医疗负担。因此,合理引导SCI病人进行治疗和康复尤为重要。硫化氢（hydrogen sulfide,H2S）是一种重要的神经信号分子,近年来H2S对SCI康复的作用机制逐渐成为研究热点,例如一些国内外研究团队对SCI后缺血-再灌注损伤（ischemia reperfusion injury,I/R injury）、降低SCI后氧化应激及抗炎作用等机制,以及SCI康复临床治疗研究均取得了一定的成果。本文通过H2S对SCI康复的机制研究和临床治疗发展进行综述,旨在为后续研究及临床应用提供参考。     

Relationship between Spinal Cord Volume and Spinal Cord Injury due to Spinal Shortening

Vertebral column resection is associated with a risk of spinal cord injury. In the present study, using a goat model, we aimed to investigate the relationship between changes in spinal cord volume and spinal cord injury due to spinal shortening, and to quantify the spinal cord volume per 1-mm height in order to clarify a safe limit for shortening. Vertebral column resection was performed at T10 in 10 goats. The spinal cord was shortened until the somatosensory-evoked potential was decreased by 50% from the baseline amplitude or delayed by 10% relative to the baseline peak latency. A wake-up test was performed, and the goats were observed for two days postoperatively. Magnetic resonance imaging was used to measure the spinal cord volume, T10 height, disc height, osteotomy segment height, and spinal segment height pre- and postoperatively. Two of the 10 goats were excluded, and hence, only data from eight goats were analyzed. The somatosensory-evoked potential of these eight goats demonstrated meaningful changes. With regard to neurologic function, five and three goats were classified as Tarlov grades 5 and 4 at two days postoperatively. The mean shortening distance was 23.6 ± 1.51 mm, which correlated with the d-value (post-pre) of the spinal cord volume per 1-mm height of the osteotomy segment (r = 0.95, p < 0.001) and with the height of the T10 body (r = 0.79, p = 0.02). The mean d-value (post-pre) of the spinal cord volume per 1-mm height of the osteotomy segment was 142.87 ± 0.59 mm³ (range, 142.19–143.67 mm³). The limit for shortening was approximately 106% of the vertebral height. The mean volumes of the osteotomy and spinal segments did not significantly change after surgery (t = 0.310, p = 0.765 and t = 1.241, p = 0.255, respectively). Thus, our results indicate that the safe limit for shortening can be calculated using the change in spinal cord volume per 1-mm height.     

少突胶质前体细胞治疗脊髓损伤的研究进展

脊髓损伤(spinal cord injury,SCI)是一种严重危害人类生命健康的疾病,其发病率呈现逐年上升的趋势,并且治疗较为困难。研究发现脊髓损伤后少突胶质细胞大量死亡,引发脱髓鞘病变,这可能是其难以治疗的原因之一。少突胶质前体细胞(OPCs)为少突胶质细胞的祖细胞,后者是中枢神经系统的成髓鞘细胞。OPCs来源于胚胎发育早期神经管腹侧神经上皮细胞,随着神经管的发育,OPCs逐渐增殖、迁移并分化为成熟OL,参与中枢神经系统轴突髓鞘的形成。随着对OPCs的不断深入研究,发现OPCs移植对SCI有较好的疗效,这可能为SCI患者开辟一条新的治疗途径。本文就OPCs治疗SCI的动物实验研究结果做一综述。     

脊髓损伤的最新治疗进展

脊髓损伤以后引起原发性损伤和继发性损伤导致损伤的神经组织难以修复。目前脊髓损伤的重点主要集中在减轻和延缓继发性损伤造成的伤害。本文总结了近年来在脊髓损伤治疗领域的进展包括传统的药物治疗,细胞移植和基因治疗。目前动物实验研究表明细胞移植和基因治疗在治疗脊髓损伤的中取得了可喜的成果,将在未来临床应用中发挥重要作用。     

