Retrograde axonal transport of an exogenous enzyme covalently linked to B-IIb fragment of tetanus toxin.

Attempt to replace enzymes in a number of fatal lysosomal storage disease involving the central nervous system have as yet been unsuccessful owing to the impermeability of the blood/brain barrier to macromolecules. In order to treat storage disease due to enzyme deficiencies, we investigated the feasibility of transporting an enzyme into the central nervous system without crossing the blood/brain barrier. Using the B-IIb fragment of tetanus toxin (because it is involved in recognition by the nerve-cell endings), retrograde axonal transport toward the spinal cord and trans-synaptic movement, and glucose oxidase as a marker, we demonstrated that a non-toxic enzyme-vector conjugate was taken up by axon terminals. After injection into the gastrocnemius muscle, the B-IIb-glucose oxidase conjugate was detected, both histologically and electrochemically, distally to a ligature on the sciatic nerve. Thus the B-IIb fragment could serve as a vector for glucose oxidase transport into the central nervous system. It was also verified that the transported enzyme retained its activity. Transport of this 150 kDa molecule by fragment B-IIb of tetanus toxin suggests that other enzymes of a lesser molecular mass may also be transported.     

Substrate deprivation therapy: a new hope for patients suffering from neuronopathic forms of inherited lysosomal storage diseases

Lysosomal storage diseases are a group of disorders caused by defects in enzymes responsible for degradation of particular compounds in lysosomes. In most cases, these diseases are fatal, and until recently no treatment was available. Introduction of enzyme replacement therapy was a breakthrough in the treatment of some of the diseases. However, while this therapy is effective in reduction of many somatic symptoms, its efficacy in the treatment of the central nervous system is negligible, if any, mainly because of problems with crossing the blood-brain-barrier by intravenously administered enzyme molecules. On the other hand, there are many lysosomal storage diseases in which the central nervous system is affected. Results of very recent studies indicate that in at least some cases, another type of therapy, called substrate deprivation therapy (or substrate reduction therapy) may be effective in the treatment of neuronopathic forms of lysosomal storage diseases. This therapy, based on inhibition of synthesis of the compounds that cannot be degraded in cells of the patients, has been shown to be effective in several animal models of various diseases, and recent reports demonstrate its efficacy in the treatment of patients suffering from Niemann-Pick C disease and Sanfilippo disease.     

Peripheral Nervous System Neuropathology and Progressive Sensory Impairments in a Mouse Model of Mucopolysaccharidosis IIIB

The lysosomal storage pathology in Mucopolysaccharidosis (MPS) IIIB manifests in cells of virtually all organs. However, it is the profound role of the neurological pathology that leads to morbidity and mortality in this disease, and has been the major challenge to developing therapies. To date, MPS IIIB neuropathologic and therapeutic studies have focused predominantly on changes in the central nervous system (CNS), especially in the brain, and little is known about the disease pathology in the peripheral nervous system (PNS). This study demonstrates characteristic lysosomal storage pathology in dorsal root ganglia affecting neurons, satellite cells (glia) and Schwann cells. Lysosomal storage lesions were also observed in the myoenteric plexus and submucosal plexus, involving enteric neurons with enteric glial activation. Further, MPS IIIB mice developed progressive impairments in sensory functions, with significantly reduced response to pain stimulation that became detectable at 4–5 months of age as the disease progressed. These data demonstrate that MPS IIIB neuropathology manifests not only in the entire CNS but also the PNS, likely affecting both afferent and efferent neural signal transduction. This study also suggests that therapeutic development for MPS IIIB may benefit from targeting the entire nervous system.     

Lipopolysaccharide-evoked activation of p38 and JNK leads to an increase in ICAM-1 expression in Schwann cells of sciatic nerves

Lipopolysaccharide is a major constituent of the outer membrane of Gram-negative bacteria. It activates monocytes and macrophages to produce cytokines such as tumor necrosis factor-alpha and interleukins IL-1beta and IL-6. These cytokines appear to be responsible for the neurotoxicity observed in peripheral nervous system inflammatory disease. It has been reported that, in the central nervous system, the expression level of intercellular adhesion molecule-1 (ICAM-1) was dramatically upregulated in response to LPS, as well as many inflammatory cytokines. ICAM-1 contributes to multiple processes seen in central nervous system inflammatory disease, for example migration of leukocytes to inflammatory sites, and adhesion of polymorphonuclear cells and monocytes to central nervous system cells. In the present study, we found that lipopolysacharide evoked ICAM-1 mRNA and protein expression early at 1 h post-injection, and the most significant increase was seen at 4 h. Immunofluorescence double-labeling suggested that most of the ICAM-1-positive staining was located in Schwann cells. Using Schwann cell cultures, we demonstrated that ICAM-1 expression in Schwann cells is regulated by mitogen-activated protein kinases, especially the p38 and stress-activated protein kinase/c-Jun N-terminal kinase pathways. Thus, it is thought that upregulation of ICAM-1 expression in Schwann cells may be important for host defenses after peripheral nervous system injury, and reducing the biosynthesis of ICAM-1 and other cytokines by blocking the cell signal pathway might provide a new strategy against inflammatory and immune reaction after peripheral nerve injury.     

