Towards New Therapies for Parkinson's Disease

TOWARDS NEW THERAPIES FOR PARKINSON'S DISEASE Edited by David I. Finkelstein Towards New Therapies for Parkinson's Dis...

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TOWARDS NEW THERAPIES FOR PARKINSON'S DISEASE Edited by David I. Finkelstein

Towards New Therapies for Parkinson's Disease Edited by David I. Finkelstein

Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Silvia Vlase Technical Editor Teodora Smiljanic Cover Designer Jan Hyrat Image Copyright GSPhotography, 2011. Used under license from Shutterstock.com First published October, 2011 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from [email protected]

Towards New Therapies for Parkinson's Disease, Edited by David I. Finkelstein p. cm. ISBN 978-953-307-463-4

free online editions of InTech Books and Journals can be found at www.intechopen.com

Contents Preface IX Part 1

Issues Regarding Current Human Therapies

Chapter 1

Controversial Issues in Deep Brain Stimulation in Parkinson's Disease 3 Shin-Yuan Chen, Sheng-Tzung Tsai and Sheng-Huang Lin

Chapter 2

Cost and Efficacy of Therapies for Advanced Parkinson's Disease 21 Francesc Valldeoriola

Chapter 3

Botulinum A Toxin Intravesical Injections in the Treatment of Refractory Overactive Bladder in Patients with Parkinson's Disease 39 Antonella Giannantoni, Silvia Proietti, Antonella Conte, Massimo Porena and Alfredo Berardelli

Part 2

Models of Disease

55

Chapter 4

Alpha-Synuclein and the Immune Response in Parkinson’s Disease 57 Cintia Roodveldt, Adahir Labrador-Garrido, Guillermo Izquierdo and David Pozo

Chapter 5

The Knoll-Concept to Decrease the Prevalence of Parkinson’s Disease 77 Ildikó Miklya

Chapter 6

Utility of Organotypic Slices in Parkinson's Disease Research 101 Fabio Cavaliere and Carlos Matute

1

VI

Contents

Part 3

Identified Targets and Growth Factors

113

Chapter 7

Therapeutic Potential of Polyphenols in Parkinson’s Disease 115 Rajeswara Babu Mythri, G. Harish, N. Raghunath and M.M. Srinivas Bharath

Chapter 8

Inhibition of Tau Phosphorylation as a Potential Strategy in Treatment of Parkinson’s Disease 151 Wang Wenya

Chapter 9

The Protective Effects of Pre-Treatment with Glutamate Metabotropic Receptor Agonists on the Development of Parkinsonian Movements Munir Qazzaz, Rateb M. Husein, Munther Metani and Abdul-Salam Abdul-Ghani

Chapter 10

GDNF and PD: Less Common Points of View 175 Ana Saavedra and Graça Baltazar

Chapter 11

The Potential of Neurotrophic Factors for the Treatment of Parkinson’s Disease 217 Aideen M. Sullivan and André Toulouse

Part 4

Gene Therapies

165

253

Chapter 12

Gene Therapy for Parkinson’s Disease 255 Michael Douglas and Jonathan Hazlehurst

Chapter 13

Gene Therapy for Parkinson’s Disease: Towards Non Invasive Approaches 269 Manuel Rodríguez, José M. Brito-Armas and Rafael Castro

Chapter 14

Epigenetic Modulation of Adenosine A2A Receptor: A Putative Therapeutical Tool for the Treatment of Parkinson’s Disease 295 Marta Barrachina, Mairena Martín, Francisco Ciruela and Isidre Ferrer

Part 5

Cell Therapies

313

Chapter 15

1980-2011: Parkinson's Disease and Advance in Stem Cell Research 315 Lidia Cova and Marie-Therese Armentero

Chapter 16

Cell Therapy for Parkinson’s Disease: Status and Perspectives 343 Pia Jensen, Christina Krabbe and Morten Meyer

Contents

Chapter 17

Transplantation of Foetal Ventral Mesencephalic Grafts in Parkinson’s Disease: A Still Evolving Concept with New Regulatory Challenges 379 Sven Möllers, Máté Döbrössy and Guido Nikkhah

