多发性硬化的轴索损伤

多发性硬化（multiple sclerosis，MS）是中枢神经系统常见的慢性炎性脱髓鞘疾病，以往认为该病病理上以脱髓鞘为主，轴索相对保留。MS患者早期或者缓解期临床上是看不到轴索损伤引起的功能缺失的，但当轴索的损伤到达一定阈值，超出中枢神经系统的代偿能力时，就会出现不可逆的神经功能缺失，最终不断累积的轴索损伤可导致MS患者进展性的神经功能缺失。关注轴索损伤对研究脱髓鞘病的病理机制有重要意义，我们将MS轴索损伤相关进展作一综述。     

多发性硬化的轴索损害

多发性硬化不仅有脱髓鞘性损害 ,还有轴索损害 ,且轴索损害与患者的功能缺损进展有关。轴索损害与炎症反应有一定关系 ,还有其他机制。认识轴索损害的存在并试图防止轴索损害有可能延缓功能缺损的进展     

多发性硬化的轴索损伤及其机制

19世纪初即有文献提及多发性硬化(MS)的轴索病变[1].Charcot和Marburg都描述了多发性硬化的病理改变:脱髓鞘、反应性神经胶质增生和轴索相对保留.1936年,Putnam报告多发性硬化病灶轴索缺失达50%;而Greenfield则认为,90%的多发性硬化病灶轴索密度正常,并指出该项研究结果与前人的差异归功于高敏感性的轴索染色方法.然而,在随后的研究中,轴索病变在多发性硬化发病机制中的作用并未引起足够重视.     

尼莫地平联合高压氧治疗弥漫性轴索损伤的临床研究

目的探讨尼莫地平联合高压氧治疗弥漫性轴索损伤的疗效。方法将176例弥漫性轴索损伤患者按随机数字表法随机分为4组:对照组(常规治疗),尼莫地平组(常规治疗+尼莫地平联合治疗),高压氧组(常规治疗+高压氧联合治疗),联合治疗组(常规治疗+尼莫地平+高压氧联合治疗),于伤后第1、4、8、15、22天采用经颅多普勒超声(TCD)测定所有患者双侧大脑中动脉及颈内动脉颅外段血流速度;分别于伤后当天,治疗后1、8、15、22d行GCS评分及治疗半年后行GOS评分,并互相比较。结果治疗22d后,联合治疗组患者GCS评分明显提高(P<0.01),预后良好率均明显高于其他三组(P<0.05),且联合治疗组脑血管痉挛明显改善。结论尼莫地平联合高压氧治疗有助于改善弥漫性轴索损伤患者的预后。     

多发性硬化轴索和神经元变性(综述)

通过磁共振和形态学研究发现 ,不断积累的轴索损伤是大多数多发性硬化 ( multiple sclerosis,MS)患者进行性功能丧失的病理基础 ,而炎症和慢性脱髓鞘病变可能是轴索横断的原因 ,故将 MS看成一种炎性神经变性疾病的观点对其临床治疗、患者监护以及未来治疗方案都有重要意义。     

尼莫地平联合甘露醇对大鼠弥漫性轴索损伤治疗效果

目的观察尼莫地平联合甘露醇对大鼠弥漫性轴索损伤(DAI)的治疗效果。方法将170只SD雄性大鼠随机分为对照组、损伤组、甘露醇组、尼莫地平组和联合干预组,后4组制作大鼠颅脑DAI模型。甘露醇组尾静脉注射甘露醇1g.kg-1.d-1及腹腔注射等量生理盐水替代尼群地平;尼莫地平组予以尼莫地平0.5mg.kg-1.d-1及等量生理盐水替代甘露醇;联合干预组予以尼莫地平及甘露醇,对照组和损伤组仅以等量的生理盐水替代甘露醇和尼莫地平。后4组伤后2～75h内每隔2.5h处死1只大鼠测脑组织含水量;受伤后2、6、24、72、168h观察动物行为。结果各实验组行为学评分在伤后2、6、24、72、168h各时相点组间有显著差异,F值分别为为:10.89、28.39、12.18、27.50、15.28(P<0.01)。除甘露醇与联合组间脑水含量差异无统计学意义外,其他各组间比较差异均有统计学意义(P<0.05)。结论尼莫地平联合甘露醇治疗DAI,有助于减轻大鼠DAI后继发性脑损害,促进神经功能恢复。     