Acyl-CoA dehydrogenase 9 (ACAD 9) is the long-chain acyl-CoA dehydrogenase in human embryonic and fetal brain

We recently reported the expression and activity of several fatty acid oxidation enzymes in human embryonic and fetal tissues including brain and spinal cord. Liver and heart showed expression of both very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) mRNA. However, while mRNA expression of LCHAD could be clearly detected in the retina and spinal cord, expression of VLCAD mRNA was low to undetectable in these tissues. Nevertheless, abundant acyl-CoA dehydrogenase (ACAD) activity was detected with palmitoyl-CoA as substrate in fetal central nervous tissue. These conflicting data suggested the presence of a different long-chain ACAD in human embryonic and fetal brain. In this study, using in situ hybridization as well as enzymatic studies, we identified acyl-CoA dehydrogenase 9 (ACAD 9) as the long-chain ACAD in human embryonic and fetal central nervous tissue. Until now, no clinical signs and symptoms of central nervous system involvement have been reported in VLCAD deficiency. A novel long-chain FAO defect, i.e., ACAD 9 deficiency with only central nervous system involvement, could, if not lethal during intra uterine development, easily escape proper diagnosis, since probably no classical signs and symptoms of FAO deficiency will be observed. Screening for ACAD 9 deficiency in patients with undefined neurological symptoms and/or impairment in neurological development of unknown origin is necessary to establish if ACAD 9 deficiency exists as a separate disease entity.     

中枢神经系统疾病治疗性抗体药物应用进展

单克隆抗体药物是一种新兴的治疗药物,具有高选择性,被用于多种疾病的治疗,如肿瘤、免疫疾病等,也可以用于中枢神经系统疾病,如阿尔茨海默病、帕金森病、中风和脑肿瘤等。然而,因为血脑屏障低通透性,限制了抗体药物在中枢神经系统疾病治疗中的应用,在很多神经系统疾病临床试验中,抗体药物并没有取得预期效果。如今,人们利用血脑屏障上内源性转运蛋白介导,设计了可以通过血脑屏障的抗体药物。对通过血脑屏障治疗性抗体药物研发进展及其应用前景进行了综述。     

Castleman's disease, plasma-cell type. Diagnosis of central nervous system involvement by cerebrospinal fluid cytology

A case of Castleman's disease of the plasma-cell type is reported in which central nervous system (CNS) involvement was diagnosed by cerebrospinal fluid (CSF) cytology. The patient had multicentric disease with constitutional symptoms, immunologic abnormalities and peripheral blood cytopenias requiring cytotoxic agents and steroids for treatment. CNS symptoms and diagnostic cytologic findings in CSF occurred in the absence of morphologic lesions demonstrable by computed tomography or magnetic resonance imaging of the brain.     

脑脊液蛋白质组技术及临床应用研究进展

脑脊液(CSF)围绕并支持中枢神经系统(CNS),包括脑室和蛛网膜下腔,由于脑脊液与中枢神经系统直接接触,所以其是寻找中枢神经系统疾病生物标记物的重要来源。国内外学者开展了大量CSF蛋白质组学的研究工作,并取得了较大进展。文中综述了近年来CSF蛋白质组学技术及临床应用研究进展。     

Adverse reactions to drugs in general practice.

Of 817 patients in a general-practice survey of adverse reactions to drugs, 41% were thought to have "certainly" or "probably" had a reaction to the drug prescribed. Adverse effects on the gastrointestinal and central nervous systems were the most frequently reported, and 90% of reactions had occurred by the fourth day of treatment. More patients given drugs acting on the central nervous system and antihistamines reported reactions than those in other categories. A higher incidence of adverse drug effects is shown in this general-practice survey than in other, mainly hospital-based, surveys. Further intensive surveillance for adverse effects of drugs is recommended to provide additional information on the burden of drug-induced disease in the community.     

