神经元内抑制神经再生的相关信号通路

神经损伤及其修复是当今医学界的研究热点和难点,以往的研究主要集中于关注如何改善神经元再生的局部微环境。近年来越来越多的研究显示,成年后的神经元本身再生能力低下是神经再生困难的核心原因。现已知神经元内部有多个信号通路对神经再生具有抑制作用,充分理解这些信号通路对于今后通过提高神经元自身的再生能力,从而促进神经修复具有重要意义。为此,通过文献复习,对神经元内部与抑制神经再生有关的信号通路进行了综述。     

脊髓损伤再生研究进展——搭建脊髓损伤修复的希望之桥

脊髓损伤是一种严重的神经损伤,脊髓损伤后在局部形成抑制神经再生的微环境,使得神经再生尤为困难.改革开放以来尤其是近20年,随着再生医学的发展,在中国科学院战略性先导科技专项、科技部重点研发计划以及国家自然科学基金委员会重点项目等支持下,我国在脊髓损伤后再生微环境的重建、脊髓损伤再生修复机制研究和临床转化研究等方面取得了显著进步.研制了具有自主知识产权的神经支架材料,建立了支架材料与再生因子或干细胞特异结合的功能生物材料制备技术;并通过移植重建有利于神经再生的微环境,建立了大段缺损的全横断脊髓损伤模型,提出神经桥接是功能生物材料促进完全性脊髓损伤动物运动恢复的主要机制;在国际上率先开展了支架材料结合细胞引导完全性脊髓损伤再生修复的临床研究,使得我国脊髓损伤再生修复的临床转化研究走在了世界前列.在国家政策的大力支持下,脊髓损伤再生修复系列产品必将填补市场空白,造福患者.     

周围神经再生过程中靶器官的诱向性作用机制

以细胞培养技术与自然凝胶电泳系统方法证明,在周围神经再生过程中,损伤的坐骨神经远侧端,即起衍生的靶器官诱导神经突起的定向生长。分析探讨与神经诱向性再生相关的活性因子,其结果提示在远侧端神经组织中出现的90kDa蛋白组分具有很强的诱向性作用,诱导神经突起在神经再生过程中能够准确地到达靶器官。由此说明雪旺细胞在神经再生过程中扮演着重要角色。     

侧脑室室管膜下区神经再生的研究进展

神经再生(Neurogenesis)是指具有自我更新能力的神经干细胞(Neural Stem Cells,NSCs)经过迁移、增殖,最终分化为具有特定功能的神经细胞的过程。以往人们认为,神经再生只存在于胚胎期或外周神经系统,近几年发现,在成年动物的中枢神经系统也存在神经再生,研究发现侧脑室室管膜下区(SVZ)是神经再生发生的主要区域之一,产生新的神经元和神经胶质细胞通过RMS通路运输至嗅球进而对嗅觉损伤部分进行修复。本文主要从成年神经再生的发展、神经再生与疾病的关系、神经再生的过程等方面进行综述。     

以髓磷脂相关抑制因子及其受体为靶点的脊髓损伤免疫治疗策略研究

脊髓损伤(spinal cord injury,SCI)往往导致患者下肢活动功能受限,甚至瘫痪,降低患者生活质量,且治愈率低。髓磷脂相关抑制因子(myelin associated inhibitors,MAIs)是抑制受损中枢神经系统(central nervous system,CNS)再生修复的一个重要因素。对MAIs及其信号通路的干扰能有效逆转CNS神经再生抑制信号,促进脊髓损伤后轴突的再生。MAIs抑制轴突再生信号通路的发现及其深入研究为损伤脊髓的免疫治疗提供了充分的理论依据和研究靶点。将对抑制神经再生信号通路中MAIs及其受体的生物学功能新进展以及以此为治疗靶点设计的脊髓损伤免疫治疗策略作一综述。     

周围神经或其组织成分移植修复成年哺乳动物视网膜节细胞的损伤

本综述重点阐述了移植周围神经或其组织成分雪旺细胞、成纤维细胞和神经营养因子,改善成年哺乳动物中枢神经系统抑制神经再生的微环境、增强受损神经元的内在再生潜力,以促进细胞损伤后的存活和轴突再生。     