大鼠脑弥漫性轴索损伤不同轴索损伤类型的形态学观察

目的 观察脑弥漫性轴索损伤(DAI)急性期轴索损伤的类型和形态学改变,并探讨其相关机制. 方法 SD大鼠24只随机数字表法分为实验组(n=16)和对照组(n=8).实验组又按损伤后不同时间(6、24 h)分为2组,每组8只,运用自制联合损伤装置致实验组大鼠DAI模型,于损伤后急性期不同时间点行HE染色,免疫荧光染色检测脑组织轴浆运输障碍标志物β-淀粉样前体蛋白(β-APP)和神经微丝结构破坏标志物(NF-68)的表达,并在电镜下观察损伤轴索的超微结构变化.结果与对照组[(6.5±1.0)min]相比,实验组[(11.9±2.7)min]大鼠伤后出现昏迷时间延长,差异有统计学意义(P<0.05).β-APP免疫组化染色显示轴索肿胀扭曲、膨胀断裂及轴索球形成;NF-68免疫荧光染色显示轴索缩窄变细呈分割状.电镜下肿胀类型的轴索骨架溶解絮乱、细胞器聚集,而另一类损伤轴索骨架排列仍较清晰,但轴索内有较多空泡形成及神经微丝汇聚. 结论 DAI急性期损伤轴索存在着轴浆运输障碍和神经微丝结构破坏等病理生理过程,相应损伤轴索的形态不同.多种检测方法的使用能更全面地评估轴索损伤的严重程度及轴索对损伤的复杂反应.     

尼莫地平对大鼠皮质脑梗塞再灌流期自由基损伤的保护作用研究

尼莫地平对大鼠皮质脑梗塞再灌流期自由基损伤的保护作用研究许国正，牛国忠，金石自由基在脑缺血再灌流期神经细胞损伤中起着重要作用［１］。本研究应用大鼠局灶性皮质脑梗塞再灌流动物模型，观察尼莫地平（ＮＰ）对自由基损伤的保护作用。材料与方法Ｗｉｓｔａｒ普通级...     

蠕虫对多发性硬化动物模型的保护作用

一、多发性硬化(MS)和实验性自身免疫性脑脊髓炎多发性硬化是中枢神经系统(CNS)白质炎症脱髓鞘性自身免疫性疾病,临床主要表现为缓解复发和阶梯进展的视力、运动和平衡障碍。MS按疾病的病程分为以下几种类型:缓解复发型、原发进展和继发进展型。MS病情的进展是髓鞘抗原特异性T细胞,以髓鞘为靶,导致CNS的炎症浸润,最后导     

神经干细胞治疗多发性硬化

多发性硬化(multiple sclerosis,MS)是一种常见的中枢神经系统炎性脱髓鞘性疾病,是青年和中年非外伤神经残疾最常见的原因,估计美国有四十万人受累,全世界有两百万MS患者。MS特征为炎症、脱髓鞘、轴索变性、神经失能累积,在疾病进程中神经轴索结构受累特征性表现为神经元凋亡、树突丢失、横断脱髓鞘的轴索[1]。MS病因至今仍然不甚明确,可能与环境因素(病毒感染等)和遗传易感性有关。目前认为MS是一种自身免疫性疾病,是细胞免疫与体液免疫共同参与导致的以脑脊髓白质损伤为主的疾病,复发率和致残率高。神经干细胞(neural stem cells,NS…     

Phosphorylation and compactness of neurofilaments in multiple sclerosis: indicators of axonal pathology

Aims

Axonal pathology extends to the axonal cytoarchitecture leaving its signature on axoskeletal proteins. This study investigated whether neurofilament (NfH) phosphorylation would relate to the dynamics of axonal pathology in multiple sclerosis (MS).

Methods

NfH phosphoforms (SMI32, SMI34, SMI35) were quantified by ELISA from microdissected samples of control and MS brain and spinal cord. Individual axons were analysed by electron microscopy, densitometrically and morphologically in adjacent tissue sections. Experiments were carried out pre- and post enzymatic dephosphorylation.