VII

Preface The current research investigating new ways to treat Parkinson’s disease (PD) is taking many directions. Current therapies successfully ameliorate the symptoms of the disease but the course of the disease appears to be unperturbed. This book is intended for the clinician or scientist looking towards the future. The brief outline of the book is as follows. Chapter 1 explores the issues surrounding the application of subthalamic nucleus deep brain stimulation (STN-DBS), for PD has been shown to induce dramatic and stable long-term improvement of patients’ motor symptoms. However some of the motor symptoms, and most of the non-motor symptoms, may not be improved by STN-DBS, and may even deteriorate after surgery. Even after the successful introduction of STNDBS as a treatment for PD, controversy still exists and this chapter examines a variety of issues: patient selection criteria, the anatomical target, imaging, targeting methods, microelectrode recordings, and anesthetic procedures. Chapter 2 discusses the economic burden of PD. The cost of therapies has become and will increasingly become a very important topic for governments and the health industry. From the perspective of a general neurologist, health economics can appear not be a priority, however it is a growing topic in most modern healthcare systems. Additional demands are being made by health policy decision makers, who can influence medical decisions through coverage and reimbursement policies. Physicians and other professional caregivers increasingly must consider the economic implications of their decisions. Chapter 3, proposes that infusion of apomorphine is a good therapeutic option, rapidly stimulating receptors, thereby assisting in the management of motor fluctuations in the advanced phase of the disease. Apomorphine has the added advantage as it is effective as a rescue therapy that can be administered with a penject. Chapter 4 examines the role of alpha-synuclein and the Immune Response in PD. This chapter proposes mechanisms through which alpha-synuclein might be affecting the immune system that appear not to be just a consequence of disease progression, but to actively contribute to the delicate balance between neuroprotection and neurotoxicity that ultimately underlies a given stage of disease.

X

Preface

Chapter 5 describes the investigations of Joseph Knoll in the early 1960’s that resulted in the development deprenyl a monoamine oxidase (MAO-B) inhibitor. The chapter reviews extensive studies and potential uses of the MAO-B inhibitors. The author proposes that the concept of the prophylactic use of deprenyl proposed by Knoll, may decrease the prevalence of neurodegenerative diseases, such as, Parkinson’s and Alzheimer’s diseases. In Chapter 6 the authors review and describe the use of organotypic cultures as a model to study molecular mechanisms of PD as well as the use as a tool for preclinical studies of pharmacological and cell therapy treatment. It is proposed that disease can be modelled by application of drugs, toxins or by various transfection systems. Various treatment options can also be explored in this versatile system. In Chapter 7 the authors present the view that polyphenols may meet the challenge for novel molecules that could simultaneously target multiple PD pathways without significant side-effects, be non-toxic at higher concentrations and have the ability to cross the blood-brain. Polyphenols are derived from various plant sources. Chapter 8: microtubule-associated protein tau has risk alleles for PD, and mutations that cause brain degenerative diseases termed tauopathies. Aggregated phosphorylated tau forms neurofibrillary tangles in these pathologies. This chapter identifies the inhibition of Tau phosphorylation as a potential strategy in treating PD. Chapter 9: The subcortical nuclei of the basal ganglia are of great importance in initiation of normal body motor activities. Excitatory amino acids play an important role in these normal activities of these nuclei but dysfunction of the transmitter system has been implicated in some neurodegenerative diseases. In this chapter the authors pre-treat animals with glutamate metabotropic receptor agonists prevent the development 6-OHDA induced Parkinsonian movements. The authors suggest that the glutamate is potential target for investigations into new therapies for PD. Chapter 10: Glial cell line-derived neurotrophic factor (GDNF) is considered a strong survival factor for dopaminergic neurons. This has led to the proposed use of GDNF as a potential therapy to slow down or even reverse neurodegeneration in PD. In this chapter the authors explore less common perspectives and alternative therapeutic approaches in PD. They believe that this chapter may draw attention to new directions of GDNF research. The authors of Chapter 11 express the views that despite the recent disappointing results in clinical trials, there remains an optimism that neurotrophic factors will prove to be useful in PD therapy. Optimisation of delivery methods is needed, and vital information is being gleaned from studies in animal models of PD. For future clinical trials, optimisation of surgical and infusion protocols, as well as careful patient selection, will be critical to advance this promising therapeutic approach. Chapters 12 and 13 consider gene therapy to be one of the most promising approaches to develop an effective treatment for PD. The existence of blood brain barrier and the

