甲基强的松龙对急性脊髓损伤的治疗效果与存在的问题

脊髓损伤的治疗是当今全球性医疗棘手问题。加强脊髓损伤的基础研究,进一步提高临床综合治疗水平,是目前我国脊髓损伤治疗研究首先要解决的问题。脊柱外科医生要充分认识外科治疗的有限性,应积极评价目前国际倡导的关于脊髓损伤“五步治疗”原则,特别是脊髓损伤早期的药物治疗,尽早地开展康复治疗。本期《专家论坛》及选登的有关脊髓损伤药物治疗的基础或临床研究,可能使我们对药物治疗的全面认识有所帮助。

Regulation of axonal regeneration following the central nervous system injury in adult mammalian

It has been well established that the recovery ability of central nervous system （CNS） is very poor in adult mammals. As a result, CNS trauma generally leads to severe and persistent functional deficits. Thus, the investigation in this field becomes a ＂hot spot＂. Up to date, accumulating evidence supports the hypothesis that the failure of CNS neurons to regenerate is not due to their intrinsic inability to grow new axons, but due to their growth state and due to lack of a permissive growth environment. Therefore, any successful approaches to facilitate the regeneration of injured CNS axons will likely include multiple steps： keeping neurons alive in a certain growth-state, preventing the formation of a glial scar, overcoming inhibitory molecules present in the myelin debris, and giving direction to the growing axons. This brief review focused on the recent progress in the neuron regeneration of CNS in adult mammals.

Roles of NF-κB in central nervous system damage and repair

NF-κB family is a kind of nuclear factors in B lymphocyte that can bind to the immunoglobulin κ-chain enhancer and enhance transcriptional activity. NF-κB/Rel proteins, as a dimeric transcription factor, control the expression of genes that regulate a broad range of biological processes through canonical and non-canonical pathways. In the central nervous system, NF-κB controls inflammatory reactions and the apoptotic cell death following nerve injury. It also contributes to the infarction and cell death in stroke models and patients. However, NF-κB is essential for neurosurvival as well. NF-κB activation is a part of recovery process that may protect neurons against oxidative-stresses or brain ischemia-induced apoptosis and neurodegeneration. Inhibition of NF-κB may reduce its neuroprotection activity. Hence the dual opposite effects of NF-κB on cells. The ultimate survival or death of neurons depends on which, where and when the NF-κB factors are activated.

Molecular actions guiding neural regeneration in planarian

Planarian is among the simplest animals that possess a centralized nervous system （CNS）, and its neural regenera- tion involves the replacement of cells lost to normal ＇wear and tear＇ （cell turnover）, and/or injury. In this review, we state and discuss the recent studies on molecular control of neural regeneration in planarians. The spatial and temporal expression patterns of genes in intact and regenerating planarian CNS have already been described relatively clearly. The bone morphogenetic protein （BMP） and Wnt signaling pathways are identified to regulate neural regeneration. During neural regeneration, conserved axon guidance mechanisms are necessary for proper wiring of the nervous system. In addition, apoptosis may play an important role in controlling cell numbers, eliminating unnecessary tissues or cells and remodeling the old tissues for regenerating CNS. The bilateral symmetry is established by determination of anterior-posterior （A-P） and dorsal-ventral （D-V） patterns. Moreover, neurons positive to dopamine, serotonin （5-HT）, and gamma-aminobutyric acid （GABA） have been detected in planarians. Therefore, planarians present us with new, experimentally accessible contexts to study the molecular actions guiding neural regeneration.

The role and the mechanism of γ-aminobutyric acid during central nervous system development

γ-aminobutyric acid （GABA） is an inhibitory neurotransmitter in adult mammalian central nervous system （CNS）. During CNS development, the role of GABA is switched from an excitatory transmitter to an inhibitory transmitter, which is caused by an inhibition of calcium influx into postsynaptic neuron derived from release of GABA. The switch is influenced by the neuronal chloride concentration. When the neuronal chloride concentration is at a high level, GABA acts as an excitatory neurotransmitter. When neuronal chloride concentration decreases to some degree, GABA acts as an inhibitory neurotransmitter. The neuronal chloride concentration is increased by Na^＋-K^＋-Cl^-Cl^- cotransporters 1 （NKCC 1）, and decreased by K^＋-Cl^- cotransporter 2 （KCC2）.

