Horizons in Neuroscience Research [1 ed.] 9781622578467, 9781613241714

Citation preview

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook



+25,=216,11(8526&,(1&( 5(6($5&+ 

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

92/80(

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, 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 herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

+25,=216,11(8526&,(1&(5(6($5&+ Additional books in this series can be found on Nova’s website under the Series tab.

Additional E-books in this series can be found on Nova’s website under the E-books tab.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.



Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

+25,=216,11(8526&,(1&(5(6($5&+

+25,=216,11(8526&,(1&( 5(6($5&+ 

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

92/80(

$1'5(6&267$ $1' (8*(1,29,//$/%$ (',7256

1RYD6FLHQFH3XEOLVKHUV,QF New York Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2012 by Nova Science Publishers, Inc. $OOULJKWVUHV HUYHG No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com 127,&(727+(5($'(5 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.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

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. Additional color graphics may be available in the e-book version of this book. /LEUDU\RI&RQJUHVV&DWDORJLQJLQ3XEOLFDWLRQ'DWD

ISSN: 2159-113X ISBN 978-1-62257-846-7 (eBook)

Published by Nova Science Publishers, Inc. †New York Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

CONTENTS vii

Preface Chapter 1

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Chapter 2

Poor Correlation between Drug Efficacies in the Mutant SOD1 Mouse Model Versus Clinical Trials of ALS Necessitates the Development of Novel Animal Models for Sporadic Motor Neuron Disease Heather M. Wilkins, Ron J. Bouchard, Nancy M. Lorenzon and Daniel A. Linseman The Role of Central Nervous System Grey Matter in the Immunopathology of Multiple Sclerosis Emma E. Frost, Prakash P. Pillai and Mike P. Namaka

Chapter 3

Grey Matter Injury in the Hypoxic-Ischemic Neonate Susan M. Sullivan

Chapter 4

Effects of Chronic Psychosocial Isolation on Limbic Brain Structures of Wistar Rats Marija Radojcic, Miroslav Adzic, Ana Niciforovic, Jelena Djordjevic, Ana Djordjevic, Constantinos Demonacos and Marija Krstic-Demonacos

Chapter 5

Chapter 6

Chapter 7

Neurophysiological Tools in OCD: From Research to Clinical Applications Svetla Velikova, Giancarlo Comi and Letizia Leocani Apolipoprotein E4 Related Changes in Cortical Gray Matter in HIV Infection Aaron M. McMurtray, Erin Saito, Eric Watson and Beau Nakamoto External Static Magnetic Field as a Device for Self-Motion Perception: A Pathophysiological Rodent Model and Its Consequences János F. László

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

1

41 71

97

127

145

163

Contents Chapter 8

Chapter 9

Chapter 10

The Extent and Functional Role of Topographic Organisation within the Cerebral Cortex Chris J. Tinsley Grey Matter Changes in Experimental Autoimmune Encephalomyelitis Jacqueline M. Orian, Hong Pham, Anton A. Ramp, Leana L. Downs, Roisin K. Briscoe and Margaret M. Ayers Transcranial Magnetic Stimulation (TMS): A Therapeutic Alternative to Drug Therapy in Migraineurs? Beverley M. Clarke, Markad V. Kamath, Adrian R. M. Upton, Claudia M. Castellanos, Sneha Gaitonde

Chapter 11

Cognitive Plasticity Ghaydaa Ahmed Shehata

Chapter 12

Diabetes, Hyperhomocysteinemia and Stroke: The Missing Link Pallab K. Ganguly, Ahmed N. AlShibi, Khalid AlShehri, Arif Abdulbaki, Anas Jobeir, Mohamed Diya Sabbagh, Thane G. Maddaford and Grant N. Pierce

Chapter 13

The Role of the Interhemispheric Pathways in Speech Processing Saskia Steinmann, Gregor Leicht and Christoph Mulert

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Index

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

203

223

241

257

271

285 297

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

35()$&( This compilation presents original study results on the leading edge of neuroscience research. Each article has been carefully selected in an attempt to present substantial research results across a broad spectrum. Included in this volume is on the role of central nervous system grey matter in the immunopathology of multiple sclerosis; transcranial magnetic stimulation (TMS) in migraine therapy; cognitive plasticity; interhemispheric pathways in speech processing; grey matter changes in experimental autoimmune encephalomyelitis and the effects of chronic psychosocial isolation on limbic brain structures of wistar rats. Chapter 1 - Amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease is a neuromuscular disease characterized by degeneration of spinal cord and cortical motor neurons, retraction of motor axons from the neuromuscular junctions, and consequent muscle wasting, paralysis, and death. Approximately 90% of ALS cases are considered sporadic and 10% have a familial origin. Of the latter group, nearly 20% are caused by mutations in the gene SOD1 (Cu/Zn-superoxide dismutase). Currently, the principal animal models of ALS include mice or rats transgenic for various SOD1 mutations. As a result, pre-clinical studies are essentially limited to testing in a model with disease etiology akin to only a small fraction (~ 2%) of ALS clinical cases. This limitation has translated into a very poor correlation between drug efficacies in pre-clinical studies using the mutant SOD1 mouse model and results observed in clinical trials of ALS. According to the ALS Association, 11 clinical trials for ALS have failed during the past 12 years.1 At the present time, riluzole, an indirect antagonist of glutamate receptor activation, is the only drug approved by the FDA for the treatment of ALS. Unfortunately, riluzole has a very modest effect on patient survival and provides only slight improvement of symptoms or quality of life. Here, the authors discuss the results of multiple clinical trials of potential ALS therapies including modulators of glutamate release and signaling, neurotrophic factors, antioxidants, and other drugs with varied modes of action. All of these agents have failed to demonstrate significant efficacy in ALS patients despite their overall positive effects in the mutant SOD1 mouse model. The ineffectiveness of the mutant SOD1 mouse model to predict success in clinical trials of ALS brings into question the advisability of initiating future drug trials based largely on this preclinical model. Furthermore, the poor correlation cited here necessitates the development of novel animal models of ALS which are based on potential causes of the much more common 1

Vincent, A., Sakowski, S., Schuyler, A., and Feldman, E. (2008). Strategic approaches to developing drug treatments for ALS. Drug Discovery Today 13, 67-72.