Preface

ability to control gene expression are currently limitations of this technology. Studies in animals studies have been developing the technologies to regulate gene expression and to deliver the materials in the periphery and have the product expressed in the neurons. These chapters consider viral and non viral ways of delivering the genes to the brain. In Chapter 14 the authors propose the use of S-adenosylmethionine (SAM, a methyl group donor molecule necessary for DNA methylation) as an epigenetic tool to increase the expression of adenosine A2A receptors in PD. It has been proposed that the inactivation of A2A receptor enhances the affinity of D2R for dopamine, this being the probable mechanism underlying the dopaminergic like effect of A2AR antagonists in some patients. Chapters 15 and 16 investigate the prospects of implantation of dopaminergic neurons as a therapy that may reverse some of the central symptoms of PD. Over the last decades, approximately 400 PD patients have been grafted, with substantial motor improvements being reported particularly in younger patients. In these chapters the authors examine the historical approaches and what has been learnt from those as well as the current status. They discuss crucial issues that remain to be resolved to develop cell replacement into an effective and safe therapy. Once the technology for transplantation of tissues into people with PD, there will be a need to resolve the regulatory issues. Chapter 17 examines the technologies involved in the transplantation of foetal ventral mesencephalic grafts in people with PD and then goes on to examine the new regulatory challenges. This book is intended for researchers and clinicians interested in developing new and innovative therapies for Parkinson’s Disease. The editor would like to thank all the authors for their contributions in the book. Finally, gratitude should be expressed also to the team at InTech for the initiative and help in publishing this book.

Assoc. Prof. David I. Finkelstein The Mental Health Research Institute, The University of Melbourne Australia

XI

Part 1 Issues Regarding Current Human Therapies

1 Controversial Issues in Deep Brain Stimulation in Parkinson's Disease Shin-Yuan Chen1,2, Sheng-Tzung Tsai2 and Sheng-Huang Lin3 1Division

of Functional Neuroscience, of Neurosurgery 3Neurology, Neuro-Medical Scientific Center Tzu Chi General Hospital / Tzu Chi University, Hualien Taiwan 2Department

1. Introduction Since 1992, the application of subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) has been shown to induce dramatic and stable long-term improvement of patients’ motor symptoms. However, some of the motor symptoms, and most of the non-motor symptoms, may not be improved by STN-DBS; in fact, they may deteriorate after surgery. Even after the successful introduction of STN-DBS as a treatment for PD, controversy still exists over a variety of issues: patient selection criteria, the anatomical target such as STN or globus pallidus (GPi), targeting methods (MRI alone, CT scan with image fusion, or ventriculography), microelectrode recordings (yes/no), and anesthetic procedures (awake with sedative or under general anesthesia). In this chapter we will discuss these controversial issues by integrating our experience with a review of the literature.

2. Patient selection for deep brain stimulation (DBS) A successful DBS surgery may involve several surgical procedures, but patient selection is always a key issue to address because it contributes to whether there is a good surgical outcome. In 1992, a common evaluation protocol for PD was suggested by the the Core Assessment Program for Intracerebral Transplantations(CAPIT) committee, which allowed for comparisons between different study groups. For example, they defined “offmedication” and “on-medication” status. The core assessment methodologies of this protocol include the following: Unified Parkinson’s Disease Rating Scale (UPDRS), Hoehn and Yahr Staging, Dyskinesia Rating Scale, Self-reporting diary, and timed test for bradykinesia [1]. In 1996, the Network for European CNS Transplantation and Restoration (NECTAR), developed a new Core Assessment Program for Surgical Interventional Therapies in PD (CAPSIT-PD) and gave advice to add evaluations for cognitive function and quality of life [2]. