视神经损伤后影响轴突再生的因素

中枢神经损伤后的再生问题一直是近年来研究的热点,视神经作为中枢神经的代表在中枢神经系统(CNS)损伤及再生的课题中得到了广泛而深入的研究。视神经损伤可导致严重的视力障碍,其病理基础是视网膜神经节细胞(retinal ganglion cells,RGCs)的损伤。损伤后视神经再生受诸多     

胰岛素在急性脊髓损伤修复中的作用

胰岛素及其受体广泛分布于中枢神经系统，胰岛素对维持神经元的存活，刺激神经元再生及神经元的突触分化和成熟，抑制损伤神经细胞的凋亡，以及脊髓损伤后神经元的恢复有重要意义。试验证明，外周胰岛素通过特殊途径进入中枢神经系统，在脊髓损伤中对神经细胞有明显的保护作用，这为脊髓损伤的治疗开辟了一个新的途径。     

睫状神经营养因子与生长相关蛋白- 43在视神经损伤修复中作用

<正>人类和其他成年哺乳动物的成熟中枢神经系统损伤后由于内在因素轴突很难再生,功能不可逆性丧失[1]。视神经作为中枢神经的一部分,由于解剖上     

Nogo-A及NgR在脑外伤大鼠脑组织中的表达

目的研究中枢神经系统损伤后Nogo-A及其受体Ng R在颅脑外伤大鼠脑组织中的表达变化。方法本课题采用SPF级SD大鼠100只,分为空白对照组(n=10)、假手术组(n=10)和损伤组(n=80)。对实验损伤组大鼠采用Feeney等自由落体撞击法制成急性中型脑外伤模型,损伤组随机分为1 d(n=16)、3 d(n=16)、5 d(n=16)、7 d(n=16)和10 d(n=16)5个组。用免疫组织化学的方法测定测量各组各时间点脑切片Nogo-A及Ng R蛋白的表达。结果颅脑创伤后1 d时创伤灶边缘脑组织中Nogo-A表达显著升高,伤后3 d Nogo-A表达有所下降,但仍高于假手术组(P<0.05),到伤后7 d Nogo-A表达又上升达到高峰,直至伤10 d,Nogo-A表达仍维持在较高的水平。创伤组Nogo-A表达均显著高于假手术组(P<0.05)。颅脑创伤后1天时创伤灶边缘脑组织中Ng R呈基础表达,与假手术组比较差别无统计学意义(P>0.05)。创伤后3 d Ng R表达较假手术组明显升高(P<0.05),在伤后7 d达到高峰值,直至伤后10 d Ng R表达仍处于峰值。结论颅脑创伤后Nogo-A呈双峰的表达规律,Nogo-A在创伤后急性期可能参与颅脑创伤的急性病理过程,在创伤修复期发挥抑制神经再生的作用,为开辟颅脑创伤救治的新方法提供依据。Ng R在颅脑创伤的恢复期显著升高,峰值持续时间长,Ng R介导颅脑创伤后神经再生的抑制,阻碍神经功能的恢复,为探寻颅脑创伤后神经功能恢复的治疗方法指出新的方向,提供实验依据。     

促进中枢神经损伤再生的探索之路

成年哺乳动物的绝大多数组织(如皮肤、肌肉、肝脏和周围神经等)，损伤后均具有显著的自我修复能力。周围神经离断后，近侧段神经内的轴突再生，穿越损伤区进入远侧段神经内并长距离生长，重新与靶组织建立突触联系，恢复丧失的功能。而中枢神经损伤后仅有最终流产的短暂性发芽，并因轴突的损伤而时常导致神经元的死亡。中枢神经系统损伤后缺乏再生修复的能力，使得脑、脊髓和视神经的损伤和病变总是造成患者的终身残疾，也使得，临床至今并无特效药物可以治愈中枢神经系统的损伤和疾患。     

髓鞘抑制因子及其受体研究进展

高等脊椎动物中枢神经系统(CNS)中的轴突损伤后通常难以再生,这是脑和脊髓永久性损伤的主要原因,也是长久以来的世界性难题[1,2]。中枢神经再生困难的原因非常复杂,其中最主要的是神经元受CNS环境的抑制,尤其是CNS髓磷脂所含的抑制因子和胶质疤痕的限制[3]。目前已确认的中枢神     

视神经损伤后促再生因素的研究进展

中枢神经系统损伤后的再生问题一直是医学研究的难点和热点问题,视神经作为中枢神经系统的一部分,由于其特殊的生理特性而成为中枢神经系统的代表.故探讨视神经损伤后的再生问题,不仅对视功能的恢复也对中枢神经系统疾病的治疗和中枢神经系统损伤后功能的恢复有着重要意义.纵观近年来对视神经损伤后促进再生因素的研究可分为三大方面:药物治疗、基因治疗、手术治疗.     