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

viii

Andres Costa and Eugenio Villalba

sporadic form of the disease. To this end, the authors propose a hypothetical model of sporadic motor neuron disease founded on the significantly higher incidence of ALS observed in military service personnel and in particular, those who served in the Gulf War. Such a model would include environmental exposures common to this population such as aluminum, organophosphate pesticides, and cyanobacterial neurotoxins. Novel animal models of sporadic motor neuron disease could be used in conjunction with the mutant SOD1 mouse model of ALS to select only the most promising drug candidates for clinical testing. Chapter 2 – Multiple Sclerosis (MS) is a chronic, predominantly autoimmune, neurological disorder, the exact cause of which is still unknown. MS characteristically affects the myelin of the central nervous system (CNS). Myelin facilitates the propagation of nerve impulses along axons that are essential for normal physiological functioning. Scarring and hardening (sclerosis) of CNS tissue with slowed nerve conduction are hallmark characteristics associated with demyelination, which result in a diverse array of clinical symptoms [1, 2]. Despite its recognized global presence, MS has a higher prevalence in the northern hemisphere. There are thought to be approximately 1,000,000 people worldwide between the ages of 17 and 65 years diagnosed with MS [3]. Although the disease primarily affects females, male MS patients often have a worse prognosis [2, 4]. There are several known gender-dependent factors in the etiology and phenotypic variability of MS [3]. For example, significant differences in the measures of activities of daily living (ADL) dependency and disability have been identified, with males slightly more likely to exhibit total ADL dependence and greater loss of voluntary movement [5]. In addition, female MS-patients tend to have significantly better cognitive performance and communication skills, and a more substantial increase in pain than male MS-patients [5]. Further, the inflammatory component of the disease is more prominent in female MS-patients [4]. MS occurs most commonly in young adults, but has also been diagnosed in children and adolescents [6, 7]. Interestingly, pediatric MS is characteristically more inflammatory than the adult onset disease [6, 8]. The diagnostic criteria for pediatric onset is essentially the same as for adult onset MS [9-11]. The exact cause of MS is still unknown, however, contributing risk factors include vitamin D deficiency [12]; genetics [13-15]; human herpes virus and varicella-zoster virus [16, 17]; Staphylococcus aureus [18]; smoking; [3]; diets high in animal/saturated fats and low in polyunsaturated fats [12]; as well as sex hormones such as estrogen also appear to be implicated in the disease [4, 12]. Chapter 3 - The grey matter of the brain consists of large numbers of neuronal cell bodies and dendrites, along with blood vessels and glial cells such as astrocytes and microglia; and is responsible for processing and initiating responses to sensory or motor stimuli. Injury to grey matter can affect individuals of all ages as a consequence of head trauma, stroke and neurodegenerative diseases such as Alzheimer’s disease. In the neonate, hypoxia/ischemia (HI, a deficiency in oxygen availability or restriction in blood supply) is a common occurrence during parturition, arising as a consequence of complications such as placental abruption and umbilical cord compression. HI events can damage both grey and white matter and cause life-long consequences such as mental retardation, cerebral palsy, epilepsy and learning disabilities. This chapter will discuss grey matter injury in the HI neonate, detailing mechanisms of damage and the changes that occur in the major cells of grey matter, the neurons and astrocytes. Grey matter damage after an HI event develops over a period of days to weeks; therefore a therapeutic window exists for treatment or intervention. Current and

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Preface

ix

future therapeutic strategies for HI neonates will be discussed with reference to reducing grey matter injury in the neonatal brain. Chapter 4 - Chronic stress is recognized as an etiological factor for the onset and exacerbation of many psychiatric disorders. Among chronic stressors, those of psychosocial and emotional origin are considered of particular importance for prominent depletion of physiological and psychological resources. The key mechanisms underlying deleterious effects of chronic stress are thought to emerge from the compromised stress response at the level of hypothalamic-pituitary-adrenal (HPA) axis feedback, and limbic brain structures, such as hippocampus (HIPPO) and prefrontal cortex (PFC). In this review the authors summarize and discuss effects of chronic psychosocial isolation (CPSI) using animal model of male Wistar rats, housed individually for 21 days lacking physical and visual contact. CPSI, as an important distress factor for normally gregarious Wistar rats, resulted in diminishment of serum corticosterone and blood glucose, and did not alter catecholamine levels, which opposes most other chronic stressors that elevate stress hormones. In the context of possibly aberrant feedback mechanism at the molecular level, the authors discuss altered glucocorticoid receptor (GR) distribution and appearance of GR phosphoisoform excessively phosphorylated on serine 232 (pGR S232), as well as, altered activities of JNK and CDK kinases that target GR for phosphorylation. The appearance of pGR S232 in the nucleus and the mitochondria of HIPPO and PFC is potentially related to a marked transcriptional activation/repression of several GR regulated nuclear genes (GR itself, CRH, BDNF) and mitochondrial genes (COX1, COX3). Another important stress and redox state sensitive transcription factor, nuclear factor kappa B (NFțB) is also discussed in terms of the disturbed redox balance (illustrated by the altered ratio of the activity of an array of antioxidant enzymes) and altered proapoptotic/proplastic signalling, since it regulates transcription of a wide array of genes (like Bcl-2, NCAM). Such cellular conditions, provoked by CPSI, are also shown to affect susceptibility to mitochondrially triggered apoptosis (illustrated by redistribution of Bcl family members and DNA fragmentation, more prominent in the PFC) and to simultaneously affect expression of main neural plasticity protein, polysialylated NCAM (PSA-NCAM). In summary, the authors present novel causal connection between the redox imbalance in the CNS, altered signalling via JNK and CDK kinases, GR phosphorylation/transactivity and NFțB transactivity, as well as their cellular imbalance, the parameters which all together yield inadequate CNS and systemic stress response. Chapter 5 - Obsessive–compulsive disorder (OCD) is considered as a manifestation of recurrent cortico-subcortical processing deficit. The analysis of electroencephalographic (EEG) oscillatory activity, mainly power and coherence, allows to investigate the integrity of thalamo-cortical and cortico-cortical circuits and have shed light on different aspects of OCD pathophysiology. Moreover, the application of advanced topographic methods of EEG analysis contributed to parallel detection of brain rhythm changes and of the corresponding cortical structures involved. On the other hand, using event-related EEG analysis to specific tasks, evidence on disturbances in conflict monitoring and executive functions has been provided. The neurophysiological approach, besides providing information on the physiopathology of OCD, has been proposed as a promising tool for phenotyping the disturbance, based upon correlation between changes in brain rhythms, clinical subtypes and response to treatment. A special interest is represented by comparative studies between findings in OCD and other

