Developmental Neurotoxicology Research: Principles, Models, Techniques, Strategies, and Mechanisms - Hardcover

Wang, Cheng; Slikker, William, Jr.

Hardcover

ISBN 10: 0470426721 ISBN 13: 9780470426722

Verlag: John Wiley & Sons Inc, 2011

Inhaltsangabe

This book describes how systems biology, pharmacogenomic and behavioral approaches, as applied to neurodevelopmental toxicology, provide a structure to arrange information in a biological model. Authors review and discuss approaches that can be used as effective tools to dissect mechanisms underlying pharmacological and toxicological phenomena associated with the exposure to drugs or environmental toxicants during development. This book presents cross-cutting research tools and animal models, along with applications to the studies associated with potential anesthetic-induced developmental neurotoxicity; the developmental basis of adolescent or adult onset of disease; risk assessment of methyl mercury and its effects on neurodevelopment; challenges in the field to identify environmental factors of relevance to autism; and the strategy and progress of epilepsy research.

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Über die Autorin bzw. den Autor

Cheng Wang is Senior Neurobiologist in the Division of Neurotoxicology at the National Center for Toxicological Research, U.S. Food and DrugAdministration. He is the author of over fifty-five peer-reviewed publications and book chapters. Dr. Wang was awarded the Outstanding Performance Award at the Society of Toxicology 44th Annual Meeting and the 2007 FDA Scientific Achievement Award for Excellence in Laboratory Science.

William Slikker, Jr., is the Director of the National Center for Toxicological Research, U.S. Food and Drug Administration. He has over 260 peer-reviewed scientific publications. Dr. Slikker has served as coeditor of several books and is an Associate Editor of the journals NeuroToxicology and Toxicological Sciences.

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How preclinical research approaches can inform clinical interventions?and vice versa

Because of the complexity and temporal features of the developing brain, the developing nervous system may be more susceptible to neurotoxic insults. The study of neurodevelopmental toxicology has great potential for helping to advance the understanding of brain-related biological processes, including neuronal plasticity, neurodegeneration/regeneration, toxicity, and effectiveness of many products. Developmental Neurotoxicology Research delineates how systems biology, pharmacogenomic, and behavioral approaches, as applied to neurodevelopmental toxicology, provide a structure to arrange information in a biological model.

The book presents:

• Cross-cutting research tools and animal models along with applications to the studies associated with potential anesthetic-induced developmental neurotoxicity

• The developmental basis of adolescent or adult onset of disease

• Risk assessment of methyl mercury and its effects on neurodevelopment

• Challenges in the field to identify environmental factors of relevance to autism

• The strategy and progress of epilepsy research

Incorporating new, post-genomic techniques, this book provides researchers with effective tools for dissecting the mechanisms underlying pharmacological and toxicological phenomena associated with the exposure to drugs or environmental toxicants during development.

Aus dem Klappentext

How preclinical research approaches can inform clinical interventions—and vice versa

Because of the complexity and temporal features of the developing brain, the developing nervous system may be more susceptible to neurotoxic insults. The study of neurodevelopmental toxicology has great potential for helping to advance the understanding of brain-related biological processes, including neuronal plasticity, neurodegeneration/regeneration, toxicity, and effectiveness of many products. Developmental Neurotoxicology Research delineates how systems biology, pharmacogenomic, and behavioral approaches, as applied to neurodevelopmental toxicology, provide a structure to arrange information in a biological model.

The book presents:

• Cross-cutting research tools and animal models along with applications to the studies associated with potential anesthetic-induced developmental neurotoxicity

• The developmental basis of adolescent or adult onset of disease

• Risk assessment of methyl mercury and its effects on neurodevelopment

• Challenges in the field to identify environmental factors of relevance to autism

• The strategy and progress of epilepsy research

Incorporating new, post-genomic techniques, this book provides researchers with effective tools for dissecting the mechanisms underlying pharmacological and toxicological phenomena associated with the exposure to drugs or environmental toxicants during development.

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Developmental Neurotoxicology Research

Principles, Models, Techniques, Strategies, and MechanismsBy Cheng Wang William Slikker, Jr

John Wiley & Sons

Copyright © 2011 John Wiley & Sons, Ltd
All right reserved.
ISBN: 978-0-470-42672-2

Chapter One

APPROACHES AND MODELS FOR EVALUATING THE TOXIC EFFECTS OF ANESTHETICS IN THE DEVELOPING NERVOUS SYSTEM

WILLIAM SLIKKER, JR., XUAN ZHANG, FANG LIU, MERLE G. PAULE, and CHENG WANG

National Center for Toxicological Research, U.S. Food & Drug Administration, Jefferson, AR, USA

1.1 INTRODUCTION

Early-life stress has been shown to cause neuroanatomical and biological alterations and to disturb homeostasis in preclinical and clinical studies. These alterations, in turn, lead to disruptions in regulatory systems and to a heightened risk for pathology. This review highlights ways in which preclinical research can help inform clinical interventions and vice versa and will present crosscutting research tools and animal models along with applications to studies associated with potential anesthetic-induced developmental neurotoxicity.

Various anesthetic protocols have been used in pediatric medicine for many decades without systematic assessments of possible adverse effects. It is known that most of the currently used general anesthetics have either N-methyl-Daspartate (NMDA) receptor blocking or gamma amino butyric acid (GABA) receptor–enhancing properties. These receptors mediate their actions by the activation of ionotropic (ligand-gated ion channels) and metabotropic (G protein-coupled) receptors and act to influence early neuronal developmental events including synapse formation, neuroplasticity, and survival.