大鼠放射性脊髓损伤脊髓血流量变化规律

目的:放射性脊髓损伤(Radiation spinal cord injury,RSCI)是头颈部、胸部及上腹部肿瘤放射治疗和射线意外照射时的常见并发症,一般认为,白质坏死、脱髓鞘为其主要的病理学变化.然而,越来越多的证据表明血-脊髓屏障破裂和血管通透性增加等血管损伤远早于白质坏死和脱髓鞘改变.所以本文阐明大鼠放射性脊髓损伤病理生理过程中脊髓血流量变化规律.方法:将60只Sprague-Dawley (SD)大鼠随机分为12组,1组为对照,其余11组采用60Co放射治疗机行30 Gy大鼠颈髓C2-T2单次照射,剂量率为153 cGy/min,源皮距为80 cm,照射时长为1153 s,照射范围为2.0× 1.0 cm,对照组大鼠于麻醉后置于60Co放射治疗机下,佯照,照射前及照射后分别采用激光多普勒法测量脊髓血流量,11组大鼠于照射前以及照射后1、3、7、14、21、30、60、90、120、150、180天进行测量,以照射前测量值为基数,各时间点以基数的百分比表示该时间点脊髓血流量.结果:大鼠放射性脊髓损伤后,脊髓血流量在照射早期即有降低,照射后90天达到最低,随后脊髓血流量进入平台期.结论:阐明了大鼠放射性脊髓损伤后脊髓血流量的变化规律.大鼠放射性脊髓损伤可影响脊髓血流量,导致脊髓长期处于持续低灌流、缺血缺氧状态,最终导致脊髓不可逆性损伤.临床上放射性脊髓损伤的病人感到疲乏无力,出现神经系统的症状体征,通常死于脑疝.本文为临床上疲乏无力,出现神经系统的症状体征,死于脑疝放射性脊髓损伤的病人的早期防治提供病理生理基础.     

Bowel Dysfunction in Spinal Cord Injury: Current Perspectives

Permanent disruptions of gastrointestinal function are very common sequel of spinal cord injury (SCI). When motor and sensory nervous integrity are severely affected, neurogenic gastrointestinal dysfunction is an inevitable consequence. Autonomic nervous system miss function has significantly diminished or lost sensory sensations followed with incomplete evacuation of stool from the rectal vault, immobility, and reduced anal sphincter tone all of those predisposing to increased risk of fecal incontinence (FI). The FI is, beside paralysis of extremities, one of the symptoms most profoundly affecting quality of life (QOL) in patients with SCI. We are reviewing current perspectives in management of SCI, discussing some pathophysiology mechanisms which could be addressed and pointing toward actual practical concepts in use for evaluation and improvements necessary to sustain SCI patients QOL.     

Spinal Cord Injury: Animal Models,Imaging Tools and the Treatment Strategies

Spinal cord injury (SCI) often leads to irreversible neuro-degenerative changes with life-long consequences. While there is still no effective therapy available, the results of past research have led to improved quality of life for patients suffering from partial or permanent paralysis. In this review we focus on the need, importance and the scientific value of experimental animal models simulating SCI in humans. Furthermore, we highlight modern imaging tools determining the location and extent of spinal cord damage and their contribution to early diagnosis and selection of appropriate treatment. Finally, we focus on available cellular and acellular therapies and novel combinatory approaches with exosomes and active biomaterials. Here we discuss the efficacy and limitations of adult mesenchymal stem cells which can be derived from bone marrow, adipose tissue or umbilical cord blood and its Wharton’s jelly. Special attention is paid to stem cell-derived exosomes and smart biomaterials due to their special properties as a delivery system for proteins, bioactive molecules or even genetic material.

     

富血小板血浆在脊柱脊髓损伤治疗中的应用进展

富血小板血浆是近些年来比较热门的一种血液制品,其来源于自体,且制备方法简单,又富含大量血小板及多种生长因子,能够加速骨愈合,增强骨再生,促进软组织及神经损伤恢复,因此得到了广泛的关注。国内外的研究人员根据富血小板血浆所具有的特点,针对各个方面对其进行了大量的研究实验,并且在临床骨科疾病的治疗中也已经开始了实验性应用,如骨缺损、骨再生,肌腱、韧带及软组织损伤,脊柱脊髓损伤等。尤其是在脊柱脊髓损伤的治疗方面,无论是单独应用富血小板血浆治疗,还是联合应用富血小板血浆与脊髓神经前体细胞、骨髓间充质干细胞等有利于脊髓神经损伤恢复的细胞因子复合物共同治疗,均取得了突破性的进展,为研究脊柱脊髓损伤的治疗提供了新的方向。     

