The Central Nervous System

Planarian peptidylglycine-hydroxylating monooxygenase, a neuropeptide processing enzyme, colocalizes with cytochrome b 561 along the central nervous system Akikazu Asada 1 , Hidefumi Orii 1 , Kenji Watanabe 1 and Motonari Tsubaki 1,2,3 1 Department of Life Science, Graduate School of Life Science, University of Hyogo (formerly Himeji Institute of Technology), Hyogo, Japan 2 CREST, Japan Science and Technology Agency (JST), Saitama, Japan 3 Department of Molecular Science and Material Engineering, Graduate School of Science and Technology, Kobe University, Hyogo, Japan Neuropeptides in the brain, in the nervous system, and in various endocrine cells are synthesized in the rough endoplasmic reticulum as large precursor proteins. After transit to vesicles and during axonal transportation along axons, several processing enzymes residing in the vesicles process the peptides to convert them to mature forms. C-terminal a-amidation of the peptides occurs in the late stage [1] and is probably a rate-limiting step in many instances [2]. Over half of peptide hormones or neuropeptides are amidated in vertebrates; in insects, greater than 90% of such peptides show the presence of a C-terminal amide moiety [3]. This C-terminal amide is very important in their functions, as its absence often disrupts the activity or receptor-binding properties of the peptide ligands [4]. Indeed, most neurotransmitters thus far identified are amidated peptides in cnidarians Keywords peptidylglycine a-hydroxylating monooxygenase; cytochrome b 561 ; planarian; neuroendocrine vesicle; neuropeptide amidation Correspondence M. Tsubaki, Department of Molecular Science and Material Engineering, Graduate School of Science and Technology, Kobe University, Rokkodai-cho, Nada-ku, Kobe, Hyogo 657-8501, Japan Fax: +81 78 803 6582 Tel: +81 78 803 6582 E-mail: mtsubaki@kobe-u.ac.jp Note The nucleotide sequence of planarian PHM in this article has been submitted to the DDBJ ⁄ EMBL ⁄ GenBank databases with accession number AB195502. (Received 27 September 2004, revised 2 December 2004, accepted 14 December 2004) doi:10.1111/j.1742-4658.2004.04528.x Planarians are one of the simplest animal groups with a central nervous system. Their primitive central nervous system produces large quantities of a variety of neuropeptides, of which many are amidated at their C terminus. In vertebrates, peptide amidation is catalyzed by two enzymes [peptidylglycine a-hydroxylating monooxygenase (PHM) and peptidyl-a- hydroxylglycine a-amidating lyase] acting sequentially. In mammals, both enzymatic activities are contained within a single protein that is encoded by a single gene. By utilizing PCR with degenerate oligonucleotides derived from conserved regions of PHM, we succeeded in cloning a full-length cDNA encoding planarian PHM. The deduced amino acid sequence showed full conservation of five His residues and one Met residue, which bind two Cu atoms that are essential for the activity of PHM. Northern blot analysis confirmed the expression of a PHM mRNA of the expected size. Distribution of the mRNA was analyzed by in situ hybridization, showing specific expression in neurons with two morphologically distinct structures, a pair of the ventral nerve cords and the brain. The distribution of PHM was very similar to that of cytochrome b 561 . This indicates that the ascorbate-related electron transfer system operates in the planarian cen- tral nervous system to support the PHM activity and that it predates the emergence of Plathelminthes in the evolutionary history. Abbreviations AsA, ascorbic acid; CNS, central nervous The Central Nervous System The Central Nervous System Bởi: OpenStaxCollege The central nervous system (CNS) is made up of the brain, a part of which is shown in [link] and spinal cord and is covered with three layers of protective coverings called meninges (from the Greek word for membrane) The outermost layer is the dura mater (Latin for “hard mother”) As the Latin suggests, the primary function for this thick layer is to protect the brain and spinal cord The dura mater also contains vein-like structures that carry blood from the brain back to the heart The middle layer is the web-like arachnoid mater The last layer is the pia mater (Latin for “soft mother”), which directly contacts and covers the brain and spinal cord like plastic wrap The space between the arachnoid and pia maters is filled with cerebrospinal fluid (CSF) CSF is produced by a tissue called choroid plexus in fluid-filled compartments in the CNS called ventricles The brain floats in CSF, which acts as a cushion and shock absorber and makes the