The amino acid L-glutamate is generally recognized as the major excitatory neurotransmitter of the mammalian central nervous system (CNS) and glutamate receptors play a major role in fast excitatory synaptic transmission. NMDA-type glutamate receptors are widely distributed throughout the CNS and operate ligand-activated ion channels that are primarily composed of three families of NMDA receptor subunits: NR1 with eight known splice variants, NR2 (A–D), and NR3A and B. The NR1 subunit is essential for receptor/channel function. Functional properties of the NMDA receptor vary throughout the CNS; the binding affinities of various ligands for recombinant NMDA receptors depend on subunit composition. NMDA receptors are involved in a variety of physiological and pathological processes, including memory and learning, neuronal development, epileptiform seizures, synaptic plasticity, and acute neuropathologies associated with stroke and traumatic injury. During the brain growth spurt, blockade of the NMDA receptor for a period of hours triggers widespread apoptotic neurodegeneration in the rodent brain.

GABA, the principal inhibitory neurotransmitter in the adult CNS, acts as an excitatory transmitter in the early postnatal stages. Functional GABA_A receptors are expressed in neurons early in development (embryonic stages), and investigations by several research teams have led to the conclusion that a transient excitatory action of GABA via GABA_A receptors represents a general feature of developing neurons. Activation of GABA_A receptors depolarizes neuroblasts and immature neurons in all regions of the CNS examined to date, including spinal cord, hypothalamus, cerebellum, cortex, hippocampus, and olfactory bulb. This depolarization is not due to unusual properties of neonatal GABA_A channels but to an elevated intracellular Cl^- concentration, probably from developmental changes in [Cl^-]_i homeostatic systems. Postsynaptic GABA_B receptor-mediated responses, that is, the activation of K⁺ and inhibition of Ca²⁺ currents, are absent from the embryonic and neonatal rat hippocampus and neocortical neurons until the end of the first postnatal week of life. The reasons for this delayed maturation of postsynaptic GABA_B receptor-mediated inhibition are not yet well understood. It may be due to a lack of coupling between receptors, G proteins, and K⁺ or Ca²⁺ channels, rather than to the late development of receptors.

It has been hypothesized that exposure of the developing brain to NMDA antagonists induces neuronal cell death, most likely through compensatory mechanisms. An important working hypothesis is that exposure of developing brains to individual anesthetics (such as ketamine), with continuous blockade of NMDA receptors, causes a compensatory up-regulation of these receptors. This up-regulation makes neurons bearing these receptors more vulnerable, after removal (washout) of the offending compound, to the excitotoxic effects of glutamate because these up-regulated NMDA receptors allow for the influx of toxic levels of intracellular free calcium under normal physiological conditions. In addition, prolonged supraphysiologic stimulation of immature neurons by GABA agonists enhances overall neuronal excitation and may contribute to increased excitability during early development. This increased excitability, along with NMDA antagonist-induced alteration of NMDA receptors, could contribute to abnormal neuronal cell death.

Modifications of synaptic efficacy are believed to play an important role in information processing and storage by neuronal networks. It has been suggested that synaptic abnormalities are important components of anesthetic-induced neurotoxicity. Synaptophysin is a synaptic vesicle-associated protein that is involved in synaptogenesis. The sialic acid polymer on neural cell adhesion molecules (PSA-NCAM) is an important regulator of cell surface interactions. PSA-NCAM is also a neuronspecific marker known to be an NMDA-regulated molecule important in synaptogenesis during development. Some experiments have been performed to determine the correlation between anesthetics and PSA-NCAM expression because quantifying the levels of PSA-NCAM following anesthetic exposure serves to validate the activity states of neuronal synaptic plasticity.

Neuronal susceptibility to neurotoxic insult varies with the stage of development. Both in vitro and in vivo approaches have been used to assess the neurotoxicity associated with a wide range of anesthetic drugs at a variety of doses and exposure durations. Although comprehensive gene expression/proteomic studies and longterm behavioral assessments remain to be completed, in vivo and in vitro models and analytical strategies have been developed to help identify the biological pathways and behavioral outcomes of anesthetic-induced cell death in the developing nonhuman primate and rodent.

1.2 NEUROTRANSMISSION, SYNAPTOGENESIS, AND ANESTHETIC-INDUCED NEURONAL CELL DEATH

Glutamate promotes certain aspects of neuronal development including migration, differentiation, and plasticity. The NMDA-type glutamate receptor NR1 subunit is widely distributed throughout the brain and is the fundamental subunit necessary for NMDA channel function. NMDA receptor density has been shown to increase in cultured cortical neurons after exposure to the NMDA receptor antagonists D-AP5, CGS-19755, and MK-801 but not after exposure to the AMPA/kainate receptor antagonist CNQX. Overactivation of NMDA receptors is known to kill neurons via a necrotic mechanism characterized by excessive sodium and calcium entry accompanied by chloride and water entry that leads to cell swelling and death. More recently, it has been shown that NMDA receptor...

Details zur Ausgabe

• Verlag: John Wiley & Sons Inc
• Erscheinungsdatum: 2011
• Sprache: Englisch
• ISBN 10: 0470426721
• ISBN 13: 9780470426722
• Einband: Gebundene Ausgabe
• Anzahl der Seiten: 646
• Kontakt zum Hersteller: Wiley-VCH GmbH; product_safety@wiley.com; ; Boschstrasse 12; Weinheim; 69469; Deutschland