New technologies to investigate the brain-gut axis

Functional gastrointestinal disorders are commonly encountered in clinical practice, and pain is their commonest presenting symptom. In addition, patients with these disorders often demonstrate a heightened sensitivity to experimental visceral stimulation, termed visceral pain hypersensitivity that is likely to be important in their pathophysiology. Knowledge of how the brain processes sensory information from visceral structures is still in its infancy. However, our understanding has been propelled by technological imaging advances such as functional Magnetic Resonance Imaging, Positron Emission Tomography, Magnetoencephalography, and Electroencephalography （EEG）. Numerous human studies have non-invasively demonstrated the complexity involved in functional pain processing, and highlighted a number of subcortical and cortical regions involved. This review will focus on the neurophysiological pathways （primary afferents, spinal and supraspinal transmission）, brainimaging techniques and the influence of endogenous and psychological processes in healthy controls and patients suffering from functional gastrointestinal disorders. Special attention will be paid to the newer EEG source analysis techniques. Understanding the phenotypic differences that determine an individual＇s response to injurious stimuli could be the key to understanding why some patients develop pain and hyperalgesia in response to inflammation/injury while others do not. For future studies, an integrated approach is required incorporating an individual＇s psychological, autonomic, neuroendocrine, neurophysiological, and genetic profile to define phenotypic traits that may be at greater risk of developing sensitised states in response to gut inflammation or injury.

BCL-XL regulates TNF-α-mediated cell death independently of NF-κB, FLIP and IAPs

Upon activation, tumor necrosis factor alpha （TNF-α） receptor can engage apoptotic or survival pathways. Inhibition of macromolecular synthesis is known to sensitize cells to TNF-α-induced cell death. It is believed that this sensitization is due to the transcriptional blockade of genes regulated by NF-κB. Nevertheless, such evidence has remained elusive in the nervous system. Here, we show that TNF-α cannot normally induce apoptosis in PC12 cells or cortical neurons. However, cells treated with Actinomycin D （ActD） become susceptible to TNF-α-induced cell death through the activation of caspase-8, generation of tBid and activation of caspase-9 and -3. Analysis of several proteins involved in TNF-α receptor signaling showed no significant downregulation of NF-κB target genes, such as IAPs or FLIP, under such conditions. However, Bcl-XL protein levels, but not those of Bcl-2, Bax and Bak, are reduced by ActD or TNF-α/ ActD treatments. Moreover, Bcl-xL overexpression fully protects cells against TNF-α/ActD-induced cell death. When endogenous levels of Bcl-XL are specifically downregulated by lentiviral-based RNAi, cells no longer require ActD to be sensitive to TNF-α-triggered apoptosis. Furthermore, Bcl-xL downregulation does not affect TNF-α-mediated NF-κB activation. Altogether, our results demonstrate that Bcl-XL, and not Bci-2, FLIP or IAPs, acts as the endogenous regulator of neuronal resistance/sensitivity to TNF-α-induced apoptosis in an NF-κB-independent manner.

S100B protein in the gut:The evidence for enteroglial-sustained intestinal inflammation

Glial cells in the gut represent the morphological and functional equivalent of astrocytes and microglia in the central nervous system （CNS）. In recent years, the role of enteric glial cells （EGCs） has extended from that of simple nutritive support for enteric neurons to that of being pivotal participants in the regulation of inflammatory events in the gut. Similar to the CNS astrocytes, the EGCs physiologically express the SIOOB protein that exerts either trophic or toxic effects depending on its concentration in the extracellular milieu. In the CNS, SIOOB overexpression is responsible for the initiation of a gliotic reaction by the release of pro-inflammatory mediators, which may have a deleterious effect on neighboring cells. SlOOB-mediated pro-inflammatory effects are not limited to the brain： SIOOB overexpression is associated with the onset and maintenance of inflammation in the human gut too. In this review we describe the major features of EGCs and SIOOB protein occurring in intestinal inflammation deriving from such.

Central nervous system vasculitis and polyneuropathy as first manifestations of hepatitis C

Sensory or motor peripheral neuropathy may be observed in a significant proportion of hepatitis C virus (HCV)-infected patients.However,central nervous system (CNS) involvement is uncommon,especially in cryoglobulin-negative subjects.We describe a case of peripheral neuropathy combined with an ischemic CNS event as primary manifestations of chronic HCV infection without cryoglobulinemia.Significant improvement was observed after antiviral therapy.We discuss the spectrum of neurological manifestations of HCV infection and review the literature.