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

x

Andres Costa and Eugenio Villalba

psychiatric disturbances, allowing the possibility for future application of methods in the differential diagnosis. However, the latter approach still requires extensive validation addressing the assessment of sensitivity and specificity of the proposed methods. Chapter 6 - The presence of the apolipoprotein E4 allele (Apo E4) is a known risk factor for development of cognitive impairment and dementia among older HIV-seropositive individuals. The Apo E4 allele likely increases risk for development of cognitive disorders in HIV infection by exacerbating neuronal cell loss and dysfunction. This has been demonstrated using cultured neurons in which expression of the Apo E4 allele is associated with increased neuronal vulnerability to the neurotoxic effects of HIV viral coat proteins. The authors own research demonstrates significant reductions in frontal lobe cortical gray matter metabolism (left side greater than right) in HIV seropositive individuals with at least one copy of the Apo E4 allele compared to those without any Apo E4 allele (p < 0.05). The changes in frontal lobe cortical metabolism were found to be clinically significant and associated with impairment in performance of neuropsychological tests of frontal lobe functions (WAIS Digit Span p = 0.03; Letter Number Sequencing p < 0.01; Trails B p = 0.015; Stroop Color/Word score p = 0.026). In conclusion, the Apo E4 allele is a risk factor for development of cognitive impairment and dementia in aging HIV-seropositive individuals. Presence of at least one copy of the Apo E4 allele is likely sufficient to cause increased neuronal susceptibility to the neurotoxic effects of HIV viral coat proteins, resulting in increased neuronal dysfunction and death, and clinically detectable differences on neuropsychological test performance of frontal lobe functions. These functional changes may be identifiable early on using positron emission tomography and precede development of detectable structural differences on magnetic resonance imaging. Chapter 7 - The perception of static magnetic fields is a frequent paradigm in the fauna used for orientation, hiding, and hunting. Do humans also have endogenous magnetic field detectors that people can use for self-motion perception in an external static magnetic field? People have bodies that are ab ovo magnetized (mostly diamagnetically), it applies flowing fluids for different material transport processes, they maintain a nervous system based on electrically charged particle transfer. It is obvious that many parts of an organism are subject to changes in an external magnetic field. Accordingly, patients often report on mild and temporary (patho)physiological effects while spending time in the bore of a high field MRI. The authors search for potential magnetic sensors by pain essays in experimental models, and conclude that their existence is highly probable. Chapter 8 - Topographic organisation has been an important concept in people’s understanding of the brain however its functional role is the subject of debate. Detailed topographic maps have been elegantly described in somatosensory, visual and motor cortices. Similar sensory and motor maps have been described elsewhere, notably in the thalamus, secondary sensory and motor cortices, cerebellum and basal ganglia. Accumulating evidence now indicates that topographic maps may also occur in some associational regions of the brain such as the prefrontal cortex, parietal cortex and temporal lobe. Studies of the anatomical connections between different parts of the brain have shown that projection pathways linking ascending sensory regions are often topographically organised. Further, the connections linking associational regions with no known topographic mapping are also often topographically organised.

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Preface

xi

This article explores the extent of topographic maps and their relationship to topographically mapped connections within the cerebral cortex. The theoretical functional importance of topography for informational coding, integration and abstract representations is also discussed. Chapter 9 - Experimental autoimmune encephalomyelitis (EAE) is the preferred model for investigations of the neuroinflammatory disorder multiple sclerosis (MS). Most commonly, it is generated by vaccination of a susceptible species with a neuropeptide derived from the sequence of a myelin protein. EAE has been controversial as an MS model, because it does not reproduce certain essential hallmarks of MS and has proven unpredictable in terms of testing potential MS therapies. However, it is generally regarded as being a useful model for neuroinflammation, providing valuable insights into immunopathogenetic mechanisms, including effector cascades for T-cell mediated damage within the central nervous system, as well as the potential contribution of humoral components of the immune system to demyelination. As with investigations based on human post-mortem tissue, the emphasis of EAE studies has been on white matter disease, whilst the contribution of grey matter damage to the overall disease progression has been overlooked. Given the recent pathological and imaging data supporting the hypothesis that MS is a global CNS disease, with different but concurrent pathological processes in white and grey matter, it is remarkable that the number of studies on EAE grey matter pathology has remained so limited. This chapter reviews imaging and pathological investigations of grey matter in EAE and describes evidence from the authors’ laboratory, of early grey matter involvement in the pathological process. The authors propose that the model should be used more extensively to obtain proof-of-principle for immunopathological mechanisms in grey matter and comparison with those operating in white matter, including during the pre-clinical disease stage. Chapter 10 - The literature reports a myriad of causes of migraine some of which are idiopathic migraine, migraine due to genetic abnormalities, hormonal dysfunction, or trauma. The pathogenesis of migraine is also unclear. Vascular theories involving cranial nerves, occipital arteries, stroke, vascular malformations and constriction of the renal artery have been reported from 1872 to the present [1-3]. Others [4-10] have subscribed to neuroinflammatory theories. Many scientists have been firm advocates of cortical hyperexcitability theories while still others believe that migraine is due to hypo function of the cortex [11-21]. In addition there are reports of autonomic nervous system dysfunction and biochemical deficits [22-24]. Research evidence reports the vascular risks associated with migraine headache and show increased levels of calcitonin gene-related peptide (CGRP), tumor necrosis factor –alpha (TNFalpha), and adhesion molecules, markers of systemic inflammation [25]. Oxidative stress, thrombosis, increased body weight, high blood pressure, hypercholesterolemia, impaired insulin sensitivity, high homocysteineine levels may all be inflammatory markers associated with migraine which can also lead to stroke and coronary heart disease. Recent research has confirmed theories confirming the importance of cortical spreading depression (CSD) as a cause of aura [26]. Altered cerebral blood flow and impaired neuro-transmission systems have been identified between headache episodes in which there may or may not be an aura. Gene expression profiling shows that alpha-fodrin was 1 of 15 genes that were differentially expressed in lymphoblasts of patients with migraine and aura [27]. Some [28] report disturbances in the brainstem, hypothalamus and thalamus. There are also reports of migraine associated with vestibulopathy [29].