brain neutrally buoyant CSF also functions to circulate chemical substances throughout the brain and into the spinal cord The entire brain contains only about 8.5 tablespoons of CSF, but CSF is constantly produced in the ventricles This creates a problem when a ventricle is blocked—the CSF builds up and creates swelling and the brain is pushed against the skull This swelling condition is called hydrocephalus (“water head”) and can cause seizures, cognitive problems, and even death if a shunt is not inserted to remove the fluid and pressure 1/10 The Central Nervous System The cerebral cortex is covered by three layers of meninges: the dura, arachnoid, and pia maters (credit: modification of work by Gray’s Anatomy) Brain The brain is the part of the central nervous system that is contained in the cranial cavity of the skull It includes the cerebral cortex, limbic system, basal ganglia, thalamus, hypothalamus, and cerebellum There are three different ways that a brain can be sectioned in order to view internal structures: a sagittal section cuts the brain left to right, as shown in [link]b, a coronal section cuts the brain front to back, as shown in [link]a, and a horizontal section cuts the brain top to bottom Cerebral Cortex The outermost part of the brain is a thick piece of nervous system tissue called the cerebral cortex, which is folded into hills called gyri (singular: gyrus) and valleys called sulci (singular: sulcus) The cortex is made up of two hemispheres—right and left—which are separated by a large sulcus A thick fiber bundle called the corpus callosum (Latin: “tough body”) connects the two hemispheres and allows information to be passed from one side to the other Although there are some brain functions that are localized more to one hemisphere than the other, the functions of the two hemispheres are largely redundant In fact, sometimes (very rarely) an entire hemisphere is removed to treat severe epilepsy While patients suffer some deficits following the surgery, they can have surprisingly few problems, especially when the surgery is performed on children who have very immature nervous systems 2/10 The Central Nervous System These illustrations show the (a) coronal and (b) sagittal sections of the human brain In other surgeries to treat severe epilepsy, the corpus callosum is cut instead of removing an entire hemisphere This causes a condition called split-brain, which gives insights into unique functions of the two hemispheres For example, when an object is presented to patients’ left visual field, they may be unable to verbally name the object (and may claim to not have seen an object at all) This is because the visual input from the left visual field crosses and enters the right hemisphere and cannot then signal to the speech center, which generally is found in the left side of the brain Remarkably, if a split-brain patient is asked to pick up a specific object out of a group of objects with the left hand, the patient will be able to so but will still be unable to vocally identify it Link to Learning See this website to learn more about split-brain patients and to play a game where you can model the split-brain experiments yourself Each cortical hemisphere contains regions called lobes that are involved in different functions Scientists use various techniques to determine what brain areas are involved in different functions: they examine patients who have had injuries or diseases that affect specific areas and see how those areas are related to functional deficits They also conduct animal studies where they stimulate brain areas and see if there are any behavioral changes They use a technique called transmagnetic stimulation (TMS) to temporarily deactivate specific parts of the cortex using strong magnets placed outside the head; and they use functional magnetic resonance imaging (fMRI) to look at changes in oxygenated blood flow in particular brain regions that correlate with specific ...BioMed Central Page 1 of 13 (page number not for citation purposes) Journal of Neuroinflammation Open Access Research Temporal expression and cellular origin of CC chemokine receptors CCR1, CCR2 and CCR5 in the central nervous system: insight into mechanisms of MOG-induced EAE Sana Eltayeb 1 , Anna-Lena Berg* 2 , Hans Lassmann 3 , Erik Wallström 1 , Maria Nilsson 4 , Tomas Olsson 1 , Anders Ericsson-Dahlstrand 4 and Dan Sunnemark 4 Address: 1 Department of Clinical Neuroscience, Center for Molecular Medicine, Neuroimmunology Unit, Karolinska Institute, S-171 76 Stockholm, Sweden, 2 Department of Pathology, Safety Assessment, AstraZeneca R&D Södertälje, S-15185 Södertälje, Sweden, 3 Brain