Nerve Growth Factor: New Research

NERVE GROWTH FACTOR: NEW RESEARCH

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NERVE GROWTH FACTOR: NEW RESEARCH

GUY K. MACINTIRE EDITOR

Nova Science Publishers, Inc. New York

Copyright © 2008 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers’ use of, or reliance upon, this material. Any parts of this book based on government reports are so indicated and copyright is claimed for those parts to the extent applicable to compilations of such works. Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Library of Congress Cataloging-in-Publication Data Nerve growth factor : new research / Guy K. MacIntire, editor. p. ; cm. Includes bibliographical references and index. ISBN 978-1-60876-336-8 (E-Book) 1. Nerve growth factor. I. MacIntire, Guy K. [DNLM: 1. Nerve Growth Factors. WL 104 N4545 2008] QP552.N36N46 2008 612.8'1--dc22 2008030075

Published by Nova Science Publishers, Inc.

New York

Contents

Preface Chapter 1

vii Roles of Neurotrophic Factors in Neuropathic Pain: From Pathogensis to Therapy Li Li and Xin-Fu Zhou

1

Chapter 2

Nerve Growth Factor in Animal Models of Atopic Dermatitis Norikazu Takano

Chapter 3

The Chemokine Stromal Cell-Derived Factor-1 (SDF-1) Promotes PC12 Cell Differentiation Ken-Ichiro Uwabe

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Innovative Strategies for Controlled Delivery and Release of NGF in Neurological Applications Gianni Ciofani, Vittoria Raffa and Silvestro Micera

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Nerve Growth Factor: A Neurokine Orchestrating NeuroimmuneEndocrine Functions Stephen D. Skaper

141

Chapter 4

Chapter 5

Chapter 6

Chapter 7

The in Vivo Role of NGF as an Intermediate in Neuroendocrine, Immune, and Redox Regulation following Peripheral or Central Inflammation Implicating Neurotransmitter Regulation Denis Arsenijevic, Hyun-Jong Yang and Denis Richard Nerve Growth Factor Signaling in Neural Cancer and Metastasis Sandra M. Morillo and Jose M. Frade

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181 203

vi Chapter 8

Contents The Role of Neurotrophins in Affective Disorders Study of Blood and Brain BDNF and NT-3 and cAMP-PKA-Regulated BDNF Expression Félicien Karege

229

Chapter 9

Neurotrophin in Female Reproductive System Chinmoy K Bose

269

Chapter 10

Nerve Growth Factor and Its Receptors in the Human Ovary Ronit Abir, Roni Garor, Asangla Ao and Benjamin Fisch

295

Chapter 11

Nerve Growth Factor and Alzheimer’s Disease: Where Do We Stand Today and Where Should We Go? Francesco Angelucci, Carlo Caltagirone, Gianfranco Spalletta and Paola Bossù

Chapter 12

Cellular Effects of the Neurotrophic Factor S100B Following Experimental Traumatic Brain Injury Andrea Kleindienst, Christine Stadelmann, Zhaohua Qu, M. Ross Bullock and Michael Buchfelder

Chapter 13

Information Processing by NGF-Activated Signaling Networks Mikhail Paveliev and Mart Saarma

Chapter 14

Nerve Growth Factor Mediated Effects in the Development of Orbitopathy Associated with Graves’ Disease Ildikó Molnár

Index

311

329

345

359 375

Preface Nerve growth factor (NGF) is a small secreted protein which induces the differentiation and survival of particular target neurons (nerve cells). It is perhaps the prototypical growth factor, in that it is one of the first to be described - that work by Rita Levi-Montalcini and Stanley Cohen was rewarded with a Nobel Prize. NGF is critical for the survival and maintenance of sympathetic and sensory neurons. NGF is released from the target cells, binds to and activates its high affinity receptor (TrkA), and is internalized into the responsive neuron. There are some data that show that NGF can be transported from the axon tip to soma, but it is unclear if this is necessary for effective cell signalling; in fact there are data showing that it is not. What is clear is that NGF binding and activation of TrkA is required for NGF-mediated neuronal survival and differentiation. This new volume presents important recent research in this rapidly-expanding field. Chapter 1 – Clinical patients with peripheral nerve injury often suffer from persistent neuropathic pain, which are refractory to conventional analgesic therapy. The mechanisms underlying post-traumatic neuropathic pain remain unclear. Over the past decade evidence has been accumulated that neurotrophic factors play critical roles in persistent pain states and emerged as an exciting new class of potential targets for development of new drugs to control neuropathic pain on the basis of their profound roles as mediators and modulator of pain. In this review, the authors present an overview of pathophysiological changes of neurotrophic factors in pain pathway in different neuropathic pain animal models, and discuss roles of neurotrophic factors in particular nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in peripheral and central pathomechanisms of nerve injury-induced neuropathic pain. Moreover, current progress on therapeutic intervention targeting neurotrophic factors in neuropathic pain and inflammatory pain is summarized. Chapter 2 – Itching is a characteristic symptom of various dermatoses, especially atopic dermatitis. The most effective strategy for treatment of atopic dermatitis would be to prevent aggravation of skin lesions and improve quality of life by reducing itching and scratching. Nerve growth factor (NGF) is an important substance in the skin, where it plays roles in nerve maintenance and repair. However, the nature of involvement of NGF in pruritic diseases such as atopic dermatitis is not yet fully understood. The authors used the NC/Nga mouse, an animal model of atopic dermatitis, to test the hypothesis that NGF plays important roles in the pathogenesis, development, and maintenance of the skin lesions of this condition.

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In these mice, nerve fibers were significantly increased in number in the epidermis of lesional skin, and NGF contents in serum and skin were significantly elevated. Furthermore, repeated administration of anti-NGF antibody or high-affinity NGF receptor inhibitors significantly improved established dermatitis and scratching behavior and decreased innervation of the epidermis. The authors’ findings suggest that NGF plays important roles in the pathogenesis of atopic dermatitis-like skin lesions, particularly via the high-affinity NGF receptor, and that inhibition of the physiological effects of NGF or suppression of increase in NGF production may prevent or moderate the symptoms of several pruritic skin diseases. Chapter 3 – Chemokines and their receptors are essential for the development and organization of the hematopoietic/lymphopoietic system. A member of the CXC chemokine subfamily, stromal cell-derived factor-1 (SDF-1) and its unique receptor CXCR4 have been shown to be expressed in embryonic and mature central nervous system (CNS). The present data show that SDF-1 causes the morphological and molecular differentiation of PC12 cells in a manner similar to nerve growth factor (NGF). PC12 cells are shown to express CXCR4. Neurite outgrowth stimulated by SDF-1 was attenuated by small interfering RNA-mediated knockdown of CXCR4 and pertussis toxin (PTX), which uncouples Gi protein. Comparison of extracellular signal-regulated kinase signaling pathways between SDF-1and NGF shows that these pathways are crucial for SDF-1 action as well as NGF. CXCR4 mRNA is upregulated by neuron in the rat facial nucleus following axotomy. Recently, several studies have demonstrated that SDF-1 and its receptor CXCR4 play an important role in the CNS development and adulthood by mediating cell migration, enhancing precursor cell proliferation. In addition to these functions, SDF-1/CXCR4 signaling may be required for neurite outgrowth during nerve regeneration. Chapter 4 – Neurotrophic molecules have a deep influence on developmental events such as naturally occurring cell death, differentiation and process outgrowth, and could be used for treating degenerative neurological conditions and promoting neural regeneration. The neurotrophin family members (nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), neurotrophins 3 (NT-3) and 4 (NT-4)) are proteins which cannot cross the bloodbrain barrier and therefore need to be administered directly to their target in the brain. Drug delivery to the nervous system remains a challenge despite advances in understanding the mechanisms involved in the development of neurodegenerative disorders and the actions of neuroactive agents. The systemic administration of neuroactive biomolecules to support neuronal regeneration has several intrinsic problems, including the toxicity and poor stability associated with many bioactive factors and access limitation by the blood-brain barrier. The best characterized trophic molecule, NGF, has a spectrum of effects on peripheral and central neurons. It has received particular attention as a potential treatment for Alzheimer’s disease because of its protective action on basal forebrain cholinergic neurons. Intraventricular infusion of NGF can prevent cholinergic cell death following fimbrial transsection in adult rodents and monkeys. Based on these data, the entrapment of NGF was performed in monolithic implantable devices. A variety of techniques to deliver therapeutics to the CNS has been established, including osmotic pumps and silicone reservoirs. However, pumps frequently become

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clogged, thus limiting their ability to sustain effective concentrations; moreover these methods are often associated to highly invasive drawbacks, including device failure and higher potentials for inflammation and infection due to their non degradable components. This chapter will focus on innovative strategies for delivering NGF both for in vivo and in vitro applications. Development of polymeric films, hydrogels and microparticles will be considered. Polymeric delivery systems, in fact, have the potential to maintain therapeutic levels of a drug, to reduce side effects and to facilitate the delivery of drugs with short in vivo half-lives. Synthetic and naturally derived polymers are widely used in controlled release devices for protein delivery. These devices are designed such that bioactive factors are released in a spatially and temporally controlled manner; for example, release can occur as the polymer degrades or by diffusion through pores in the polymer matrix. In neural applications, two types of delivery devices have been primarily used: polymer matrices and microspheres. Particular attention will be devoted to the recent advancements in the field of neuronal tissue engineering and of neuronal regeneration. Finally, possibility to integrate NGF delivery techniques to regeneration-type (sieve) neuronal interfaces will be analysed and discussed. Chapter 5 – Nerve growth factor (NGF) is widely recognized as a target-derived factor responsible for the survival and maintenance of the phenotype of specific subsets of peripheral neurons and basal forebrain cholinergic nuclei during development and maturation. Considerable evidence has accumulated over the last twenty years to indicate that the actions of NGF extend far beyond “classical” effects on cells of the nervous system, to encompass a role for this molecule in the interplay between the nervous, immune, and endocrine systems. NGF as well as brain-derived neurotrophic factor, another member of the protein family of neurotrophins, have been implicated in the pathophysiological mechanisms of many diseases of the nervous and the immune systems, such as multiple sclerosis, neuropathy, pain, allergic bronchial asthma and neurotrophic keratitis. The concentration of NGF is elevated in a number of inflammatory and autoimmune states in conjunction with increased accumulation of mast cells. Like NGF, brain-derived neurotrophic factor serum levels are also increased in asthmatics. Mast cells and NGF appear to be involved in neuroimmune interactions and tissue inflammation. Mast cells themselves are capable of producing and responding to NGF, suggesting that alterations in mast cell behavior may trigger maladaptive neuroimmune tissue responses, including those of an autoimmune nature. Moreover, NGF exerts a modulatory role on sensory nociceptive nerve physiology in the adult, and appears to correlate with hyperalgesic phenomena occurring in tissue inflammation. NGF can thus be viewed as a multifactorial modulator in the reciprocal crosstalk between neurons, immune cells and endocrine cells. Chpater 6 – A major consequence of severe chronic infection is the often massive loss of body weight (=cachexia), which is directly linked to increased morbidity and reduced survival, similarly large increases in body weight leading to obesity are also associated with reduced survival. Animal models must be used to determine the mechanisms involved and this may led to the development of appropriate therapy. The authors’ use of chronic murine infection models and brain inflammatory models suggests that in vivo the site of initiation of the inflammatory process be it peripheral or central is of prime importance to the subsequent pathology. Neuroendocrine interactions with the immune system have recently been

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suggested to be of importance in determining the degree of pathology due to dysregulation of the immune system. In particular peripheral hormones involved in energy balance, such as leptin and ghrelin have been shown to be important in regulating immune function and susceptibility to infection. The authors observed that following permanent middle cerebral artery occlusion (pMCAO) or in acute/chronic infection models all of which induce changes in circulating ghrelin. These changes in ghrelin are associated with altering nerve growth factor (NGF) and redox regulatory factors such as monoamine oxidase (MAO), uncoupling protein 2 (UCP2) and glutathione (GSH). The authors’ studies suggest that NGF can play a role in modifying neuroendocrine systems involving peripheral/central MAO activity, UCP2 and GSH. The authors also have evidence that NGF may play a specific role in food intake regulation following inflammation. In this review the authors will focus on their in vivo studies demonstrating regulatory circuits involving NGF modulation by ghrelin and leptin. Furthermore they will show a role for NGF in modifying central MAO activity, UCP2, cytokine production and glutathione levels. Finally the authors will discuss the role of NGF on food intake and energy expenditure based on their studies. The role of NGF as a integrator of neuroendocrine system, immune function and physiological systems will be evaluated. Chapter 7 – Nerve growth factor (NGF), the founder member of the neurotrophin family, plays an essential role in the development and functioning of the vertebrate nervous system. It regulates survival and function of different neuron populations of the central and peripheral nervous system through two different membrane-associated receptors: the p75 common neurotrophin receptor (p75NTR), a member of the tumor necrosis factor receptor superfamily, and the tyrosine kinase receptor TrkA. NGF is not only active in the nervous system, but also in other different cell types including tumor cells. Changes in the neurotrophin signaling system are significant for the pathogenesis of malignancies at the initiation stage as well as during subsequent tumor progression steps. NGF and its receptors can affect malignant cells and tissues in different ways, acting on cell proliferation, cell maintenance and survival, apoptosis, and metastasis regulation. Differences in mechanisms and outcomes of NGF action depend on the cell and tissue type in which this neurotrophin works, as well as the ratio p75NTR/TrkA present in the cell. In this chapter, the authors summarize the current information on the NGF signaling network in various neural tumors and demonstrate its contribution to the disease course. Furthermore, they show that nuclear translocation of the intracellular domain of p75NTR (p75ICD) induced by NGF in RN22 schwannoma cells, reduces the proliferative capacity of these cells. This provides a novel mechanism by which p75NTR can act as a tumor suppressor gene. Chapter 8 – The neurotrophins - nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3 and NT-4 - represent a family of proteins essential for neuronal survival and plasticity. Recent reports have suggested that these molecules, particularly BDNF, play an important role in neuropsychiatric disorders such as major depression (MDD), suicide, bipolar disorder (BD) and eating disorders (ED). A comprehensive study of the biology of BDNF is an important step in developing its clinical relevance. Following the neuroplastic hypothesis of affective disorders the authors have led an investigation of BDNF’s biology and related molecules. Blood and brain BDNF and NT-3 levels were measured in rodents and in psychiatric subjects. These studies aimed to associate the dysregulation of neurotrophic factors and psychiatric pathologies. The authors also

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investigated the regulation of BDNF mRNA expression in drug-treated cells through cAMP transduction pathways. Results showed that, in major depression disorder (MDD), subjects are characterized by decreased serum BDNF levels, and that the decrease was correlated with the severity of illness. Moreover, the decrease was reversed after an antidepressant treatment. The authors also observed that, during the postnatal maturation period in the rat, changes in serum and brain BDNF protein levels followed the same development scheme and were positively correlated. Neurotrophin protein levels (BDNF and NT-3) have also been measured in postmortem human brains. The data indicated a significant decrease in BDNF and NT-3 levels in both the hippocampus and prefrontal cortex of drug-free depressed suicide subjects compared to non-depressed controls. The decrease was observed in different suicide groups whatever the diagnosis, indicating either a suicide-specific trait or a trait common to other psychiatric diagnoses. Subjects who were under drug treatment at the time of death did not differ from non-suicide controls. By using lymphoblasts (from BD patients), the authors assessed the drug-manipulated BDNF expression as downstream target of the cAMP-Protein kinase A (PKA) and the transcription factor CREB signaling axis. It was observed that, in BD-derived cells, BDNF mRNA expression was decreased, but that the decrease was masked by an upregulated PKA-CREB signaling pathway, resulting in normalization of BDNF mRNA levels. In conclusion, these studies on neurotrophins have identified BDNF and NT-3 as potential biological markers of neuroplasticity in the affective disorders. Given the reported morphological deficits associated with affective disorders, the study of neurotrophins could be a promising track for drug development. Chapter 9 – The neurotrophins (NT) including nerve growth factor (NGF) are a family of related growth factors and their respective receptor tyrosine kinases that are of major importance in the regulation of neuronal survival and differentiation. Since Rita Levi Montalcini and Stanley Cohen received Nobel Prize for their pioneering work on NGF, its role in female reproductive system has been reinforced in last two decades. While role of NGF in mast cell-mediated egg implantation and inhibition of rejection were primary concern at their time, in the ovary they can help in the differentiation process by which ovarian follicles become responsive to gonadotrophins. They help in follicular maturation, steroid secretion and ovulation in the ovary, by inducing the FSH receptor (FSHR). Due to the pleiotropism, NGF is mandatory for the success of pregnancy, while progesterone helping to maintain local levels of NGF in utero. Perimenopausal ovarian surface epithelium (OSE) can also express FSHR. NGF deregulates expression of FSHR in OSE and secretion of FSH from the pituitary and also has the ability to increase VEGF expression. This phenomenon strongly suggests an autocrine role of NGF in epithelial ovarian cancer (EOC). From endometriosis to EOC, NGF is implicated in a variety of female reproductive disorder. Thus its study will infuse new insight in health and disease of female reproductive system. Chapter 10 – The nerve growth factor (NGF) receptor-signaling system is composed of the neurotrophin receptor p75 and the tyrosine kinase A (TrkA) receptor. Recent studies suggest that NGF plays important roles in both the normal development and function of the human ovary as well as with the promotion of ovarian cancer. NGF and its receptors were investigated in human ovaries from fetuses, girls and women and in granulosa cells (GCs) and oocytes from in vitro fertilization (IVF) cycles. The NGF protein was identified in all GCs, and in oogonia and oocytes from preantral follicles. The