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

xii

Andres Costa and Eugenio Villalba

The management of migraine headache is complex and outcomes, as reported by patients, are largely unsatisfactory [30]. Often pain is not the prime underlying mechanism of migraine. Currently, there is not a unified theory of pathophysiology of migraine. Further there is not a unified theory of the physiological mechanisms of drug therapy interventions or of neuro-stimulation techniques. Consequently, this paper argues that based on the above limitations, it is not possible to ascertain that any one of the current treatment interventions supersedes another and ethical practice demands that patients are informed about the reasons for the choice of one treatment method over another and the scientifically observed expectations of effectiveness that have been reported. This chapter will argue that if the above problems are to be resolved, research studies and the treatment interventions advocated in these studies, must be evaluated according to criteria other than the mere presence or absence of pain. Chapter 11 - Cognitive plasticity is the capacity to acquire or improve cognitive skills (e.g., the ability to solve problems or recall events). It varies across individuals, species, and throughout the lifespan, and can be influenced by health and training. For the nervous system to translate experience into memory and behavior, lasting structural changes at the synapses must occur. Neural networks exhibit adaptations of their activity by altering the strength of synaptic connections (i.e., synaptic plasticity). Synaptic plasticity in the hippocampus has been extensively studied, because this region plays a critical role in long-term memory formation. In addition, synaptic plasticity in the prefrontal cortex has the functions of shortterm storage of information; behavioral flexibility, attention, and decision making undergo dynamic neuronal adaptation processes through the induction of synaptic plasticity. Modulation of the strength of synaptic connections is dependent on NMDA receptors. Moreover, Calcium mobilisation is an important step in multiple forms of plasticity. Understanding the mechanisms that constrain cognitive plasticity is fundamental to developing new technologies and educational practices that maximize intellectual advancements. Transcranial Magnetic Stimulation is complementary to more traditional neuroimaging studies based on haemodynamics function MRI or metabolic (Positron Emission Tomography) approaches to cognitive plasticity. Pharmacological drugs, Exercise, cognitive reserve, improvement of working memory and TMS can improve cognitive plasticity. Chapter 12 - A deficiency in any enzyme or co-factor required for the metabolism of homocysteine can lead to an accumulation of plasma homocysteine. For example, nutritional deficiencies of folate and vitamin B12 can lead to reduced remethylation of homocysteine to methionine and an increased plasma homocysteine levels. The most common genetic cause of elevated homocysteine in the general population is the C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) gene preventing adequate enzyme function. Hyperhomocysteinemia has several pathophysiological consequences. For example, hyperhomocysteinemia has been identified as an important independent risk factor for atherosclerosis, particularly in patients with Type 2 diabetes. In addition, elevated plasma levels of homocysteine are associated with the development of stroke. The mechanistic association of stroke with hyperhomocysteinemia is unclear. Because hyperhomocysteinemia is related to the development of atherosclerosis, this may explain the association of homocysteinemia with a stroke. Hyperhomocysteinemia has now been associated with a variety of brain disorders including dementia and Alzheimer's disease. It is possible that the additional effects of homocysteine may involve a more direct action on the brain itself that

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Preface

xiii

could augment neuronal damage in a stroke. In support of this hypothesis, homocysteine can induce direct neurotoxicity by activating the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor and can trigger the release of excitatory amino acids and catecholamines in specific areas of the hypothalamus. These effects may be more predominant in hypertension superimposed with Type 2 diabetes. The identification of catecholamines and excitatory amino acids as important detrimental factors in hyperhomocysteinemia-induced neuronal damage may represent the missing links for the development of stroke in patients with hyperhomocysteinemia and Type 2 diabetes. Chapter 13 - The ability to produce and to understand language is one of the most complex and fascinating phenomena of the human brain. The neural correlates of language are examined today using several neuroimaging methods which provided an unprecedented opportunity to improve the knowledge about the relationship between neurobiological structures and functional behaviour. During speech processing a timely coordinated interaction of a relative broad distributed cortical and subcortical interhemispheric network is required. Diverse linguistical types, such as phonemes, morphemes, syllables, phrases, words, plus the syntactic relation between them as well as the prosodic information have to be identified. In healthy righthanders linguistic language processing is typically arranged by the left hemisphere (LH), whereas the right hemisphere (RH) plays a stronger role in the processing of prosodic information. Prosody reflects the individual characteristics of spoken utterances (speech tempo, breaks, pitch). Thus, to enable effective speech processing both hemispheres have to communicate via the Corpus Callosum (CC). The CC represents the main commissural tract connecting both hemispheres for information transfer, consisting of 200-350 million pathways and is located at the base of the longitudinal fissure. The crucial neuroanatomical structure for the interhemispheric transfer of the auditory cortices marks the posterior third of the CC. Interestingly, Magnetic Resonance Imaging (MRI) analyses revealed great interindividual variability in size and shape of the CC. This variability correlates with the quality of connectivity: Stronger anatomical pathways between auditory cortices support a better information transfer and, consequently, improve speech perception. The following review article summarizes and discusses the recent findings concerning the interhemispheric pathways and their structural plus functional meaning in speech processing as well as their role in speech-related symptoms like acoustic verbal hallucinations (AVH).