梓醇对局灶性脑缺血大鼠感觉运动皮质轴突再生限制性微环境的影响

目的观察梓醇对大鼠局灶性脑缺血后对侧感觉运动皮质轴突再生限制性微环境的影响。方法 SD大鼠42只,随机分为假手术组、模型组、生理盐水组、梓醇低、中、高剂量治疗组(剂量分别为1、5、10 mg.kg-1)和胞磷胆碱(剂量为0.5 g.kg-1)对照组。制备局灶永久性脑缺血模型,造模后24 h,首次经腹腔注射梓醇进行干预,每天1次,连续7 d。于造模后15 d断头取脑,制备脑片和脑组织匀浆,采用免疫荧光组织化学染色和Western blot检测对侧感觉运动皮质Nogo-A及其受体NgR蛋白表达。结果 Nogo-A阳性细胞被Cy3标记,胞质和突起呈红色,细胞核未见红色荧光。假手术组可见少量Nogo-A阳性细胞,模型组Nogo-A阳性细胞数较假手术组明显增加(P<0.05);梓醇中、高剂量组Nogo-A阳性细胞数较模型组和胞磷胆碱组明显减少(P<0.05)。NgR阳性细胞被FITC标记,具有神经元形态特征,胞质和突起呈绿色,细胞核未见绿色荧光。假手术组可见少量NgR阳性细胞,模型组NgR阳性细胞较假手术组稍增加(P>0.05);梓醇呈剂量依赖性下调NgR表达,中、高剂量组NgR阳性细胞数均比模型组和胞磷胆碱组明显减少(P<0.05)。Western blot分析与免疫荧光原位检测结果一致。结论梓醇下调脑缺血大鼠感觉运动皮质Nogo-A及其受体NgR蛋白表达,有助于改善轴突再生限制性微环境。     

红景天苷对大鼠局灶性脑缺血/再灌注损伤的神经保护作用

目的探讨红景天苷(salidroside,Sal)对大鼠局灶性脑缺血/再灌注损伤的神经保护作用及其机制。方法健康成年♂SD大鼠36只,随机分为3组:假手术组(sham)、模型对照组(MCAO组)、红景天苷给药组(MCAO+Sal组)。通过线栓法制作大鼠局灶性脑缺血/再灌注损伤模型,Longa评分法对大鼠神经功能损伤评分,焦油紫染色法对神经细胞内尼氏(Nissl)小体染色,RT-q PCR技术检测大鼠缺血侧脑组织Neun、Nogo-A与Ng R m RNA的表达,Western blot法检测大鼠缺血侧脑组织Bcl-2、Neun、BDNF、NGF、Nogo-A与Ng R蛋白的表达。结果与MCAO组比较,红景天苷能明显降低神经功能损伤,增加Nissl阳性细胞的数量,促进Bcl-2、Neun、NGF、BDNF的蛋白表达,降低Nogo-A及其受体Ng R的m RNA及蛋白表达。结论红景天苷能够降低MCAO模型大鼠神经功能损伤,增加Nissl阳性细胞数目,提高Neun的表达,具有神经保护作用,此作用是通过促进抗凋亡因子Bcl-2及神经营养因子NGF、BDNF的蛋白表达,下调轴突生长抑制因子Nogo-A及其受体Ng R的蛋白表达所实现。     

