Central Nervous System In Order Research Articles

Behaviour of oligodendrocytes and Schwann cells in an experimental model of toxic demyelination of the central nervous system.

Oligodendrocytes and Schwann cells are engaged in myelin production, maintenance and repairing respectively in the central nervous system (CNS) and the peripheral nervous system (PNS). Whereas oligodendrocytes act only within the CNS, Schwann cells are able to invade the CNS in order to make new myelin sheaths around demyelinated axons. Both cells have some limitations in their activities, i.e. oligodendrocytes are post-mitotic cells and Schwann cells only get into the CNS in the absence of astrocytes. Ethidium bromide (EB) is a gliotoxic chemical that when injected locally within the CNS, induce demyelination. In the EB model of demyelination, glial cells are destroyed early after intoxication and Schwann cells are free to approach the naked central axons. In normal Wistar rats, regeneration of lost myelin sheaths can be achieved as early as thirteen days after intoxication; in Wistar rats immunosuppressed with cyclophosphamide the process is delayed and in rats administered cyclosporine it may be accelerated. Aiming the enlightening of those complex processes, all events concerning the myelinating cells in an experimental model are herein presented and discussed.

Cytokine gene therapy of autoimmune demyelination revisited using herpes simplex virus type-1-derived vectors.

The peripheral delivery of drugs in patients affected by central nervous system (CNS)-confined diseases is therapeutically ineffective due to the presence of the blood-brain barrier which forms an inaccessible wall to the majority of CNS targeting molecules. When molecules with an anti-inflammatory profile have been systemically administered to patients affected by a chronic inflammatory demyelinating disease of the CNS, such as multiple sclerosis (MS), results have been disappointing. A successful therapeutic approach in MS should therefore consider the delivery of anti-inflammatory molecules directly into the CNS in order to inhibit blood-borne CNS-confined mononuclear cells which act as ultimate effector cells directly destroying oligodendrocytes and/or releasing myelinotoxic substances. Biological and physical vectors engineered with heterologous genes coding for immunomodulatory cytokines with an anti-inflammatory profile might represent the appropriate tool to deliver therapeutic genes into the CNS of patients with MS. So far, cytokine gene therapy has never been attempted in MS, but encouraging results have been obtained in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), using viral vectors or plasmids engineered with cytokine genes and then injected systemically, either in the blood stream or circulating encephalitogenic T cells, or into the CNS. Here, we critically discuss the various attempts made in EAE using gene therapy protocols based on the delivery of immunomodulatory cytokine genes. Special emphasis is put on the use of non-replicative herpes simplex type-1 (HSV)-derived vectors engineered with the gene of the immunomodulatory cytokine interleukin (IL)-4.

Immunocytochemical localization of the insulin-responsive glucose transporter 4 (Glut4) in the rat central nervous system.

We have previously reported that the insulin-responsive glucose transporter GLUT4 is strongly expressed by discrete areas of the rat brain (Leloup et al. [1996] Molec. Brain Res. 38:45-53). In the present study, a sensitive immunocytochemical technique has been used to analyze extensively the anatomical and ultrastructural localizations of GLUT4 in the rat central nervous system in order to gain insight into the physiological role of this transporter. We confirm that GLUT4 is expressed by numerous neurons of the brain and spinal cord, whereas glial cells are more scarcely labeled. In both light and electron microscopy, we observe that the immunoreactivity for GLUT4 is localized mainly in the somatodendritic portion of neurons, where some cisterns of rough endoplasmic reticulum, ribosomal rosettes, certain Golgi saccules, and some intracytoplasmic vesicles are labeled. In contrast, axons and nerve terminals are only occasionally immunostained in certain brain regions such as the neocortex and the ventricular surfaces for example. The GLUT4-immunoreactive structures appear concentrated and most prominently immunostained in motor areas, such as the sensorimotor cortex, most basal ganglia and related nuclei, the cerebellum and deep cerebellar nuclei, a number of reticular fields, motor nuclei of cranial nerves, and motor neurons of the ventral horn of the spinal cord. The labeled regions, which also include some sensory nuclei, are often those in which Vissing et al. ([1996] J. Cerebral Blood Flow Metab. 16:729-736) have shown that exercise stimulates local cerebral glucose utilization, so that GLUT4 might be involved in this effect. On the other hand, the fact that the anatomical localizations of GLUT4 reported here generally agree with the distribution of insulin- or insulin-receptor- related receptors is important since it indicates that the translocation of GLUT4 might also be regulated by insulin in the central nervous system.

Epigenetic factors up-regulate expression of myelin proteins in the dysmyelinating jimpy mutant mouse.