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved. Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

In: Horizons in Neuroscience Research. Vol. 5 Editors: A. Costa and E. Villalba

ISBN 978-1-61324-171-4 © 2012 Nova Science Publishers, Inc.

Chapter 1

3225&255(/$7,21%(7:((1'58*()),&$&,(6 ,17+(087$1762'0286(02'(/9(5686 &/,1,&$/75,$/62)$/61(&(66,7$7(6 7+('(9(/230(172)129(/$1,0$/02'(/6 )256325$',&027251(8521',6($6( Heather M. Wilkins, Ron J. Bouchard, Nancy M. Lorenzon and Daniel A. Linseman

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Department of Biological Sciences and Eleanor Roosevelt Institute, University of Denver, Denver, Colorado, U.S.A. Research Service, Veterans Affairs Medical Center, Denver, Colorado, U.S.A. Division of Clinical Pharmacology and Toxicology, Department of Medicine and Neuroscience Program, University of Colorado Denver, Aurora, Colorado, U.S.A.

$%675$&7 Amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s disease is a neuromuscular disease characterized by degeneration of spinal cord and cortical motor neurons, retraction of motor axons from the neuromuscular junctions, and consequent muscle wasting, paralysis, and death. Approximately 90% of ALS cases are considered sporadic and 10% have a familial origin. Of the latter group, nearly 20% are caused by mutations in the gene SOD1 (Cu/Zn-superoxide dismutase). Currently, the principal animal models of ALS include mice or rats transgenic for various SOD1 mutations. As a result, preclinical studies are essentially limited to testing in a model with disease etiology akin to only a small fraction (~ 2%) of ALS clinical cases. This limitation has translated into a very poor correlation between drug efficacies in pre-clinical studies using the mutant SOD1 mouse model and results observed in clinical trials of ALS. According to the ALS

To whom correspondence should be addressed: Department of Biological Sciences and Eleanor Roosevelt Institute, University of Denver, 2199 S. University Blvd., Denver, CO 80208; Tel.: (303) 871-5654; Fax: (303) 871-3471; E-mail: [email protected]

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

2

Heather M. Wilkins, Ron J. Bouchard, Nancy M. Lorenzon et al. Association, 11 clinical trials for ALS have failed during the past 12 years.1 At the present time, riluzole, an indirect antagonist of glutamate receptor activation, is the only drug approved by the FDA for the treatment of ALS. Unfortunately, riluzole has a very modest effect on patient survival and provides only slight improvement of symptoms or quality of life. Here, we discuss the results of multiple clinical trials of potential ALS therapies including modulators of glutamate release and signaling, neurotrophic factors, antioxidants, and other drugs with varied modes of action. All of these agents have failed to demonstrate significant efficacy in ALS patients despite their overall positive effects in the mutant SOD1 mouse model. The ineffectiveness of the mutant SOD1 mouse model to predict success in clinical trials of ALS brings into question the advisability of initiating future drug trials based largely on this pre-clinical model. Furthermore, the poor correlation cited here necessitates the development of novel animal models of ALS which are based on potential causes of the much more common sporadic form of the disease. To this end, we propose a hypothetical model of sporadic motor neuron disease founded on the significantly higher incidence of ALS observed in military service personnel and in particular, those who served in the Gulf War. Such a model would include environmental exposures common to this population such as aluminum, organophosphate pesticides, and cyanobacterial neurotoxins. Novel animal models of sporadic motor neuron disease could be used in conjunction with the mutant SOD1 mouse model of ALS to select only the most promising drug candidates for clinical testing.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

,1752'8&7,21 Lou Gehrig was a Hall of Fame baseball player for the New York Yankees in the 1920s and 1930s. His nickname was the “Iron Horse” because of his great athleticism and stamina. Lou Gehrig established the record for the most consecutive games played at 2,130, a record which stood for nearly six decades in the major leagues. In 1939, on his 36th birthday, Lou Gehrig was diagnosed with ALS and less than two years later he succumbed to this devastating disease [www.LouGehrig.com]. Lou Gehrig’s story is indeed tragic, but perhaps what is more tragic is that the prognosis for a patient diagnosed with ALS today is essentially the same as that which Lou Gehrig received more than 70 years ago. Individuals diagnosed with ALS, or Lou Gehrig’s disease, have a typical life span of only 1-5 years. Currently, there is only one FDA approved therapy for ALS, riluzole, which only extends survival by approximately 3 months and has limited beneficial effects on quality of life. Thus, new and more effective therapeutics are critically needed for ALS patients. Although ALS is classified as a rare disorder by the National Organization of Rare Disorders (NORD), ALS is one of the most prominent neurodegenerative diseases with an incidence 5 times greater than that of Huntington’s disease and half the incidence of Multiple Sclerosis [NORD www.rarediseases.org; Bertram and Tanzi, 2005; Robert Packard Center for ALS at Johns Hopkins www.alscenter.org]. ALS is responsible for 2 deaths per 100,000 annually, with approximately 5,600 people diagnosed in the U.S. each year [ALS association, www.alsa.org]. At any given time, ALS affects approximately 30,000 patients overall in the U.S. The pathology underlying ALS involves the apoptotic death of spinal and cortical motor neurons and retraction of motor axons from the neuromuscular junctions [Luo and O’Leary, 1

Vincent, A., Sakowski, S., Schuyler, A., and Feldman, E. (2008). Strategic approaches to developing drug treatments for ALS. Drug Discovery Today 13, 67-72.

