The role of macrophage subpopulations in autoimmune disease of the central nervous system

Summary In this review the role of various subpopulations of macrophages in the pathogenesis of experimental autoimmune encephalomyetitis is discussed. Immunohistochemistry with macrophage markers shows that in this disease different populations of macrophages (i.e. perivascular cells, microglia and infiltrating blood-borne macrophages) are present in the central nervous system. These subpopulations partially overlap in some functional activity while other activities seem to be restricted to a distinct subpopulation, indicating that these subpopulations have different roles in the pathogenesis of encephalomyelitis. The studies discussed in this review reveal that immunocytochemical and morphological studies, combined with new techniques such asin situ nick translation and experimental approaches like the use of bone marrow chimeras and macrophage depletion techniques, give valuable information about the types and functions of cells involved in central nervous system inflammation. The review is divided in three parts. In the first part the experimental autoimmune encephalomyelitis model is introduced. The second part gives an overview of the origin, morphology and functions of the various subpopulations. In the third part the role of these subpopulations is discussed in relation to the various stages (i.e. preclinical, clinical and recovery) of the experimental disease.     

Methods for analyzing neuronal structure and activity in Caenorhabditis elegans

The model research animal Caenorhabditis elegans has unique properties making it particularly advantageous for studies of the nervous system. The nervous system is composed of a stereotyped complement of neurons connected in a consistent manner. Here, we describe methods for studying nervous system structure and function. The transparency of the animal makes it possible to visualize and identify neurons in living animals with fluorescent probes. These methods have been recently enhanced for the efficient use of neuron-specific reporter genes. Because of its simple structure, for a number of years, C. elegans has been at the forefront of connectomic studies defining synaptic connectivity by electron microscopy. This field is burgeoning with new, more powerful techniques, and recommended up-to-date methods are here described that encourage the possibility of new work in C. elegans. Fluorescent probes for single synapses and synaptic connections have allowed verification of the EM reconstructions and for experimental approaches to synapse formation. Advances in microscopy and in fluorescent reporters sensitive to Ca²⁺ levels have opened the way to observing activity within single neurons across the entire nervous system.     

Irradiation potentiation of cellular transfer of EAE: time course and locus of effect in irradiated recipient Lewis rats.

Further studies of the potentiating effect of 500 rads total body irradiation on cellular transfer of experimental allergic encephalomyeliatis (EAE) in Lewis rats have revealed two findings bearing on underlying mechanisms. First, the effect is transitory, potentiation of disease being observed in recipients irradiated 1 or 4 days before transfer of syngeneic sensitized donor lymphoid cells but not among animals irradiated 7 or 14 days before cell transfer. Second, lead shielding selectively excluding the central neuraxis from irradiation results in relatively little augmentation of EAE compared to that observed in non-shielded irradiated animals. We believe irradiation potentiation of EAE results from transitory alterations in central nervous system target tissue rendering it more vulnerable to host immunologic attack.     

Central nervous system involvement in experimental Trypanosomiasis cruzi.

A review of the available literature on central nervous system involvement in experimental trypanosomiasis cruzi is undertaken. From a critical analysis of 26 works on experimental infections with Trypanosoma cruzi (23 on the acute phase, 2 on the chronic phase, and one describing sequentially both phases), all supported by neuropathologic studies, it can be concluded that: 1) central nervous system involvement during the acute phase, in the form of encephalitis in multiple foci, with variable intensity of the parasitism and inflammatory changes, is frequent and well documented; 2) in animals with more severe central nervous system involvement death occurs as a result of the brain lesions or acute chagasic myocarditis, the latter being always present; 3) in animals with more discrete brain involvement death during the acute phase is due to complications not related to the nervous system, among which congestive heart failure secondary to acute chagasic myocarditis, a condition that is always present, regardless of whether or not the central nervous system is infected; 4) it is possible that in surviving animals that had mild encephalitis the inflammatory changes from the acute phase usually regress as the infection progress to the chronic phase.     

Mesenchymal stem cells neuronal differentiation ability: a real perspective for nervous system repair?