脊髓损伤的基因治疗

基因治疗脊髓损伤（SCI）既不存在胎儿神经组织移植的组织来源问题,且比外周神经组织移植引起的排异性低,是目前脊髓损伤治疗中最有前途的方法.基因治疗的转基因方式有两种：一是将目的基因直接导入体内靶细胞令其表达;二是将基因在体外导入适当的细胞内,并筛选出高效表达的移植细胞作为转基因中介移植到体内靶组织.不论采用何种方式,将基因导入细胞又可用多种手段实现：如微注射、脂质体等物理或化学手段;利用缺陷病毒作为载体感染细胞的生物学手段.因为用生物学手段转基因的细胞移植方法空间定位明确,所以目前最常采用它作为基因治疗效果的研究.虽然SCI基因治疗目前仍停留在实验探索阶段,一些问题尚待解决,但随着基因治疗技术方法的不断提高,它的临床应用前景可以预见.     

Arachidonic Acid-Induced Oxidative Injury to Cultured Spinal Cord Neurons

Spinal cord trauma can cause a marked release of free fatty acids, in particular, arachidonic acid (AA), from cell membranes. Free fatty acids, and AA by itself, may lead to secondary damage to spinal cord neurons. To study this hypothesis, cultured spinal cord neurons were exposed to increasing concentrations of AA (0.01-10 microM). AA-induced injury to spinal cord neurons was assessed by measurements of cellular oxidative stress, intracellular calcium levels, activation of nuclear factor-KB (NF-kappaB), and cell viability. AA treatment increased intracellular calcium concentrations and decreased cell viability. Oxidative stress increased significantly in neurons exposed to 1 and 10 microM AA. In addition, AA treatment activated NF-kappaB and decreased levels of the inhibitory subunit, IKB. It is interesting that manganese superoxide dismutase protein levels and levels of intracellular total glutathione increased in neurons exposed to this fatty acid for 24 h, consistent with a compensatory response to increased oxidative stress. These results strongly support the hypothesis that free fatty acids contribute to the tissue injury observed following spinal cord trauma.     

间充质干细胞-透明质酸-多聚赖氨酸治疗脊髓损伤的实验研究

目的研究间充质干细胞—透明质酸—多聚赖氨酸复合物治疗脊髓损伤的可行性,评价其治疗效果并探讨其可能机制。方法从人骨髓中分离、培养人骨髓间充质干细胞（human bone marrow mesenchymal stem cell,hBMSC）;制作大鼠脊髓半横断模型,按照实验分组分别将hBMSC、透明质酸-多聚赖氨酸（hyaluronic acid-poly-L-lysine,HA-PLL）、hBMSC-HA-PLL复合物注入损伤区域,单纯损伤组作为对照。术后按照不同时间点评价损伤和移植后的大鼠运动功能。8周后杀死大鼠,观察不同移植组体内轴突和血管生长的情况,对不同细胞、材料及复合物移植对大鼠脊髓损伤修复效果进行评估。结果 hBMSC移植组和hBMSC-HA-PLL移植组的大鼠运动功能的改善显著好于单纯损伤及HA-PLL移植组。电镜结果证实复合物移植组可显著促进轴突和血管生长,新生的轴突和血管结构较为完整。结论 hBMSC具有促进神经功能恢复的作用,将其与HA-PLL相结合,可以促进大鼠脊髓损伤修复,其机制可能包括材料框架作用和hBMSC在体内对大鼠神经细胞的营养作用以及促进微血管的生成。     

Long-Term Changes in Spinal Cord Evoked Potentials After Compression Spinal Cord Injury in the Rat