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TrkA protein was expressed mainly in oocytes, but also in GCs and in theca cells of antral follicles. The mRNA transcripts of NGF and TrkA were also identified. The p75 protein and mRNA transcripts were predominantly localized in stroma cells surrounding the oogonia/oocytes of fetuses aged up to 22 gestational weeks, but also in neuronal-like cells or fibers among blood vessels, in neuronal bodies, and in theca cells from fetuses and babies. The proteins and mRNA transcripts for NGF and TrkA were identified in cultured GCs and unfertilized mature oocytes from IVF cycles. NGF treatment of these GCs resulted in an increase in 17-β estradiol (E2) production and a decrease in progesterone levels; the addition of NGF together with FSH, induced higher E2 secretion. NGF also promoted an increase in FSH receptor mRNA; this action was blocked by a Trk inhibitor (K252a). Studies indicate that p75 might be involved in follicular assembly during normal fetal ovarian development, as it is expressed mainly around this period. NGF, by promoting E2 production and reducing progesterone levels, prevents early luteinization and induces follicular acquisition of the FSH receptors required for their growth. NGF and its two receptors have also been identified in various ovarian cancers. The NGF and TrkA proteins as well as TrkA mRNA were overexpressed in epithelial ovarian cancer, and the expression of TrkA was found to be a prediction of better outcome in the advancedstage serous epithelial ovarian cancer. NGF probably promotes postmenopausal epithelial ovarian cancer by reducing FSH levels and by stimulating the expression of FSH receptors on the ovarian surface epithelium. NGF also stimulates angiogenesis in surface epithelium cancer directly or by promoting the production of vascular endothelial growth factor. Studies have shown that this increase is inhibited by the addition of an anti-NGF antibody and by K252a. Therefore, blocking NGF action could be a therapeutic target in ovarian cancer. Chapter 11 – Nerve growth factor (NGF) and other members of the neurotrophin family are critical for the survival and differentiation of neurons in the central nervous system (CNS) and have been implicated in the pathophysiology of numerous disease states. Several studies have sought to demonstrate that neurodegeneration during disease and in old age is associated with reduced support of neurotrophins. Because NGF maintains the magnocellular cholinergic neurons that are damaged in Alzheimer's disease (AD), over the past decade, this neurotrophin has gained attention as a candidate therapeutic agent for the disease. However, because NGF does not cross the blood-brain barrier, inconvenient pharmacokinetics and adverse side-effect profiles have limited its clinical usefulness and therapeutic potential. Nevertheless, in recent years, alternative strategies have been developed with particular emphasis on small molecules able to modulate NGF function in AD. Compounds that mimic NGF signaling and overcome the pharmacokinetic and side-effect barriers may have therapeutic potential. Here, the authors review the past and recent preclinical studies and advances into clinical development on the therapeutic effect of NGF in AD and illustrate additional strategies to target (modulate) NGF production and/or its signal transduction pathways. Moreover, since inflammation has been proposed as a possible pathogenic mechanism of AD and NGF is a key mediator of neuronal and immune cross talk, the potential involvement of immune system on NGF-based therapeutic approaches are also discussed. The development of studies on the role of immune-mediated mechanisms in AD and in the regulation of NGF expression can open the door to new frontiers for therapeutic intervention in AD.

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Chapter 12 – Objective: The neurotrophic factor S100B has been promoted as a clinical marker of brain damage and high serum levels are considered to correlate with the severity of injury and a poor prognosis. However, experimental research demonstrated increased cerebral levels of S100B to enhance hippocampal neurogenesis and to improve cognitive recovery following traumatic brain injury (TBI). The purpose of the present study was to elucidate the cellular effects of S100B and thus to differentiate beneficial and detrimental ones. Methods: Following lateral fluid percussion injury in male rats (n=32), the authors infused S100B (50ng/hr) or vehicle into the lateral ventricle for 7 days using an osmotic micro-pump. The animals were sacrificed on day 5 or 5 weeks post-injury, and 5μm sections, 100μm apart (bregma -3.3 to -5.6mm) were analysed histologically. Cell death was assessed using TUNEL and hematoxylin-eosin staining, axonal damage and microglial activation by APP and ED1 immunostaining, and gliosis applying the glial markers GFAP and S100B. Results: TUNEL-positive cells were present directly beneath the lesion site in vehicle and S100B-treated animals on day 5 post-injury (238±6 and 234±24 cells/mm, respectively, n.s.), but not after 5 weeks. The intraventricular S100B infusion did not significantly affect the early (TBI p=0.004, TBI+S100B p=0.036) or late (TBI p=0.039, TBI+S100B p=0.002) axonal injury, but resulted in an unspecific microglial activation opposite to the injury site as documented by an increased ED1 expression (TBI+S100B p=0.001). After 5 weeks, both injury and S100B treatment resulted in an increased number of GFAP expressing cells in the corpus callosum (TBI p=0.005, TBI+S100B p=0.003, sham+S100B p=0.005), while in the hippocampal granular cell layer (GCL) this effect was only present in non-injured control animals (p=0.048). The S100B expression in the GCL was increased by a S100B treatment after 5 weeks, both in injured and non-injured animals (p=0.017 and p