Mesenchymal Stem Cells (MSCs) are a bone marrow-derived population present in adult tissues that possess the important property of dividing when called upon and of differentiating into specialized cells. The evidence that MSCs were able to transdifferentiate into specialized cells of tissues different from bone marrow, in particular into nervous cells, opened up the possibility of using MSCs to substitute damaged neurons, that are normally not replaced but lost, in order to repair the Nervous System. The first neuronal differentiation protocols were based on the use of a mixture of toxic drugs which induced MSCs to rapidly acquire a neuronal-like morphology with the expression of specific neuronal markers. However, many subsequent studies demonstrated that the morphological and molecular modifications of MSCs were probably due to a stress response, rather than to a real differentiation into neuronal cells, thus throwing into question the possible use of MSCs to repair the nervous system. Currently, some papers are suggesting again that it may be possible to induce neuronal differentiation of MSCs by using several differentiation protocols, and by accompanying the morphological evidence of differentiation with functional evidence, thus demonstrating that MSC-derived cells not only seem to be neurons, but that they also function like neurons. In this review, we have attempted to shed light on the capacity of MSCs to genuinely differentiate into nervous cells, and to identify the most reliable protocols for obtaining neurons from MSCs for nervous system repair.     

Sympathetic nervous system and bone adaptive response to its mechanical environment

While bone adaptive response to its mechanical environment was considered to be controlled locally by cytokines and systemic hormones, some recent work suggests that it could also be neuronally regulated. Bone is indeed very densely innervated and many experimental and clinical studies have previously shown the involvement of the nervous system in the control of bone metabolism. The demonstration that the central nervous system regulates bone mass via the sympathetic nervous system (SNS) has prompted recent studies aimed to investigate the role of the SNS in the bone mechano-adaptive response. This review will focus on this work and summarize the evidence for a contribution of the beta-adrenergic signalling in the response of bone cells to mechanical loading. The apparent conflicting results obtained in diverse experimental models of loading and unloading, at different skeletal sites, and in relation to various hormonal levels, will be discussed. While those studies do not support a major influence of the SNS on the bone mechano-adaptive response, there is nevertheless strong evidence that the SNS is part of a complex system which contributes to the metabolic regulation of bone.     

Glial cells more than support cells?

Glial cells are the most abundant cells in the human brain and have long been considered as passive supporting cells for neurons. In contrast to the extensive studies on various neuronal functions in the nervous system, we still have limited knowledge about glial cells. Recently a number of pioneering studies have provided convincing evidence that glia play active roles in development and function of the central nervous system. This review discusses recent advances in our understanding of the molecular mechanisms underlying glial cell differentiation. We then highlight some of the novel findings about glial function, i.e. the role of glia in synaptogenesis and the intricate relationship between astrocytes and adult neural stem cells. Finally, we summarize the emerging studies that implicate abnormalities in the formation or maintenance of glia leading to severe brain diseases, such as Alexander disease, glioblastoma and multiple sclerosis, and potential therapeutic strategies to tackle these diseases.     

中枢神经系统中的胃泌素释放肽：在厌恶性情绪记忆中的作用及机制研究

胃泌素释放肽(gastrin-releasing peptide,GRP)是蛙皮素(bombesin,BB/BN)在哺乳动物中的同系物,在中枢神经系统中广泛分布,是一种重要的脑内神经调质,参与动物的多种生理功能和本能行为,在大脑的高级功能方面也发挥一定的作用.在神经系统中,随着GRP水平的改变,动物的记忆特别是与恐惧、焦虑相关记忆的形成、巩固和消退以及突触可塑性均发生不同程度的变化.GRP及其受体还被认为与神经系统性疾病有关,是潜在的神经系统性疾病的治疗靶点,但其相关的机制尚未明确.很多研究者基于不同实验方法提出了相关假设.本文从传统药理学、遗传学和电生理学方面对GRP系统在厌恶性情绪驱动的记忆、突触可塑性变化以及在中枢神经系统中的作用机制进行综述,希望为进一步明确GRP系统在中枢神经系统中的作用研究提供新的思路.     

The antioxidant effect of Green Tea Mega EGCG against electromagnetic radiation-induced oxidative stress in the hippocampus and striatum of rats