鹿茸再生相关蛋白研究进展

鹿茸是迄今为止发现的唯一能够周期性再生的哺乳动物器官,它的生长速度极快却没有发生癌变。而蛋白质是生命活动的体现者,是生命活动的功能执行者,鹿茸相关蛋白的研究是揭开鹿茸再生秘密的重要途径。综述了鹿茸再生相关蛋白的筛选、血管生成相关蛋白、软骨形成相关蛋白、神经再生相关蛋白以及其他与鹿茸再生相关蛋白的研究进展,旨在为从蛋白质水平上揭示鹿茸再生过程提供基础资料。     

再生神经中微管,神经丝与轴突截面积的变化

用电镜及图象分析的方法研究了再生轴突中微管、神经丝与轴突截面积的变化,发现神经再生过程中微管及神经丝的密度增加,并与轴突截面积呈相关关系,而且微管的变化更早,更明显。由于微管参与了轴浆转运的机制,微管的增加提示其在神经再生中起了重要的作用。     

诱导神经再生治疗阿尔茨海默病的机制研究进展

阿尔茨海默病(Alzheimer’s disease,AD)是一种以进行性认知障碍和记忆减退为主要特征的中枢神经退行性疾病,已经成为老年医学中最棘手的、亟待解决的问题之一. AD的病理机制仍不清楚,尚无特效治疗药物.目前,探索AD神经再生逐渐成为研究的热点领域,通过诱导神经再生可以有效地改善AD的症状.研究表明,运用药物、物理刺激或干细胞移植方法,可以提高大脑成体神经再生,是延缓AD的病理症状和认知障碍的有效治疗策略.本文综述诱导神经再生的方法及其治疗AD的作用机制,为神经再生治疗实施提供理论依据.     

中枢神经原位再生技术及其治疗前景

中枢神经再生长期以来一直是成年哺乳类动物大脑损伤或者发生退行性病变后悬而未决的世界性难题.在过去的数十年里,干细胞疗法在神经再生领域取得了一系列成果,同时也遇到了重大挑战.近些年兴起的中枢神经原位再生技术利用内源性的胶质细胞可以自我分裂再生的特点,通过表达神经转录因子或其他方法将胶质细胞原位转化为功能性神经元,避免了建立体外干细胞库的高成本和外源细胞移植的问题.本文总结了目前国内外运用体内胶质细胞进行原位神经再生的前沿进展,着重介绍了中枢神经原位再生技术在治疗重大脑疾病,包括脑卒中、阿尔茨海默症、帕金森病、亨廷顿舞蹈症以及视觉系统疾病和脊髓损伤等方面的潜在应用前景.虽然该技术还处在摇篮阶段,并且像任何新技术一样都有它自身的局限性,但是本团队在灵长类脑卒中模型上已经证明了中枢神经原位再生的可行性,为将来进一步的临床研究开辟了一条新途径.     

PACAP facilitate the nerve regeneration factors in the facial nerve injury

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been reported as a strong neurotrophic factor in the various sites of nervous system. The facial nerve injury is one of the common problems in patients at the Otolaryngology since the nerve damage could occur easily due to the anatomical characteristics. Once it happens, the regeneration is little observed and functional recovery is poor. Thus, we investigated that PACAP might have some influence for regeneration after the facial nerve transaction in the guinea pig. PACAP treatment accelerated time for the appearance of compound muscle action potentials (CMAP) after the nerve transaction (first appeared at 1 versus 2 weeks in control) and shortened the latency at 4 weeks. The number of myelinated fibers increased at 4 weeks. Histochemical demonstration of GAP-43, a growth cone protein, was observed at the injury area at 2-4 days. PACAP increased the level of glial cell line-derived neurotrophic factor (GDNF), a neurotrophin, in facial target muscles at 1 day-4 weeks. These data indicated that PACAP promotes the regeneration factors and increases the possibility of functional recovery following the facial nerve injury.     

Aberrant cutaneous nerve of the thigh arising from the sciatic nerve in the human

An aberrant cutaneous nerve of the thigh arising from the peroneal portion of the human sciatic nerve or common peroneal nerve was observed in 9 cases (4.6% of sides). After giving a branch to the short head of the biceps femoris muscle and a branch to the knee joint, this cutaneous nerve reaches the subcutaneous tissue by passing between the short head of the biceps femoris and the vastus lateralis or by piercing through the biceps femoris. The authors presume that the cutaneous nerve shows the presence of the potential cutaneous nerve routes from the common peroneal nerve to the skin of the lateral aspect of the thigh.     