SUMMARY 1. After traumatic spinal cord injury (SCI), histological and neurological consequences are developing for several days and even weeks. However, little is known about the dynamics of changes in spinal axonal conductivity. The aim of this study was to record and compare repeated spinal cord evoked potentials (SCEP) after SCI in the rat during a 4 weeks’ interval. These recordings were used: (i) for studying the dynamics of functional changes in spinal axons after SCI, and (ii) to define the value of SCEP as an independent outcome parameter in SCI studies.2. We have used two pairs of chronically implanted epidural electrodes for stimulation/recording. The electrodes were placed below and above the site of injury, respectively. Animals with implanted electrodes underwent spinal cord compression injury induced by epidural balloon inflation at Th8–Th9 level. There were five experimental groups of animals, including one control group (sham-operated, no injury), and four injury groups (different degrees of SCI).3. After SCI, SCEP waveform was either significantly reduced or completely lost. Partial recovery of SCEPs was observed in all groups. The onset and extent of recovery clearly correlated with the severity of injury.There was good correlation between quantitated SCEP variables and the volumes of the compressing balloon. However, sensitivity of electropohysiological parameters was inferior compared to neurological and morphometric outcomes.4. Our study shows for the first time, that the dynamics of axonal recovery depends on the degree of injury. After mild injury, recovery of signal is rapid. However, after severe injury, axonal conductivity can re-appear after as long as 2 weeks postinjury.In conclusion, SCEPs can be used as an independent parameter of outcome after SCI, but in general, the sensitivity of electrophysiological data were worse than standard morphological and neurological evaluations.     

Biomaterials and Magnetic Stem Cell Delivery in the Treatment of Spinal Cord Injury

Spinal cord injury (SCI) is a serious trauma, which often results in a permanent loss of motor and sensory functions, pain and spasticity. Despite extensive research, there is currently no available therapy that would restore the lost functions after SCI in human patients. Advanced treatments use regenerative medicine or its combination with various interdisciplinary approaches such as tissue engineering or biophysical methods. This review summarizes and critically discusses the research from specific interdisciplinary fields in SCI treatment such as the development of biomaterials as scaffolds for tissue repair, and using a magnetic field for targeted cell delivery. We compare the treatment effects of synthetic non-degradable methacrylate-based hydrogels and biodegradable biological scaffolds based on extracellular matrix. The systems using magnetic fields for magnetically guided delivery of stem cells loaded with magnetic nanoparticles into the lesion site are then suggested and discussed.

     

Kininogen and Kinin in Experimental Spinal Cord Injury

Activation of the kallikrein-kinin system has been implicated in the pathogenesis of vasogenic brain edema and posttraumatic vascular injury. We determined the levels of kininogen and kinin in an experimental spinal cord injury model in the rat. Kininogen content in traumatized cord segments increased in a time-dependent manner. Western blot analysis showed that the kininogen in traumatized cord comigrates with 68K low-molecular-weight kininogen or T-kininogen. Trypsin treatment of the kininogen in traumatized cord released both bradykinin and T-kinin, which were separated by HPLC and quantified with a kinin radioimmunoassay. Endogenous kinin levels in the frozen spinal cord also increased up to 40-fold 2 h after injury as compared with controls. The results demonstrate an increased accumulation of kininogen and its conversion to vasoactive kinins in experimental spinal cord injury.     

Aberrant Crossed Corticospinal Facilitation in Muscles Distant from a Spinal Cord Injury

Crossed facilitatory interactions in the corticospinal pathway are impaired in humans with chronic incomplete spinal cord injury (SCI). The extent to which crossed facilitation is affected in muscles above and below the injury remains unknown. To address this question we tested 51 patients with neurological injuries between C2-T12 and 17 age-matched healthy controls. Using transcranial magnetic stimulation we elicited motor evoked potentials (MEPs) in the resting first dorsal interosseous, biceps brachii, and tibialis anterior muscles when the contralateral side remained at rest or performed 70% of maximal voluntary contraction (MVC) into index finger abduction, elbow flexion, and ankle dorsiflexion, respectively. By testing MEPs in muscles with motoneurons located at different spinal cord segments we were able to relate the neurological level of injury to be above, at, or below the location of the motoneurons of the muscle tested. We demonstrate that in patients the size of MEPs was increased to a similar extent as in controls in muscles above the injury during 70% of MVC compared to rest. MEPs remained unchanged in muscles at and within 5 segments below the injury during 70% of MVC compared to rest. However, in muscles beyond 5 segments below the injury the size of MEPs increased similar to controls and was aberrantly high, 2-fold above controls, in muscles distant (>15 segments) from the injury. These aberrantly large MEPs were accompanied by larger F-wave amplitudes compared to controls. Thus, our findings support the view that corticospinal degeneration does not spread rostral to the lesion, and highlights the potential of caudal regions distant from an injury to facilitate residual corticospinal output after SCI.