Electromagnetic radiation (EMR) of cellular phones may affect biological systems by increasing free radicals and changing the antioxidant defense systems of tissues, eventually leading to oxidative stress. Green tea has recently attracted significant attention due to its health benefits in a variety of disorders, ranging from cancer to weight loss. Thus, the aim of the present study was to investigate the effect of EMR (frequency 900 MHz modulated at 217 Hz, power density 0.02 mW/cm², SAR 1.245 W/kg) on different oxidative stress parameters in the hippocampus and striatum of adult rats. This study also extends to evaluate the therapeutic effect of green tea mega EGCG on the previous parameters in animals exposed to EMR after and during EMR exposure. The experimental animals were divided into four groups: EMR-exposed animals, animals treated with green tea mega EGCG after 2 months of EMR exposure, animals treated with green tea mega EGCG during EMR exposure and control animals. EMR exposure resulted in oxidative stress in the hippocampus and striatum as evident from the disturbances in oxidant and antioxidant parameters. Co-administration of green tea mega EGCG at the beginning of EMR exposure for 2 and 3 months had more beneficial effect against EMR-induced oxidative stress than oral administration of green tea mega EGCG after 2 months of exposure. This recommends the use of green tea before any stressor to attenuate the state of oxidative stress and stimulate the antioxidant mechanism of the brain.     

A-like cells of the gastric mucosa as a possible source of prostaglandins

AL cells of the oxyntic stomach area were studied in rats using ultrastructurometric technique. High-threshold, short-term direct electrical vagostimulation (5 V, 4 msec, 30 Hz, 10 sec) was performed in experimental group of 12 animals. Animals were killed 1, 10 and 30 min after stimulation. High post-stimulation lipolytic activity of AL cells and intensification of "granule autophagy" phenomenon were noted. Our findings as well as the literature data suggest a hypothesis on possible prostaglandin production by AL cells. Direct evidence in favour of this hypothesis is difficult to obtain due to the lack of sufficiently reliable methods of their morphological detection in cells.     

Viral vectors as part of an integrated functional genomics program.

Over the past decade, viral vectors have slowly gained mainstream acceptance in the neuroscience and genetics communities for the in vivo study of gene function [1]. Using stereotactic techniques, it is possible to characterize neuroanatomical relationships through the delivery of neurotropic viral vectors to specific brain regions. More sophisticated studies combine viral vectors with other methods of genetic manipulation such as germline transgenic mice. As more is learned about the properties of different viral vectors, it has become possible to use viral vectors to test hypotheses about the function of genes, through targeted in vivo delivery to the central nervous system (CNS). The effects of gene expression in the brain can be measured on the molecular, biochemical, electrophysiological, morphological, and behavioral levels. We propose that viral vectors should be considered as part of an integrated functional genomics platform in the CNS.     

Magnetic resonance microscopy and histology of the CNS

High-resolution magnetic resonance (MR) imaging or MR microscopy of small animals is rapidly becoming an important tool for non-invasive assessment of the anatomy and function of various tissues, particularly the central nervous system. The availability of multiple MR modalities provides the opportunity to generate many different types of endogenous or exogenous tissue contrast, which enables new types of histology. For instance, it is possible to obtain contrast based on intrinsic differences in the chemical composition of tissue, including the presence of iron, plaques or myelin fibers. Cells can also be identified by marking with an exogenous contrast label or ‘magnetic dye’ before their introduction into tissue. As MR histology is non-invasive, serial studies can be performed, enabling a unique dynamic evaluation of cellular events within the same individual.     

Experimental validation of the use of an ultrasonic surgical instrument in neurophysiology

The effect of ultrasonic and surgical instruments on nervous tissue in chronic experiments on the cats were investigated with electrophysiological and morphological methods. The authors compared the results of removal of the neocortex zones using ultrasonic and surgical instruments or routine methods. Electrophysiological and morphological studies have shown small injury effects made by ultrasonic and surgical instruments on the surrounding brain tissue.     

Roentgenogrammetry and roentgenodensitometry in assessment of several morphologic changes]

The work deals with the significance of quantitative rentgenological methods in morphological studies. The results of these methods used for estimation of certain developmental changes in the skeleton as well as for estimation of experimental data on the reparation of the bone tissue are analyzed. It is also shown that the quantitative rentgenological estimation of the state of soft tissues is possible. The role of rentgenogrammetry and rentgendensitometry in the intravital characteristics of the morphological changes associated with different factors is stressed.     