新型冠状病毒与系统损伤研究

自2019年12月全国及世界范围爆发了新型冠状病毒性肺炎(corona virus disease 2019,COVID-19),给中国和全球公共卫生安全带来了极大的挑战.研究发现,新型冠状病毒(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)不仅损...     

BOMT (6 alpha-bromo-17 beta-hydroxy-17 alpha-methyl-4-oxa-5 alpha-androstan-3-one) is not an androgen antagonist within the central nervous system.

This study investigates the efficiency of BOMT as an androgen antagonist within the central nervous system. The efficiency of BOMT in suppressing neural receptor binding of testosterone, and the ability of this antiandrogen to block the feedback loop of testosterone onto the central nervous system, as evidenced by plasma testosterone levels, is reported. BOMT was found to be unable to open the feedback loop of testosterone onto the central nervous system, which was correlated with the low competing efficiency of this antiandrogen for receptor sites in vitro within the hypothalamic-preoptic area of the brain - a region known to be involved in gonadotrophin secretion. The observed divergence in the degree of antiandrogenicity of BOMT between peripheral and central target tissues of testosterone is discussed.     

B-lymphocyte requirement for vaccine-mediated protection from Theiler's murine encephalomyelitis virus-induced central nervous system disease.

The role of humoral immunity in the protection of vaccinated SJL/J mice from central nervous system disease induced by the DA strain (DAV) of Theiler's murine encephalomyelitis virus was investigated in B-cell-deficient mice. Mice were depleted of B cells by treatment with a mouse monoclonal antibody specific for immunoglobulin M. DAV-vaccinated, B-cell-deficient mice failed to clear viral infection and were no longer protected from Theiler's murine encephalomyelitis virus-mediated central nervous system disease. CD4+ T cells are required in this model of protection to provide help for the development of an antiviral antibody response in the central nervous system.     

重症显微镜下多血管炎1例报告并文献复习

目的:显微镜下多血管炎(microscopic polyangiitis,MPA)通常易侵犯肾脏,很少累及神经系统,而同时累及肺及中枢神经系统的重症病例较少见。本文旨在探讨重症显微镜下多血管炎(MPA)的临床表现、诊断与治疗,为临床提供借鉴。方法:回顾性分析重症显微镜下多血管炎(MPA)的文献资料,结合本中心病例,54岁女性,尿检异常6年,咳血3年因肾功能衰竭合并心衰入院。结合实验室检查及影像学改变,诊断为重症AASV,考虑MPA可能性大。结果:入院后即给予激素联合环磷酰胺冲击治疗,病情明显好转;3周后出现病情反复,再次激素冲击治疗,效果不如前。继而出现脑出血,病情进一步恶化,最终因肾、肺、脑等多器官功能衰竭于入院5周后死亡。结论:对MPA患者关键在于早发现早治疗;而对缓解重症MPA患者病情,激素联合环磷酰胺冲击治疗在初始阶段有效。     

Changes in Retinal Function and Morphology Are Early Clinical Signs of Disease in Cattle with Bovine Spongiform Encephalopathy

Bovine spongiform encephalopathy (BSE) belongs to a group of fatal, transmissible protein misfolding diseases known as transmissible spongiform encephalopathies (TSEs). All TSEs are caused by accumulation of misfolded prion protein (PrP^Sc) throughout the central nervous system (CNS), which results in neuronal loss and ultimately death. Like other protein misfolding diseases including Parkinson’s disease and Alzheimer’s disease, TSEs are generally not diagnosed until the onset of disease after the appearance of unequivocal clinical signs. As such, identification of the earliest clinical signs of disease may facilitate diagnosis. The retina is the most accessible part of the central nervous system, and retinal pathology in TSE affected animals has been previously reported. Here we describe antemortem changes in retinal function and morphology that are detectable in BSE inoculated animals several months (up to 11 months) prior to the appearance of any other signs of clinical disease. We also demonstrate that differences in the severity of these clinical signs reflect the amount of PrP^Sc accumulation in the retina and the resulting inflammatory response of the tissue. These results are the earliest reported clinical signs associated with TSE infection and provide a basis for understanding the pathology and evaluating therapeutic interventions.     

In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice

Metachromatic leukodystrophy (MLD) is a lipidosis caused by deficiency of arylsulfatase A (ARSA). Although the genetics of MLD are known, its pathophysiology is not understood. The disease leads to progressive demyelination and early death and no effective treatment is available. We used lentiviral vectors to deliver a functional ARSA gene (human ARSA) into the brain of adult mice with germ-line inactivation of the mouse gene encoding ARSA, As2. We report sustained expression of active enzyme throughout a large portion of the brain, with long-term protection from development of neuropathology and hippocampal-related learning impairments. We show that selective degeneration of hippocampal neurons is a central step in disease pathogenesis, and provide evidence that in vivo transfer of ARSA by lentiviral vectors reverts the disease phenotype in all investigated areas. Therefore, in vivo gene therapy offers a unique option for MLD and other storage diseases affecting the central nervous system.     