脐血干细胞移植治疗脑卒中的作用机制

<正>脑卒中后形成的瘢痕组织会阻碍神经元的再生,而且神经纤维组织的变性、坏死以及中枢神经系统内微环境的改变等会妨碍神经系统的恢复,从而形成各种后遗症,主要临床表现为:一侧肢体瘫痪或感觉障碍;意识、认知、语言、记忆力、排尿排便、性功能等障碍;肌肉不同程度的萎缩等。过去,脑卒中属于难治性疾病,因为中枢神经被认为是无再生能力的,损坏的神经是不可修复和再生的,但是近年来经临床实验研究发现,损伤的神经轴突在周围环境改变后会产生再生能力从而恢复部     

Rho-ROCK inhibitors as emerging strategies to promote nerve regeneration

Several myelin-associated proteins in the central nervous system (CNS) have been identified as inhibitors of axonal regeneration following the injury of the adult vertebrate CNS. Among these inhibitors, myelin-associated glycoprotein (MAG), Nogo, and oligodendrocyte-myelin glycoprotein (OMgp) are well characterized. Recently, the repulsive guidance molecule (RGM) was included as a potent myelin-derived neurite outgrowth inhibitor in vitro and in vivo. The discovery of the receptors and downstream signals of these inhibitors enabled further understanding of the mechanism underlying the failure of axonal regeneration. The activation of RhoA and its effector Rho kinases (ROCK) after the ligation of these inhibitors to the corresponding receptors has been shown to be a key element for axonal growth inhibition. Blockade of the Rho-ROCK pathway reverses the inhibitory effects of these inhibitors in vitro and promotes axonal regeneration in vivo. Therefore, the Rho-ROCK inhibitors have a therapeutic potential against injuries to the human CNS, such as spinal cord injuries.     

Targeting neurite growth inhibitors to induce CNS regeneration

Prominent among the several endogenous inhibitors known to limit recovery and plasticity after CNS injury are Nogo (neurite outgrowth inhibitor) and MAG (myelin associated glycoprotein). The effects of these inhibitors on axonal regeneration can be reduced by administration of specific antagonists, some of which are commercially available for experimental investigation. There are three aspects of therapeutic manipulations: targeting the inhibitory proteins, antagonizing the known receptor, and inhibiting the intracellular signal transduction of these inhibitory molecules. Infusion of an antibody against Nogo improves behavioral deficits and enhances corticospinal tract regeneration in animals after stroke and spinal cord injury (SCI). Similarly, peripheral injection of a mouse monoclonal antibody directed against MAG results in dramatic preferential motor reinnervation in mice after transection of the femoral nerve, indicating that interference with the repellant function of MAG facilitates reinnervation of correct pathways by motor neurons. Further, antagonism of the Nogo receptor by the peptide NEP 1-40 (Nogo extracellular peptide residues 1-40) can promote axonal regeneration in rats after SCI. Blockade of signal transduction also can be effective. The p75 neurotrophin receptor probably represents the signaling part of the receptor complex for neurite growth inhibitors. There is evidence in vitro that the inhibitory actions of MAG and myelin are blocked if neurons are primed with a variety of neurotrophins. Thus, there are several therapeutic approaches to overcome the actions of endogenous neurite growth inhibitors so as to promote CNS regeneration.     

The Nogo66 receptor pathway and CNS axon regeneration: new hopes for treating CNS injuries and neurodegeneration

The neuronal leucine-rich repeat Nogo66 receptor (NgR) interacts with the myelin proteins Nogo66, myelin associated glycoprotein and oligodendrocyte myelin glycoprotein to inhibit axon growth. Modulation of these cell surface NgR-dependent interactions or the inhibitory intracellular signalling pathways may promote axon growth in the CNS after injury and present an attractive axon regeneration platform for treating CNS injuries or even neurodegenerative disorders. Multiple NgR antagonism approaches, including soluble NgR proteins, anti-NgR antibodies, a Nogo-derived antagonist peptide and NgR signal transduction modulators, have demonstrated striking efficacies in promoting functional recoveries in animal models of spinal cord injury, stroke and multiple sclerosis. This review summarises the neurobiology of the NgR pathway and the various drug discovery strategies that are specifically based on modulation of the myelin–NgR interaction.     