Proteolipid protein (PLP) is a major structural component of central nervous system (CNS) myelin. Evidence exists that PLP or the related splice variant DM-20 protein may also play a role in early development of oligodendrocytes (OLs), the cells that form CNS myelin. There are several naturally occurring mutations of the PLP gene that have been used to study the roles of PLP both in myelination and in OL differentiation. The PLP mutation in the jimpy (jp) mouse has been extensively characterized. These mutants produce no detectable PLP and exhibit an almost total lack of CNS myelin. Additionally, most OLs in affected animals die prematurely, before producing myelin sheaths. We have studied cultures of jp CNS in order to understand whether OL survival and myelin formation require production of normal PLP. When grown in primary cultures, jp OLs mimic the relatively undifferentiated phenotype of jp OLs in vivo. They produce little myelin basic protein (MBP), never immunostain for PLP, and rarely elaborate myelin-like membranes. We report here that jp OLs grown in medium conditioned by normal astrocytes synthesize MBP and incorporate it into membrane expansions. Some jp OLs grown in this way stain with PLP antibodies, including an antibody to a peptide sequence specific for the mutant jp PLP. This study shows that: (1) an absence of PLP does not necessarily lead to dysmyelination or OL death; (2) OLs are capable of translating at least a portion of the predicted jp PLP; (3) the abnormal PLP made in the cultured jp cells is not toxic to OLs. These results also highlight the importance of environmental factors in controlling OL phenotype.

Biological Gene-Product Delivery to the Brain: A Protocol for Retroviral Gene Transfer into Cultured Cells and Intracerebral Transplantation

Immortalized and primary cells in culture can be genetically engineered to deliver several types of gene products to the central nervous system. This paper describes methods of retroviral gene transfer into Immortalized rat fibroblasts to create cells capable of secreting neurotrophic factors. These cells can subsequently be implanted into discrete loci in the central nervous system in order to examine the effects and trophic mechanisms of neurotrophic factors.

Vasopressin in human cerebrospinal fluid.

Arginine vasopressin was measured by RIA in samples of plasma and cerebrospinal fluid (CSF) taken synchronously from 62 patients with proven or suspected disorders of the central nervous system in order to determine the relationship between the secretion of vasopressin into the systemic circulation and that into the CSF. In 12 patients without endocrine or brain disease, mean plasma values (+/- SD) were 2.8 +/- 0.7 pg/ml and CSF values were 2.4 +/- 0.7 pg/ml. Thirty-six patients with various intracranial disorders had plasma and CSF values which were both within the range of 1-4 pg/ml. Eight patients had raised plasma concentrations, but their CSF levels were within the normal range. One patient with posttraumatic diabetes insipidus and 2 patients with subarachnoid hemorrhage had concentrations of CSF vasopressin which were greater than plasma levels. These results indicate that a blood CSF barrier to vasopressin exists in man and that under certain pathological conditions excessive amounts of the hormone can be secreted into the CSF independently of that which is released into the blood, a finding which could have clinical significance in disorders of brain function.

Introduction

In summary, the Neonatal Behavioral Assessment Scale attempts to capture the complexity of behavioral responses to social stimuli as the neonate moves from sleep states to crying and to alert states of consciousness. The 20 relfex items tap neurological intergrity. The 27 behavioral items attempt to assess the neonate's capacity to respond to the environment. As such, these item scores become a reflection of the baby's capacity to organize his or her autonomic and central nervous system in order to respond to stimuli (both animate and inanimate), and the exam is used to predict to the environment's response to the baby as an individual. Characteristic of this exam is that it scores the infant's "best" performance, which is captured after a series of trials often without a fixed order, and assesses the baby's capacity to organize responses within different states of consciousness.

Axonal transport of [3H]serotonin in an identified neuron of Aplysia californica.

A population of characteristic ellipsoidal dense-core vesicles was identified in axons of the giant cerebral neuron of the mollusc Aplysia. We injected [3H]serotonin into the cell body of this identified serotonergic neuron in the isolated central nervous system in order to study the subcellular components associated with the neurotransmitter. Subcellular fractionation by differential centrifugation indicated that injected serotonin was rapidly taken up into particulate form. [3H]Serotonin appeared in the axons within 2 h after injection, and export continued at a constant rate of 6% of the total in the neuron/h thereafter. The dependence of the total amounts of [3H]serotonin which appeared in the axons in 6 h (export from the cell body) on the amounts injected was consistent with the idea that export is a saturable process, possibly depending on the capacity of somatic vesicles or of some unidentified carrier for serotonin. [3H]Serotonin moved into both major branches of the axon, where it was translocated rapidly. The transmitter, which was shown by autoradiography to be restricted to the axons of the injected cell, was distributed along axons in accumulations of radioactivity; in contrast, its precursor, [5-3H]hydroxytryptophan, moved slowly along axons in a smooth, declining curve, its kinetics consistent with diffusion. Quantitative electron microscope autoradiography revealed that the dense-core vesicles and the cytosol of axons fixed with glutaraldehyde were labeled with [3H]serotonin.

NEUROHISTOPATHOLOGIC CHANGES WITH METRAZOL AND INSULIN SHOCK THERAPY

Insulin and metrazol shock therapy for mental diseases is finding wider application in the hands of investigators. Originally intended for the treatment of schizophrenia, it is now being advocated and used in the management of many other neuropsychiatric conditions. According to Stief and Tokay, 1 insulin is employed in the treatment of neurasthenia, morphine addiction, delirium tremens, exophthalmic goiter, negativistic refusal of food and manic-depressive psychosis, as well as of dementia praecox. Many of the conditions for which insulin and metrazol are used have a comparatively good prognosis with less drastic therapeutic measures. It therefore becomes necessary to study the behavior of these substances in the central nervous system in order to evaluate not only the good which these drugs may do but also the untoward reactions. Questions which have confronted every worker since the introduction of these two drugs in the treatment of schizophrenia are: Do these substances benefit