Adrenergic nerve fibers in the human fetal sciatic nerve.

The adrenergic innervation was studied in the human sciatic nerve at the gestational age of 16, 17, 18 and 21 weeks. Formaldehyde-induced catecholamine fluorescence, tyrosine hydroxylase (TH) and neuropeptide Y (NPY) peroxidase-antiperoxidase immunohistochemistry methods were used. At the gestational age of 16, 17 and 18 weeks no adrenergic or NPY-positive nerve fibers were seen. At 21 weeks both fluorescence microscopy and TH immunohistochemistry showed adrenergic nerve fibers around arterioles in the epiperineurium and single nerve fibers in the endoneurium not related to blood vessels. The number of adrenergic nerve fibers appeared to be higher in the sciatic than in the tibial segment of the nerve. At this age, as at earlier stages of gestation, no NPY-positive nerve fibers were seen either in the epiperineurium or in the endoneurium. The results suggest that adrenergic nerve fibers may be associated with the epiperineurial blood vessels in the human sciatic nerve, and that the innervation starts to develop between 18 and 21 weeks of gestational age.     

Target-specific nerve regeneration through a nerve guide in the rat

Nerve regeneration across a gap in peripheral nerve has been achieved through various nonneural nerve guides in both lower and primate species. This technique can only be useful if the regenerated nerve cable grows specifically to and reinnervates the appropriate distal target. In this study, the proximal peroneal fascicle of rat sciatic nerve was inserted into the proximal limb of a Y-shaped nerve guide. Distal peroneal and tibial fascicles were placed within the two distal limbs of the same Y. The proximal peroneal nerve grew preferentially by a 2:1 ratio to the appropriate distal peroneal fascicle suggesting that target-specific reinnervation is possible through a nerve guide.     

After-depolarization of the frog nerve and single nerve fiber

Experiments on frogs (Rana ridibunda) showed that, unlike in the whole nerve, prolonged after-depolarization and the associated phase of summation are absent in the single node of Ranvier of isolated nerve fibers. If, however, special measures are taken to prevent the stretching of the Ranvier node of single fibers, prolonged after-depolarization can be found in them. It is concluded that the absence of prolonged after-depolarization in single Ranvier nodes of nerve fibers isolated without additional precautions is the result of injury to the excitable membrane or to disturbance of the integrity of the ionic barrier surrounding it as a result of stretching of the fibers during dissection.     

Acetylcholinesterase activity of motor and sensory nerve fibers in the spinal nerve roots of the rat

Summary The histochemical and cytochemical distribution of acetylcholinesterase activity in the anterior and posterior spinal nerve roots and ganglia of the rat was demonstrated by the Karnovsky method using acetyl and butyrylthiocholine as substrates and eserine and DFP as inhibitors. Light and electron microscopic examination of transverse frozen sections enabled the simultaneous visualization of end product in relationship to the various fiber components of each nerve root. While the enzymatic activity of the anterior roots was consistantly observed in the large extrafusal and small intrafusal motor fibers a relatively greater amount of precipitate occurred in aggregates of myelinated and unmyelinated fibers believed to represent preganglionic sympathetic nerves. In contrast, no significant enzymatic activity could be demonstrated in the myelinated nerve fibers of the posterior root. In the sensory sytem, the limited enzymatic precipitate was largely restricted to the unmyelinated afferent fibers and to their small cell bodies in the dorsal root ganglia. The ultrastructural distribution of enzymatic activity was located in the granular endoplasmic reticulum and perinuclear spaces of the ganglion cells. Within peripheral nerves this end product occurred between the apposing axonal and Schwann cell membranes and along the membranous aspect of occasional axoplasmic vesicles of both myelinated and unmyelinated nerve fibers.This study was supported by grants NB 04161-04 and NB 04161-05 of the National Institute of Neurological Diseases and Blindness. — The author would like to thank MissMaria C. la Valle for her skillful technical assistance.