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Poor Correlation between Drug Efficacies in the Mutant SOD1 Mouse Model …

3

2005; Sathasivam and Shaw, 2005]. Reactive astrogliosis also appears to play a significant role in disease progression [Schiffer et al., 1996; Schiffer and Fiano, 2004]. Finally, micoglial inflammation may similarly contribute to motor dysfunction in ALS [Henkel et al., 2004; Sargsyan et al., 2005; Dewil et al., 2007]. During disease progression, ALS patients experience muscle wasting, eventual paralysis, and inevitably death which is commonly caused by respiratory failure. The etiology of ALS overall is unknown; however, approximately 10% of cases are familial while the remaining majority are sporadic. Mutations in several genes such as Cu/Zn-superoxide dismutase (SOD1), TAR DNA binding protein (TDP-43), and fused in sarcoma/translated in liposarcoma (FUS/TLS) have begun to elucidate the mechanisms of familial ALS (FALS) and to a lesser extent, sporadic forms of the disease [Rosen et al., 1993; Kabashi et al., 2008; Sreedharan et al., 2008; Kwiatkowski et al., 2009]. Approximately 130 discrete mutations have been identified in the SOD1 gene, each leading to single amino acid changes. However, only 20% of FALS cases are caused by mutations within this gene. Mouse and rat models transgenic for SOD1 mutations such as G93A, G37R, and G85R are commonly utilized in ALS pre-clinical research. In particular, the G93A mutant SOD1 mouse is most often utilized in pre-clinical studies despite representing far less than 2% of all human ALS cases. Currently, ALS research is lacking an important pre-clinical tool, an animal model of sporadic ALS. This is evident from the strong negative correlation between the results obtained in pre-clinical studies largely conducted in the mutant SOD1 mouse and human clinical trials. According to the ALS Association, 11 clinical trials have failed in the past 12 years [Vincent et al., 2008; www.alsa.org]. Pre-clinical models have limitations, according to Jeffrey Rothstein from Johns Hopkins University, who states “…potential inappropriateness of a familial model - the ALS mutant SOD1 mouse is based on a single molecular defect that accounts for only 1-2% of all ALS cases.” He continues to discuss how a therapy ameliorating the toxic effects of mutant SOD1 may not be expected to have positive effects on the larger sporadic ALS population despite possible common mechanisms of disease etiology [Rothstein, 2004]. Here, we review pre-clinical data and clinical trial outcomes of 18 drug candidates targeting various disease etiologies such as glutamate excitotoxicity, neurotrophic factor deprivation, and oxidative stress, among others (Table 1). Each of the drug candidates were initially tested in pre-clinical disease models such as the G93A mouse or rat, the wobbler mouse, or the progressive motor neuropathy (pmn) mouse, as well as various cell culture models of neuronal degeneration. Overall, positive results in these pre-clinical models and in particular, the mutant SOD1 mouse model, failed to accurately predict clinical trial outcomes which were uniformly negative. This poor correlation between pre-clinical testing in the FALS-based, mutant SOD1 mouse model and clinical trial outcomes underscores the importance of developing novel animal models of ALS founded on sporadic disease mechanisms. To this end, we propose an animal model based on the high incidence of sporadic ALS observed in military personnel, particularly those who served in the Gulf War. This hypothetical model of sporadic motor neuron disease would involve exposure of mice to environmental toxins common to these military personnel such as aluminum, organophosphate pesticides, and cyanobacterial neurotoxins.

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

G93A mouse high and low copy number G93A mouse Organotypic motor neuron cell cultures Wobbler mouse

G93A mouse and rat

Pmn mouse

Antagonist of glutamate action Antagonist of glutamate action

Neurotrophic

Neurotrophic

G93A mouse

G93A mouse G93A mouse

Neurotrophic

Antioxidant Antioxidant Antioxidant Antioxidant Antioxidant

G-CSF Granulocyte colony stimulating factor Vitamin E (alpha tocopherol) CoQ10 (coenzyme Q10)

N-Acetylcysteine

Combination therapy Edaravone

G93A mouse Wobbler mouse G93A mouse G93A mouse

Animal Model

Method of Action

Drug

BDNF Brain derived neurotrophic factor IGF-I Insulin like growth factor Xaliproden SR 57746A Neurotrophic

G93A mouse and rat

Antagonist of glutamate action

Riluzole** **Only FDA approved therapy for ALS Gabapentin

Topiramate

Animal Model

Method of Action

Drug

Delay onset Slows progression Prolonged survival Delays Onset Prolonged survival Preserved MN Prolonged survival Prevent MN loss Delays motor deficits Prolongs survival Delays progression

Delays onset Prolongs survival

Pre-Clinical Effect

In males only; prolongs survival, delay onset, delayed motor deficits Prolongs survival Slows progression

Slows motor neuron (MN) dysfunction

No effect on G93A mouse Protective in cell cultures

Prolongs survival

Prolongs survival

Pre-Clinical Effect

Double blind Placebo Randomized Double blind Placebo Randomized Double Blind Randomized Dose escalation Open Phase II only Double Blind Phase III

Double blind Placebo

Clinical Trial

Double blind Placebo Randomized

Double blind Placebo Randomized

Double blind Placebo Randomized

Double blind Placebo Randomized Double blind Placebo Randomized

Double blind Placebo Randomized

Clinical Trial

(-) (-) Awaiting outcome

(-)

(-)

(-)

Correlation (Clinical to Preclinical) (-)

(-)

(-)

(-)

(-)

(-)

Correlation (Clinical to Pre-clinical) (+/-)

7DEOH3UHFOLQLFDOGDWDDQGFOLQLFDOWULDORXWFRPHVRIGUXJFDQGLGDWHVWKDWWDUJHWYDULRXVGLVHDVHHWLRORJLHV

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

l)

k)

j)

i)

h)

g)

References

f)

e)

d)

c)

b)

a)

References

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Animal Model

Method of Action

HDAC inhibitor

GAPDH inhibitor

Antidepressant

Creatine Monohydrate Drug

Sodium Phenylbutyrate

TCH346 CGP 3466B

Lithium

No effect on G93A mouse Increased survival in pmn mouse Prolongs survival No effect in 2/3 studies