Results

In control tissue a rostro-caudal gradient of NfH indicated an increase in axonal density from the brain gray matter towards the spinal cord. The highest levels of phosphorylated and hyperphosphorylated NfH were found in acute lesions of brain and spinal cord, in contrast to chronic lesions where levels were lower than in white matter, consistent with axonal loss. Dephosphorylated NfH was higher, but less densly packed in MS white matter axons compared to control tissue.

Conclusions

The findings suggest that a less organised/compact axoskeleton or impaired axonal transport may represent an early sign of axonal pathology within the normal appearing white matter in MS. Subsequently a proportional increase of dephosphorylated NfH, aberrant phosphorylation and/or aggregation may occur whilst the protein is transported through the white matter towards the MS plaque, where hyperphosphorylated NfH dominates.     

尼莫地平对大鼠急性脑缺血再灌注损伤早期保护作用的研究

目的探讨尼莫地平对急性脑缺血再灌注损伤的早期保护作用。方法线栓法复制大鼠急性脑缺血模型。30只雄性Wistar大鼠随机分为假手术、模型、尼莫地平3组。模型组采取缺血2h再灌注2h。尼莫地平组大鼠在缺血0时刻起每小时腹腔注射给药一次,剂量为5mg/kg。各组大鼠在手术4h后实验结束后,行腹主动脉采血,同时取完整脑组织。脑组织切片进行TTC染色,并比较各组脑组织梗死面积。检测各组大鼠血清及脑组织匀浆中SOD、MDA、NO含量。结果与模型组相比,尼莫地平组大鼠脑组织梗死面积显著减少。血清生化指标显示,模型组SOD含量显著低于假手术组,给予尼莫地平治疗后,SOD含量增加明显。模型组MDA、NO含量明显高于假手术组,尼莫地平组明显降低血清中MDA、NO。结论尼莫地平对大鼠急性脑缺血再灌注损伤有保护作用,这种保护作用与NO和氧化应激密切相关。     

Global hypoxia per se is an unusual cause of axonal injury

Irreversible hypoxic brain damage and axonal injury are present in over 90% of fatal blunt head injuries. Given the frequency of each, difficulties arise as to whether or not they are due to different mechanisms and, as such, can be separately recognised and quantified. Recent literature has raised the possible role of hypoxia in the formation of axonal bulbs. The present study of 17 cases of cardio-respiratory arrest, 12 of status epilepticus, 3 of carbon monoxide poisoning and 12 controls was designed to test the relationship between hypoxia and axonal injury and to test the hypothesis whether or not the two entities can be separated into primary and secondary forms of traumatic brain injury. Axonal damage was seen in 9/17 and 7/12 of the cases with cardiac arrest and status epilepticus, respectively, in most of whom there was also evidence of raised intracranial pressure (ICP). All 3 cases of carbon monoxide poisoning had evidence of white matter damage in keeping with the classical pattern of selective vulnerability. It is concluded that the great majority of axonal damage identified in cases dying after cardiac arrest and status epilepticus can be attributed to raised ICP and the vascular complications of internal herniation. However, in some cases, axonal damage was seen in the absence of an elevated ICP, although its amount and distribution were different from diffuse axonal injury. In many cases there was an increase in expression of neuronal β amyloid precursor protein. Received: 25 November 1999 / Revised: 27 Janury 2000 / Accepted: 3 February 2000     

实验性脑积水轴索细胞骨架的变化

目的探讨脑积水中轴索损伤的发展变化规律.方法以枕大池穿刺注射白陶土的方法建立犬脑积水模型,分为3 d组、2周组、8周组及对照组,每组5只.通过免疫组化方法观察半球白质内轴索的形态变化,并使用电脑图像分析系统定量测定轴索细胞骨架的结构亚单位微管相关蛋白-2(MAP-2)和神经微丝(NF)蛋白亚单位含量.结果①轴索随脑积水发展相继出现扭曲、肿胀、断裂以及轴索球形成等形态学改变;②3 d组MAP-2含量与对照组相比无显著差异(P>0.05),NF蛋白有下降(P<0.05),在2周组和8周组,两者则进行性减少(P<0.05).结论脑积水中的轴索损伤是以细胞骨架破坏为起始的一个渐进过程,它在早期阶段是可逆的,通过综合治疗有望阻断这一过程.     