CNS regeneration after chronic injury using a self-assembled nanomaterial and MEMRI for real-time in vivo monitoring

To speed up the process of central nervous system (CNS) recovery after injury, the need for real-time measurement of axon regeneration in vivo is essential to assess the extent of injury, as well as the optimal timing and delivery of therapeutics and rehabilitation. It was necessary to develop a chronic animal model with an in vivo measurement technique to provide a real-time monitoring and feedback system. Using the framework of the 4 P's of CNS regeneration (Preserve, Permit, Promote and Plasticity) as a guide, combined with noninvasive manganese-enhanced magnetic resonance imaging (MEMRI), we show a successful chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. We also show that a chronic optic tract (OT) lesion is able to heal, and axons are able to regenerate, when treated with a self-assembling nanofiber peptide scaffold (SAPNS). FROM THE CLINICAL EDITOR: The authors of this study demonstrate the development of a chronic injury model to measure CNS regeneration, combined with an in vivo measurement system to provide real-time feedback during every stage of the regeneration process. In addition, they determined that chronic optic tract lesions are able to heal with axonal regeneration when treated with a self-assembling nanofiber peptide scaffold (SAPNS).     

Eph/ephrin signaling as a potential therapeutic target after central nervous system injury

Recent work indicates that the expression of Eph and ephrin proteins is upregulated after injury in the central nervous system (CNS). Although to date, much of the interest in these protein families in the nervous system has been on their roles during development, their presence in the adult CNS at multiple time points after injury suggest that they play significant roles in key aspects of the nervous system's response to damage. Several fundamental features of Eph and ephrin biology, such as bidirectional signaling, promiscuity of ligand-receptor binding, and potential cis regulation of function, present challenges for the formulation of rational and effective Eph/ephrin based strategies for CNS axon regeneration. However, recent work that have identified specific functions for individual Ephs and ephrins in injury-induced phenomena such as axon sprouting, cellular remodeling, and scar formation has begun to tease apart their contributions and may provide a number of potential entry points for beneficial therapeutic intervention.     

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.     

Role of PACAP in neural stem/progenitor cell and astrocyte--from neural development to neural repair

After central nervous system (CNS) injury, reactive astrocytes display opposing functions, inducing neural repair and axonal regeneration via the release of growth factors, or forming a glial scar which acts as a barrier to axonal regeneration. Endogenous neural stem/progenitor cells have also recently been identified at the site of CNS injury, where they have been shown to differentiate into mature neurons in an animal model of ischemia. However, the pathophysiological mechanisms underpinning the contribution of reactive astrocytes and neural stem/progenitor cells to neural repair are still to be fully elucidated. Pituitary adenylate cyclase activating polypeptide (PACAP) is widely expressed in the CNS, where it has been shown to exert numerous biological effects. This review will summarize the current state of knowledge regarding the expression of PACAP and its receptors during neural development, as well as the involvement of PACAP in astrocytes and neural stem/progenitor cell biology. In addition, we will also discuss emerging evidence that implicates PACAP in neurogenesis and neural repair in response to brain pathophysiology.     

Therapeutic vaccination for central nervous system repair

1. Vaccination against infectious agents has been heralded as a triumph in modern medicine and, more recently, cancer vaccines have risen in prominence. The present review looks towards the use of vaccine therapy to attenuate damage after injury to the central nervous system (CNS). 2. Significant debility is associated with brain injury, most commonly occurring as a result of physical trauma or stroke. This end result reflects the inability of neurons and axons to regenerate following injury to the CNS. This unconductive environment is due, in large part, to the presence of myelin and oligodendrocyte-related inhibitors of neurite outgrowth. 3. We review how a vaccine-based approach has been variably used to circumvent this issue and promote axonal regeneration and repair following traumatic injury and other neurodegenerative disorders. In addition, emerging evidence suggests that the immune response to injury in the CNS may be manipulated so as to reduce cellular damage. Vaccine-directed approaches using this concept are also outlined.     

Cross-talk between adenosine and opioid receptors

Opioid and adenosine receptors are implicated in numerous physiological and pathophysiological states. Moreover, both G-protein-coupled receptor families have been demonstrated to provide significant protection against ischemic injury in the myocardium and central nervous system (CNS). Much recent data report a tight interaction between these two receptor families, from alterations in receptor sensitivity to release of endogenous adenosine in the presence of morphine. Indeed, it appears that the cardioprotective effects of adenosine can be abolished by opioid receptor antagonists and vice-versa. This review aims to highlight some of the research, derived from both the CNS and myocardium, supporting this interesting interaction.