Central nervous system regulation of adipocyte metabolism

The white adipose tissue was initially largely known only as an energy storage tissue. It is now well recognized that white adipose tissue is a major endocrine and secretory organ, which releases a wide range of protein signals and factors termed adipokines. The regulation of adipocyte metabolism is an important factor for the understanding of obesity, and some mechanisms are still unknown. Many homeostatic processes, including appetite and food intake, are controlled by neuroendocrine circuits involving the central nervous system. There is substantial evidence demonstrating that the central nervous system also directly regulates adipocyte metabolism. In this review, we discuss the central actions of some peptides with an important role in energy balance regulation on adipocyte metabolism and the physiological relevance of these actions.     

内源性硫化氢在中枢神经系统中的作用研究进展

硫化氢是继NO和CO之后发现的又一种新的气体信号分子,其被认为是一种神经递质,在中枢神经系统中起着重要的作用。内源性H2S主要由胱硫醚-β合酶(CBS)和胱硫醚γ-裂解酶(CSE)合成,其不仅可以直接作用于中枢神经系统发挥作用,还能通过抗氧化、调节神经内分泌及脑血管功能,进而间接影响中枢神经系统功能,具有广泛的生理作用。近年来,越来越多的研究发现内源性H2S在AD、热惊厥、PD、脑卒中、缺血再灌注脑损伤及遗传性疾病脑损害等神经系统疾病的发病过程中也起着重要作用。本文简要介绍H2S的生化和生理特点,并总结其在中枢神经系统中作用的进展。     

When clocks go bad: neurobehavioural consequences of disrupted circadian timing

Progress in unravelling the cellular and molecular basis of mammalian circadian regulation over the past decade has provided us with new avenues through which we can explore central nervous system disease. Deteriorations in measurable circadian output parameters, such as sleep/wake deficits and dysregulation of circulating hormone levels, are common features of most central nervous system disorders. At the core of the mammalian circadian system is a complex of molecular oscillations within the hypothalamic suprachiasmatic nucleus. These oscillations are modifiable by afferent signals from the environment, and integrated signals are subsequently conveyed to remote central neural circuits where specific output rhythms are regulated. Mutations in circadian genes in mice can disturb both molecular oscillations and measurable output rhythms. Moreover, systematic analysis of these mutants indicates that they can express an array of abnormal behavioural phenotypes that are intermediate signatures of central nervous system disorders. Furthermore, the response of these mutants to psychoactive drugs suggests that clock genes can modify a number of the brain’s critical neurotransmitter systems. This evidence has led to promising investigations into clock gene polymorphisms in psychiatric disease. Preliminary indications favour the systematic investigation of the contribution of circadian genes to central nervous system disease.     

Neurological effects of American trypanosomyiasis: clinical aspects

Trypanosoma cruzi, causative agent of Chagas disease, affects not only cardiac and intestinal structures but also neurological structures. A high prevalence of T. cruzi infection occurs in Colombia, prompting the present study. First, a qualitative metaanalysis was undertaken using the PubMed database, the electronic internet engine Altavista, Colombian journals indexed by Colciencias, and three relevant textbooks. The following key words were used: Trypanosoma, Chagas disease, nervous system, spinal cord, central nervous system, peripheral nervous system, neuromuscular junction, autonomic nervous system, muscle, muscle disorders, neuromuscular disease, neuromuscular disorders, synapticopathies and dysautonomia. The documents analyzed numbered 116 and included original papers, reviews, case reports, editorials, brief communications, conferences and book chapters. At minimum, each document included data involving ELISA testing, indirect immunofluorescense, or parasitemia levels in the clinical, serological or histopathological studies. Polymerase chain reaction (PCR) studies were not included because of the recent introduction of PCR as a confirmatory technique for Chagas disease in Colombia. Chagas disease affects the central, the peripheral and the autonomic nervous system in humans, although its effects on the antonomic system is most commonly investigated in Colombia. Neurological lesions must be evaluated carefully, because patients may be misdiagnosed and treated as carriers of 'idiopathic' diseases. Neurological pathologies poses a serious threat in Colombia due to the prevalence of Chagas disease.