Research Institute, University of Vienna, Vienna, Austria and 4 Department of Disease Biology, Local Discovery Research Area CNS and Pain Control, AstraZeneca R&D Södertälje, S-151 85 Södertälje, Sweden Email: Sana Eltayeb - Sana.Eltayeb@ki.se; Anna-Lena Berg* - Anna-Lena.Berg@astrazeneca.com; Hans Lassmann - Hans.Lassmann@meduniwien.ac.at; Erik Wallström - Erik.Wallstrom@ki.se; Maria Nilsson - Maria.Nilsson@astrazeneca.com; Tomas Olsson - Tomas.Olsson@ki.se; Anders Ericsson-Dahlstrand - Anders.Ericsson-Dahlstrand@astrazeneca.com; Dan Sunnemark - Dan.Sunnemark@astrazeneca.com * Corresponding author Abstract Background: The CC chemokine receptors CCR1, CCR2 and CCR5 are critical for the recruitment of mononuclear phagocytes to the central nervous system (CNS) in multiple sclerosis (MS) and other neuroinflammatory diseases. Mononuclear phagocytes are effector cells capable of phagocytosing myelin and damaging axons. In this study, we characterize the regional, temporal and cellular expression of CCR1, CCR2 and CCR5 mRNA in the spinal cord of rats with myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE). While resembling human MS, this animal model allows unique access to CNS-tissue from various time-points of relapsing neuroinflammation and from various lesional stages: early active, late active, and inactive completely demyelinated lesions. Methods: The expression of CCR1, CCR2 and CCR5 mRNA was studied with in situ hybridization using radio labelled cRNA probes in combination with immunohistochemical staining for phenotypic cell markers. Spinal cord sections from healthy rats and rats with MOG-EAE (acute phase, remission phase, relapse phase) were analysed. In defined lesion stages, the number of cells expressing CCR1, CCR2 and CCR5 mRNA was determined. Data were statistically analysed by the nonparametric Mann-Whitney U test. Results: In MOG-EAE rats, extensive up-regulation of CCR1 and CCR5 mRNA, and moderate up-regulation of CCR2 mRNA, was found in the spinal cord during episodes of active inflammation and demyelination. Double staining with phenotypic cell markers identified the chemokine receptor mRNA-expressing cells as macrophages/microglia. Expression of all three receptors was substantially reduced during clinical remission, coinciding with diminished inflammation and demyelination in the spinal cord. Healthy control rats did not show any detectable expression of CCR1, CCR2 or CCR5 mRNA in the spinal cord. Section III. Drugs Acting on the Central Nervous System Chapter 12. Neurotransmission and the Central Nervous System Overview Drugs that act upon the central nervous system (CNS) influence the lives of everyone, every day. These agents are invaluable therapeutically because they can produce specific physiological and psychological effects. Without general anesthetics, modern surgery would be impossible. Drugs that affect the CNS can selectively relieve pain, reduce fever, suppress disordered movement, induce sleep or arousal, reduce the desire to eat, or allay the tendency to vomit. Selectively acting drugs can be used to treat anxiety, mania, depression, or schizophrenia and do so without altering consciousness (see Chapters 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders and 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania). The nonmedical self-administration of CNS-active drugs is a widespread practice. Socially acceptable stimulants and antianxiety agents produce stability, relief, and even pleasure for many. However, the excessive use of these and other drugs also can affect lives adversely when their uncontrolled, compulsive use leads to physical dependence on the drug or to toxic side effects, which may include lethal overdosage (see Chapter 24: Drug Addiction and Drug Abuse). The unique quality of drugs that affect the nervous system and behavior places investigators who study the CNS in the midst of an extraordinary scientific challenge—the attempt to understand the cellular and molecular basis for the enormously complex and varied functions of the human brain. In this effort, pharmacologists have two major goals: to use drugs to elucidate the mechanisms that operate in the normal CNS and to develop appropriate drugs to correct pathophysiological events in the abnormal CNS. Approaches to the elucidation of the sites and mechanisms of action of CNS drugs demand an understanding of the cellular and molecular biology of the brain. Although knowledge of the anatomy, physiology, and chemistry of the nervous system is far from complete, the acceleration of interdisciplinary research on the CNS has led to remarkable progress. This chapter introduces