Prolongs survival Delays motor deficits

Prolongs survival Delays onset Preserved MN Prolongs survival Pre-Clinical Effect

Open label Dose escalation Phase II only Double blind Placebo Randomized

Double blind Placebo Randomized Double blind Placebo Randomized Clinical Trial

(-)

Correlation (Clinical to Preclinical) (-)

(-)

(-)

p)

o)

References

n)

m)

Double Blind (-) q) Placebo Randomized Celecoxib Anti-inflammatory G93A mouse Prolongs survival Delays Double Blind (-) r) motor deficits Placebo a) Bensimon et al., (1994); Dunlop et al., (2003); Gurney et al., (1996), (1998); Lacomblez et al., (1996a, b); Miller et al., (2007); Traynor et al., (2003); and Zoccolella (2007). b) Gurney et al., (1996); Miller et al., (1996, 2001) c) Cudkowicz et al., (2003); Maragakis (2003) d) Beck et al., (2005); Ikeda et al., (1995); Ochs et al., (2000) e) Borasio (1998); Franz et al., (2009); Lai et al., (1997); Lepore et al., (2007); Sorenson et al., (2008) f) Duong et al., (1998); Lacomblez et al., (2004); Meininger et al., (2004) g) Komine-Kobayashi et al., (2006); Nefussy et al., (2010); Pitzer et al., (2008); Solaroglu et al., (2006) h) Desnuelle et al., (2001); Graf et al., (2005); Gurney (1996) i) Kaufman et al., (2009); Lass & Sohal (2000); Matthews et al., (1998) j) Andreassen et al., (2000); Henderson et al., (1996); Louwerse et al., (1995) k) Mari et al., (2009); Nagano et al., (2003); Vyth et al., (1996); Zhang et al., (2004) l) Ito et al., (2008); Takahashi (2009); Yamamoto et al., (1997); Yoshino & Kimura (2006) m) Festoff et al., (2006); Filipovic & Zecevic (2008); Gordon et al., (2007); Krady et al., (2005); Kriz et al., (2002); Lee et al., (2004);Tikka et al., (2002); Van Den Bosch et al., (2002) n) Drory & Gross (2002); Groeneveld et al., (2003); Klivenyi et al., (1999); Rosenfeld et al., (2008); Shefner et al., (2004) o) Cudkowica et al., (2009); Ryu et al., (2005) p) Groenveld et al., (2004); Hara et al., (2006); Miller et al., (2007); Sagot et al., (2000) q) Aggarwal et al., (2010); Fornai et al., (2008); Gill et al., (2009); Pasquali (2009); Pizzasegol et al., (2009) r) Cudkowicz et al., (2006); Drachman et al., (2002)

G93A mouse

G93A mouse Pmn mouse

G93A mouse

G93A mouse G37R mouse G93A mouse

Antibiotic/ Antiinflammatory Supplement

Minocycline

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

6

Heather M. Wilkins, Ron J. Bouchard, Nancy M. Lorenzon et al.

These particular toxins are not restricted to military personnel (although they may experience a higher level of exposure than the civilian population) and therefore, exposures to such toxins may also underlie a significant fraction of sporadic ALS cases in the general population. We propose that a novel mouse model of sporadic ALS could be utilized in conjunction with available FALS animal models to provide an additional level of stringency in pre-clinical testing. Such an approach could significantly enhance the ability of researchers and clinicians to predict which drug candidates will ultimately demonstrate therapeutic efficacy in the ALS patient population for those who overwhelmingly suffer from a sporadic form of disease.

7+(087$1762'0286(02'(/,6$322535(',&7252) 7+(5$3(87,&()),&$& 100 patients per trial) ALS clinical trials, creatine failed to demonstrate any positive therapeutic effects on survival or the rate of functional decline [Groeneveld et al., 2003; Shefner et al., 2004; Rosenfeld et al., 2008]. In contrast to its dramatic effects in the mutant SOD1 mouse model, multiple clinical trials have shown that creatine does not provide any discernible therapeutic benefit to ALS patients. Sodium Phenylbutyrate Transcriptional dysregulation, such as decreased transcription of antioxidant genes upon mutant SOD1 expression has been implicated as a possible mechanism of ALS pathology [Kirby et al., 2005]. This transcriptional dysregulation can be caused by an imbalance in the opposing activities of histone acetyl transferases (HATs) and histone deacetylases (HDACs) [Schmalbach and Petri, 2010]. In this context, specific HDAC isoforms have recently been reported to show differential levels of expression in brain and spinal cord samples taken postmortem from ALS patients versus controls [Janssen et al., 2010]. Sodium phenylbutyrate is an HDAC inhibitor that has been shown to increase histone acetylation, induce the NFNBdependent transcription of pro-survival Bcl-2, decrease spinal motor neuron loss and reactive astrogliosis, and markedly enhance survival in G93A mutant SOD1 mice [Ryu et al., 2005]. A recent phase II, dose escalation, clinical trial did not show any positive therapeutic effects of phenylbutyrate in a small cohort of 40 ALS patients; however, the drug did decrease histone acetylation by approximately 50% in blood [Cudkowicz et al., 2009]. Unfortunately, only 26 patients completed the 20-week treatment phase of the study due to intolerance of higher doses of the drug. It is presently unclear if a longer treatment phase with a more tolerable dose of phenylbutyrate would demonstrate any significant therapeutic effect in ALS. TCH346 (CGP 3466B) Nuclear accumulation of the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has been suggested to play a causative role in neuronal apoptosis and neurodegeneration [Mazzola and Sirover, 2002]. For example, cultured cerebellar granule neurons showed a 5-fold increase in the nuclear accumulation of GAPDH which correlated