Hypoxia-like tissue injury as a component of multiple sclerosis lesions

Recent data suggest that the mechanisms of demyelination and tissue damage in multiple sclerosis (MS) are heterogenous. In this review, evidence is discussed, which show that in a subset of multiple sclerosis patients the central nervous system (CNS) lesions show profound similarities to tissue alterations found in acute white matter stroke, thus suggesting that a hypoxia-like metabolic injury is a pathogenetic component in a subset of inflammatory brain lesions. Both, vascular pathology as well as metabolic disturbances induced by toxins of activated macrophages and microglia may be responsible for such lesions in multiple sclerosis.     

犬脑积水后轴索损伤的神经微丝免疫组化研究

目的探讨脑积水后大脑半球白质内轴索损伤的特点及意义.方法20只成年雄性犬通过枕大池穿刺注射白陶土的方法建立脑积水模型,按处死时间分为3 d组、2周组、8周组及对照组,每组5只.观察实验犬的行为及神经功能,并通过神经微丝免疫组化染色研究大脑半球白质内轴索的变化,同时观察轴索骨架系统超微结构改变.结果各实验组实验犬均有不同程度的行为学改变,但明显的神经功能障碍仅出现于脑积水诱导8周后;白质内轴索在3 d组即有损害发生,并随病程进展而进行性加重,在3 d组和2周组限于脑室周围,8周组则范围扩大,累及皮层下区域.结论轴索损伤贯穿于脑积水的早中晚期,其损害程度和范围与神经功能障碍密切相关.     

Therapeutic action of cannabinoid on axonal injury induced by peroxynitrite

This study examined whether the potent cannabinoid HU210 ameliorates axonal injury through its indirect action to stimulate the secretion of corticosterone. We observed that HU210 dramatically reduced peroxynitrite-induced axonal injury in rats receiving adrenalectomy and corticosterone replacement treatment. These results suggest that the ameliorating effects of cannabinoids on axonal injury associated with multiple sclerosis are achieved by its direct action, but not by its indirect action to elevate the serum corticosterone levels.     

尼莫地平对实验性脑损伤的治疗作用

目的研究钙拮抗剂尼莫地平对实验性颅脑创伤的治疗作用及其机制.方法采用家兔落体致伤闭合性颅脑创伤模型,致伤后静脉给予尼莫地平治疗,于电子显微镜下观察脑组织超微结构变化;以干湿法测定脑组织含水量;荧光标记法测定神经细胞胞浆内游离Ca2+水平;经颅多普勒超声仪观察大脑中动脉血流速度变化;并结合颅内压监测综合评定尼莫地平对实验性颅脑创伤的治疗作用.结果尼莫地平治疗组家兔神经细胞胞浆内的游离Ca2+水平显著下降,脑组织毒性损害表现减轻,大脑中动脉痉挛得到改善,脑水肿程度减轻,但颅内压变化与未用药组相比差异无显著性意义(P＞0.05).结论尼莫地平可阻断脑损伤后神经细胞"钙超载"引起的一系列病理过程,解除脑血管痉挛,改善脑血流量,具有保护脑组织的作用.     

尼莫地平减轻蛛网膜下腔出血后脑损伤

目的 探讨尼莫地平对蛛网膜下腔出血(SAH)后脑损伤的防治作用。方法 用血管内穿刺法制作大鼠SAH模型。对SAH组和尼莫地平处理组观察24h内局部脑血流量(rCBF)和脑组织水、电解质含量的动态变化。结果 SAH后rCBF迅速降低，1h达最低值，24h内持续于低水平状态。SAH后6h、24h脑组织含水率和Na^ 含量明显增加，K^ 含量减低；脑组织Ca^2 含量在SAH后1h开始显著增加。尼莫地平对上述的指标均有改善作用。结论 尼莫地平可减轻实验性SAH后脑损伤。