Construction of Free Amino Acids Composition Data Base for Food

Significant amounts of free amino acids exist in commercially sold vegetables and fruits. Despite of the fact, only a little information is available about the free amino acid contents in foods. To utilize information of free amino acids in food, we have carried out the experiments to quantitate the free amino acids by derivatized with NBD-F （4-fluoro-7-nitrobenzofurazan） and analyzed on reversed-phase UHPLC （ultra-high pressure liquid chromatography） equipped with ultraviolet visible detector. Almost all of food extracts contained free amino acids including GABA （T-amino butyrate）. Contents of free amino acids vary considerably depending upon vegetables and fruits. Principal free amino acids found in vegetables and fruits were asparagine, glutamine, arginine and GABA, which are involved in important metabolic pathways in human. About 140 species of vegetables and fruits were subjected for the data base. All of the plants and fruits we examined exhibit significant amount of free amino acids, those are clearly distinct from data bases obtained after acid hydrolysis treated food samples. Since glutamate and GABA act as excitatory and inhibitory neurotransmitters in CNS, respectively; free amino acids in vegetables and fruits that we eat daily, should be an important source for the cellular metabolic activities.

Current understanding on the pathogenesis of polyglutamine diseases

Polyglutamine （polyQ） diseases are a family of neurodegenerative disorders including Huntington’s disease, spinobulbar muscular atrophy,dentatorubral-pallidoluysian atrophy and several spinocerebellar ataxias.polyQ diseases are caused by abnormal expansion of CAG repeats in certain genes.The expanded CAG repeats are then translated into a series of abnormally expanded polyQ tracts.Such polyQ tracts may induce misfolding of the disease-causing proteins.The present review mainly focuses on the common characteristics of the pathogenesis of these polyQ diseases,including conformational transition of proteins and its influence on the function of these proteins,the correlation between decreased ability of proteoly-sis and late-onset polyQ diseases,and the relationship between wide expression of disease-causing proteins and selective neuronal death.

Mechanism of Integrative Body-Mind Training

Integrative Body-Mind Training（IBMT） originates from ancient Eastern tradition.The method stresses no effort to control thoughts,but instead a state of restful alertness that allows a high degree of awareness of the body,breathing,and external instructions.A series of studies indicates that IBMT improves attention and self-regulation through interaction between the central（brain） and the autonomic（body） nervous systems.The present review mainly summarizes the recent results of IBMT studies and proposes how it changes the state of brain and body to lead to positive outcomes.Future directions in this field are also discussed.

Research development of the pathogenesis pathways for neuroschistosomiasis

The infection of the central nervous system （CNS） by schistosome may or may not have clinical manifestations. When symptomatic, neuroschistosomiasis （NS） is one of the most severe presentations of schistosome infection. Among the NS symptoms, cerebral invasion is mostly caused by Schistosoma japonicum （S. japonicum）, and the spinal cord symptoms are mainly caused by S. mansoni or S. haematobium. There are 2 main pathways by which schistosomes cause NS： egg embolism and worm migration, via either artery or vein system, especially the valveless perivertebral Batson＇s plexus. The adult worm migrates anomalously through the above pathways to the CNS where they lay eggs. Due to the differences in species of schistosomes and stages of infection, mechanisms vary greatly. The portal hypertension with hepatosplenic schistosomiasis also plays an important role in the pathogenesis. Here the pathways through which NS occurs in the CNS were reviewed.

Treatment of multiple sclerosis by transplantation of neural stem cells derived from induced pluripotent stem cells

Multiple sclerosis(MS) is an autoimmune disease of the central nervous system(CNS), with focal T lymphocytic infiltration and damage of myelin and axons. The underlying mechanism of pathogenesis remains unclear and there are currently no effective treatments. The development of neural stem cell(NSC) transplantation provides a promising strategy to treat neurodegenerative disease. However, the limited availability of NSCs prevents their application in neural disease therapy. In this study, we generated NSCs from induced pluripotent stem cells(iPSCs) and transplanted these cells into mice with experimental autoimmune encephalomyelitis(EAE), a model of MS. The results showed that transplantation of iPSC-derived NSCs dramatically reduced T cell infiltration and ameliorated white matter damage in the treated EAE mice. Correspondingly, the disease symptom score was greatly decreased, and motor ability was dramatically rescued in the iPSC-NSC-treated EAE mice, indicating the effectiveness of using iPSC-NSCs to treat MS. Our study provides pre-clinical evidence to support the feasibility of treating MS by transplantation of iPSC-derived NSCs.