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

20

Heather M. Wilkins, Ron J. Bouchard, Nancy M. Lorenzon et al.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

with the induction of apoptosis and furthermore, pre-treatment with GAPDH antisense oligonucleotides prevented both GAPDH nuclear accumulation and apoptosis [Ishitani et al., 1998]. GAPDH nuclear translocation appears to be mediated via its S-nitrosylation by nitric oxide and subsequent binding to the E3 ubiquitin ligase, Siah1 [Hara et al., 2005]. The nuclear localization signal present on Siah1 allows GAPDH to gain entry to the nucleus where it apparently stabilizes Siah1 and facilitates its degradation of nuclear proteins. Recently, GAPDH conformation and activity have been found to be altered in G93A and H46R/H48Q mutant SOD1 mouse tissues; effects which may result from increased oxidative or nitrosative stress (e.g., nitric oxide) and subsequent induction of protein aggregation and loss of enzymatic activity [Pierce et al., 2008]. TCH346 (also referred to as CGP 3466B) is an anti-apoptotic compound which inhibits the S-nitrosylation of GAPDH, the binding of GAPDH to Siah1 and the nuclear translocation of GAPDH [Hara et al., 2006]. TCH346 had no significant effects on disease onset or survival in the G93A mutant SOD1 mouse [Groeneveld et al., 2004]. However, in the pmn mouse model, TCH346 treatment was associated with a significant 57% increase in lifespan [Sagot et al., 2000]. In contrast to the positive effects observed in the pmn mouse model, a double-blind, phase II/III clinical trial with TCH346 failed to show any evidence of significant therapeutic effect on disease progression, survival, muscle strength, time to tracheostomy, or forced vital capacity when compared to placebo [Miller et al., 2007].

Lithium Lithium has a number of potentially neuroprotective activities including but not limited to, inhibition of the pro-apoptotic kinase, glycogen synthase kinase-3E, induction of autophagy, and suppression of reactive astrogliosis [Klein and Melton, 1996; Fornai et al., 2008; Pasquali et al., 2009]. In an initial pre-clinical study using the G93A mutant SOD1 mouse, lithium treatment was reported to prolong survival from 110.8 (+/- 5.0) days to 148 (+/- 4.3) days, as well as increasing rotarod, grip strength, and stride length scores. In addition, time to disease onset and paralysis were stated to be delayed [Fornai et al., 2008]. Other positive effects reported for lithium treatment in this pre-clinical study included decreased mitochondrial vacuolization and increased number of mitochondria within spinal cord motor neurons. Moreover, the number of autophagic vacuoles also increased within spinal cord motor neurons of lithium-treated G93A mutant SOD1 mice suggesting a druginduced autophagic response [Fornai et al., 2008]. In a human clinical trial reported in the same study, lithium given as add on therapy to riluzole was shown to significantly reduce the decrement in the Norris rating scale from 46.1% in the riluzole treatment group to 10.6% in the lithium + riluzole treatment group. Similarly, the decrement in the ALSFRS-R was reduced from 39.8% with riluzole to 14.3% with lithium + riluzole. Other improvements were noted in forced vital capacity and survival. The authors state that no clinical trial participants receiving lithium succumbed during the trial, while 29% died in the riluzole treatment group [Fornai et al., 2008]. Another pre-clinical study utilized specifically female mice of two different genetic backgrounds (129S2/Sv and C57BL/6J) with the G93A SOD1 mutation. Neither strain showed any positive effect of lithium treatment on measures of body weight, grip strength, rotarod, disease onset, survival, disease duration, or preservation of motor neurons in lumbar spinal cord sections [Pizzasegola et al., 2009]. An additional pre-clinical study utilized a sibling-matched, gender-balanced, investigator-blinded trial of lithium treatment in G93A mutant SOD1 mice; however, no positive benefits on survival, disease

Horizons in Neuroscience Research, edited by Andres Costa, and Eugenio Villalba, Nova Science Publishers, Incorporated, 2011. ProQuest Ebook

Poor Correlation between Drug Efficacies in the Mutant SOD1 Mouse Model …

21

onset, body weight, or neurological severity scores were observed [Gill et al., 2009]. Most recently, a large multicenter, randomized, double-blind, placebo-controlled clinical trial of lithium in combination with riluzole was terminated at an interim analysis point as a result of meeting a pre-established criterion for futility [Aggarwal et al., 2010]. Thus, lithium was reported to have dramatic therapeutic effects in initial pre-clinical and clinical tests; however, subsequent pre-clinical studies and a large clinical trial have failed to duplicate these promising results.

Copyright © 2011. Nova Science Publishers, Incorporated. All rights reserved.

Celecoxib Cyclooxygenase-2 (COX-2) is responsible for the synthesis of prostaglandins which, in turn, stimulate astrocytic glutamate release and reactive oxygen species production [Drachman and Rothstein, 2000]. In patients with sporadic ALS, COX-2 expression and prostaglandin E2 levels were shown to be markedly increased in spinal cord and cerebrospinal fluid, respectively [Maihöfner et al., 2003]. Celecoxib is a COX-2 inhibitor which has been shown to normalize prostaglandin E2 levels in spinal cords of G93A mutant SOD1 mice [Drachman et al., 2002]. Moreover, celecoxib was shown to significantly delay the onset of motor deficits measured by rotarod testing and the drug significantly prolonged survival by 28 days. Celecoxib also demonstrated protection of spinal motor neurons and decreased astrogliosis and microglial inflammation in the G93A mutant SOD1 mouse [Drachman et al., 2002]. However, in a double-blind, placebo-controlled clinical trial, celecoxib failed to provide any significant therapeutic effect for grip strength, vital capacity, ALSFRS-R, time to tracheostomy, or survival in ALS patients. Upon examination of prostaglandin E2 levels in cerebrospinal fluid, no significant difference was found between celecoxib treatment and placebo [Cudkowicz et al., 2006]. Thus, the positive therapeutic effects observed with celecoxib in pre-clinical studies using the G93A mutant SOD1 mouse were not predictive of clinical trial outcomes in human ALS patients.

,1&5($6(',1&,'(1&(2)$/6,10,/,7$5