Concepts of nerve fiber development, 1839–1930

Conclusion It was thus the combination of observational and experimental approaches that ultimately led to confirmation of the outgrowth theory. The observational method was essential for defining various possible methods of nerve fiber development. The multicellular, protoplasmic bridge and outgrowth theories were each postulated to explain purely observational evidence. However, the lack of truly suitable equipment and techniques to study the developing nervous system made it impossible to agree on a single theory on this basis alone. The experimental method provided a means of choosing between these theories. Without the preceding observations that had led to the formulation of various hypotheses, however, the experimental approach might not have been so successful, for the power of this method is more of selection than of generation.Therefore it is impossible to weigh separately the contributions of the observational and experimental approaches to the question of nerve fiber development. Both were necessary for the ultimate acceptance of the outgrowth theory. *** DIRECT SUPPORT *** A8402051 00004     

Evolution of eumetazoan nervous systems: insights from cnidarians

Cnidarians, the sister group to bilaterians, have a simple diffuse nervous system. This morphological simplicity and their phylogenetic position make them a crucial group in the study of the evolution of the nervous system. The development of their nervous systems is of particular interest, as by uncovering the genetic programme that underlies it, and comparing it with the bilaterian developmental programme, it is possible to make assumptions about the genes and processes involved in the development of ancestral nervous systems. Recent advances in sequencing methods, genetic interference techniques and transgenic technology have enabled us to get a first glimpse into the molecular network underlying the development of a cnidarian nervous system—in particular the nervous system of the anthozoan Nematostella vectensis. It appears that much of the genetic network of the nervous system development is partly conserved between cnidarians and bilaterians, with Wnt and bone morphogenetic protein (BMP) signalling, and Sox genes playing a crucial part in the differentiation of neurons. However, cnidarians possess some specific characteristics, and further studies are necessary to elucidate the full regulatory network. The work on cnidarian neurogenesis further accentuates the need to study non-model organisms in order to gain insights into processes that shaped present-day lineages during the course of evolution.     

D-aspartic acid in the nervous system of Aplysia limacina: possible role in neurotransmission

In the marine mollusk Aplysia limacina, a substantial amount of endogenous D-aspartic acid (D-Asp) was found following its synthesis from L-aspartate by an aspartate racemase. Concentrations of D-Asp between 3.9 and 4.6 micromol/g tissue were found in the cerebral, abdominal, buccal, pleural, and pedal ganglia. In non nervous tissues, D-Asp occurred at a very low concentration compared to the nervous system. Immunohistochemical studies conducted on cultured Aplysia neurons using an anti-D-aspartate antibody demonstrated that D-Asp occurs in the soma, dendrites, and in synaptic varicosities. Synaptosomes and synaptic vesicles from cerebral ganglia were prepared and characterized by electron microscopy. HPLC analysis revealed high concentrations of D-Asp together with L-aspartate and L-glutamate in isolated synaptosomes In addition, D-Asp was released from synaptosomes by K+ depolarization or by ionomycin. D-Asp was one of the principal amino acids present in synaptic vesicles representing about the 25% of total amino acids present in these cellular organelles. Injection of D-Asp into live animals or addition to the incubation media of cultured neurons, caused an increase in cAMP content. Taken as a whole, these findings suggest a possible role of D-Asp in neurotransmission in the nervous system of Aplysia limacina.     

Nervous system pathology: the fibrin perspective

Studies of extracellular matrix (ECM) biology in the nervous system have mainly focused on laminin, fibronectin and tenascin-R, proteins that are present during nervous system development and normal function. However, during disease, fibrin, which physiologically is not present in the nervous tissue, is detected at nervous tissue lesions. This review summarizes evidence that correlates fibrin deposition with neuropathology and presents recent findings on cellular mechanisms and intracellular signaling pathways regulated by fibrin that might contribute to nervous system disease.     

Recent Reports of Wi-Fi and Mobile Phone-Induced Radiation on Oxidative Stress and Reproductive Signaling Pathways in Females and Males

Environmental exposure to electromagnetic radiation (EMR) has been increasing with the increasing demand for communication devices. The aim of the study was to discuss the mechanisms and risk factors of EMR changes on reproductive functions and membrane oxidative biology in females and males. It was reported that even chronic exposure to EMR did not increase the risk of reproductive functions such as increased levels of neoantigens abort. However, the results of some studies indicate that EMR induced endometriosis and inflammation and decreased the number of follicles in the ovarium or uterus of rats. In studies with male rats, exposure caused degeneration in the seminiferous tubules, reduction in the number of Leydig cells and testosterone production as well as increases in luteinizing hormone levels and apoptotic cells. In some cases of male and female infertility, increased levels of oxidative stress and lipid peroxidation and decreased values of antioxidants such as melatonin, vitamin E and glutathione peroxidase were reported in animals exposed to EMR. In conclusion, the results of current studies indicate that oxidative stress from exposure to Wi-Fi and mobile phone-induced EMR is a significant mechanism affecting female and male reproductive systems. However, there is no evidence to this date to support an increased risk of female and male infertility related to EMR exposure.