guidelines and fundamental principles for the comprehensive analysis of drugs that affect the CNS. Specific therapeutic approaches to neurological and psychiatric disorders are discussed in the chapters that follow in this section (see Chapters 13: History and Principles of Anesthesiology, 14: General Anesthetics, 15: Local Anesthetics, 16: Therapeutic Gases: Oxygen, Carbon Dioxide, Nitric Oxide, and Helium, 17: Hypnotics and Sedatives, 18: Ethanol, 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders, 20: Drugs and the Treatment of Psychiatric Disorders: Psychosis and Mania, 21: Drugs Effective in the Therapy of the Epilepsies, 22: Treatment of Central Nervous System Degenerative Disorders, 23: Opioid Analgesics, and 24: Drug Addiction and Drug Abuse). Organizational Principles of the Brain The brain is an assembly of interrelated neural systems that regulate their own and each other's activity in a dynamic, complex fashion. Macrofunctions of Brain Regions The large anatomical divisions provide a superficial classification of the distribution of Minireview The long term effects of chemotherapy on the central nervous system Patricia K Duffner Address: Department of Neurology, Women and Children’s Hospital of Buffalo, University of Buffalo School of Medicine, 219 Bryant St., Buffalo, NY 14222, USA. Email: PatriciaDuffner@aol.com Although the long-term effects of irradiation on the central nervous system (CNS) are now well-known and accepted, the long term consequences of most chemotherapeutic agents have rarely been considered, either in the develop- ment of multi-institutional cancer group studies or in the follow-up of survivors. In this issue of Journal of Biology, Mark Noble and colleagues [1] describe an interesting and important series of experiments that helps define the cellular basis for cognitive decline and white matter diseases (leukoencephalopathy) in patients treated with chemotherapy. Noble and colleagues [1] have now shown that standard chemotherapeutic agents, given in dosages comparable to those used in the clinical arena, are even more toxic to CNS progenitor cells and oligodendrocytes than they are to cancer cell lines, causing both decreased cell division and cell death. The authors conducted four groups of experiments. In the first, DNA cross-linking agents - 1,3-bis(2-chlorethyl)-1-nitrosourea (BCNU) and cisplatin (CDDP) - were applied in vitro to purified populations of neuroepthelial stem cells, neural-restricted precursor cells, glial-restricted precursor cells, and oligodendrocyte precursor cells (O-2A/OPCs) as well as to a variety of human cancer cell lines. They found that clinically relevant concentrations of BCNU or CDDP were more toxic to lineage-committed precursor cells and neuroepithelial stem cells than to cancer cells. These effects were seen even at very low levels of exposure. Moreover, the vulnerability was not restricted to dividing cells, as non-dividing oligodendrocytes were as much at risk as the rapidly dividing neural progenitor cells. In the second in vitro experiment, O-2A/OPCs exposed to sublethal concentrations of CDDP and BCNU were found to have both reduced cell division and increased differen- tiation into oligodendrocytes. Thus, the chemotherapy compromised the ability of the O-2A/OPCs to continue cell division and form new precursor cells. In the third experiment, mice were treated systemically with BCNU and CDDP and then examined for evidence of cell death and cell division in the CNS. As with the in vitro experiments, neuronal and glial progenitor cells and oligodendrocytes were adversely affected, particularly in the subventricular zone, the corpus callosum and the dentate gyrus of the hippocampus. By examining incorporation of bromodeoxyuridine (BrdU) in adult animals, the authors found that cell proliferation in putative germinal zones was Abstract Cranial radiotherapy is known to have adverse effects on intelligence. A new study shows that chemotherapy is also toxic to the central nervous system, especially to neural progenitor cells and oligodendrocytes. By identifying the cell populations at risk, these results may help explain the neurological problems previously seen after chemotherapy. BioMed Central Journal of Biology Journal of Biology 2005, 5:21 Published: 30 November 2006 Journal of Biology 2006, 5:21 The electronic version of this article is the complete one and can be found online at http://jbiol.com/content/5/7/21 © 2006 BioMed Central Ltd reduced for at least 6 weeks following repeated injections of BCNU. Overall, the effects of CDDP were more transient than those produced by BCNU. In the fourth experiment, AraC (an antimetabolite) was found to be highly toxic in vitro for neural progenitor cells in concentrations equivalent to those used in clinical trials. As with BCNU and CDDP, O-2A/OPCs were more sensitive to adverse effects than were the leukemia and lymphoma cell lines. In addition, sublethal concentrations of the drug were associated with suppression of cell division in clonal assays. Research article SSyysstteemmiicc 55 fflluuoorroouurraacciill ttrreeaattmmeenntt ccaauusseess aa ssyynnddrroommee ooff ddeellaayyeedd mmyyeelliinn ddeessttrruuccttiioonn iinn tthhee cceennttrraall nneer rvvoouuss ssyysstteemm Ruolan Han*, Yin M Yang*, Joerg Dietrich † , Anne Luebke ‡ , Margot Mayer-Pröschel* and Mark Noble* Addresses: *Department of Biomedical Genetics and University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center, Elmwood Avenue, Rochester, NY 14642, USA. † Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Fruit Street, Wang 835, Boston, MA 02114, USA. ‡ Department of Neurobiology and Anatomy, University of Rochester Medical Center, Elmwood Avenue, Rochester, NY 14642, USA. Correspondence: Mark Noble. Email: mark_noble@urmc.rochester.edu AAbbssttrraacctt BBaacckkggrroouunndd:: Cancer treatment with a variety of chemotherapeutic agents often is associated with delayed adverse neurological consequences. Despite their clinical importance, almost nothing is known about the basis for such effects. It is not even known whether the occurrence of delayed adverse effects requires exposure to multiple chemotherapeutic agents, the presence of both chemotherapeutic agents and the body’s own response to cancer, prolonged damage to the blood-brain barrier, inflammation or other such changes. Nor are there any animal models that could enable the study of this important problem. RReessuullttss:: We found that clinically relevant concentrations of 5-fluorouracil (5-FU; a widely used chemotherapeutic agent) were toxic for both central nervous system (CNS) progenitor cells and non-dividing oligodendrocytes in vitro and in vivo . Short-term systemic administration of 5-FU caused both acute CNS damage and a syndrome of progressively worsening delayed damage to myelinated tracts of the CNS associated with altered transcriptional regulation in oligodendrocytes and extensive myelin pathology. Functional analysis also provided the first demonstration of delayed effects of chemotherapy on the latency of impulse conduction in the auditory system, offering the possibility of non-invasive analysis of myelin damage associated with cancer treatment. CCoonncclluussiioonnss:: Our studies demonstrate that systemic treatment with a single chemo- therapeutic agent, 5-FU, is sufficient to cause a syndrome of delayed CNS damage and provide the first animal model of delayed damage to white-matter tracts of individuals treated with systemic chemotherapy. Unlike that caused by local irradiation, the degeneration caused by 5-FU treatment did not correlate with either chronic inflammation or extensive vascular damage and appears to represent a new class of delayed degenerative damage in the CNS. BioMed Central Journal of Biology 2008, 77:: 12 Open Access Published: 22 April 2008 Journal of Biology 2008, 77:: 12 (doi:10.1186/jbiol69) The electronic version of this article is the complete one and can be found online at http://jbiol.com/content/7/4/12 Received: 19 June 2007 Revised: 3 January 2008 Accepted: 19 February 2008 © 2008 Han et al. ; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. BBaacckkggrroouunndd Most treatments used to kill cancer cells also kill a diverse range of normal cell types, leading to a broad range of adverse side effects in multiple organ systems. In the hematopoietic system, the tissue in which such adverse effects have been most extensively studied, their detailed analysis has led to the discoveries that bone marrow transplants and cytokine therapies can improve the out- come of many forms of cancer treatment. In contrast, there has been no comparable level of analysis for most other ... following the surgery, they can have surprisingly few problems, especially when the surgery is performed on children who have very immature nervous systems 2/10 The Central Nervous System These illustrations... among other symptoms, and is eventually fatal 6/10 The Central Nervous System The limbic system regulates emotion and other behaviors It includes parts of the cerebral cortex located near the center... Gray’s Anatomy) Brain The brain is the part of the central nervous system that is contained in the cranial cavity of the skull It includes the cerebral cortex, limbic system, basal ganglia, thalamus,