Human endogenous retrovirus W env increases nitric oxide production and enhances the migration ability of microglia by regulating the expression of inducible nitric oxide synthase

Human endogenous retrovirus W env(HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis(MS). These diseases are accompanied by immunological reactions in the central nervous system(CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter – nitric oxide(NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase(hi NOS) and enhanced the promoter activity of hi NOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases.

Liquid metal as reconnection agent for peripheral nerve injury

This study demonstrated an unconventional way to cure peripheral nerve injury(PNI) with liquid metal gallium employed as the reconnection agent. In vivo experiments were performed, in which transected sciatic nerve of mouse was reconnected by liquid metal gallium.The nerve signals detected was found to be almost the same as those from the complete nerve, where the negative bursting firing caused by PNI was absent on the neural discharge curve after nerve-reconnection surgery. Meanwhile the atrophy tendency of gastrocnemius muscle was distinctly procrastinated according to the results of pathological examinations, which showed fibrillation potentials emerged immediately for mice with PNI but did not emerge until the third month for those received nerve-reconnection surgery. Furthermore, physical properties of gallium were studied, showing that its impedance was slightly influenced by the frequency of transmitted signal and the temperature, which confirmed the stability of gallium in future clinical usage. This technology is expected to perform well in clinical surgery for PNI and even central nervous system injury in the coming time.

Foxn4:A multi-faceted transcriptional regulator of cell fates in vertebrate development

Vertebrate development culminates in the generation of proper proportions of a large variety of different cell types and subtypes essential for tissue,organ and system functions in the right place at the right time.Foxn4,a member of the forkhead box/winged-helix transcription factor superfamily,is expressed in mitotic progenitors and/or postmitotic precursors in both neural(e.g.,retina and spinal cord)and non-neural tissues(e.g.,atrioventricular canal and proximal airway).During development of the central nervous system,Foxn4 is required to specify the amacrine and horizontal cell fates from multipotent retinal progenitors while suppressing the alternative photoreceptor cell fates through activating Dll4-Notch signaling.Moreover,it activates Dll4-Notch signaling to drive commitment of p2 progenitors to the V2b and V2c interneuron fates during spinal cord neurogenesis.In development of non-neural tissues,Foxn4 plays an essential role in the specification of the atrioventricular canal and is indirectly required for patterning the distal airway during lung development.In this review,we highlight current understanding of the structure,expression and developmental functions of Foxn4 with an emphasis on its cell-autonomous and non-cell-autonomous roles in different tissues and animal model systems.

Identification of CNS neural circuitry involved in the innervation of C7 spinal nerve： a viral transsynaptic tracing study

Objective： Contralateral C7 spinal nerve transfer is a useful operation for the treatment of brachial plexus root avulsion. The recovery of the independent function at the ipsilateral side, however, depends on neural circuitry reorganization in the central nervous system （CNS）.This study tried to locate the CNS neuronal elements involved in the innervation ofC7 spinal nerve.Method： Pseudorabies virus （PRV, TK/gG-,2 μl）, which expressed green fluorescent protein （GFP）, was injected into the left C7 spinal nerve in 20 adult Sprague Dawley rats.After rats survived for 6 h, 12 h, 24 h and 36 h, the C1-C7segments of the spinal cord and brain were processed using a polyclonal immunohistochemical antibody against PRV.Results： PRV-labeled neurons were found mainly in gray matter of the C1-C7 segments of the spinal cord and at the following structures of the brain： lateral vestibular nucleus, lateral paragigantocellular nucleus, A5 cells, red nucleus, primary and secondary motor cortexes, primary and secondary somatosensory cortexes. Although located bilaterally, the PRV-labeled neurons existed predominantly in the ipsilateral side of the spinal cord and the contralateral side of the brain at 6-12 h after injection （p.i.）. The number of PRV-labeled neurons in the CNS was increasing with rat＇s survival time and the distribution of these neurons turned bilateral with no obvious dominance to either side at 24 h and 36 h （p.i.）.Conclusion： By use of transsynaptic tracing technique with PRV, the anatomically connected set of neurons,which modulates the activity of C7 spinal nerve, is located successfully in the CNS.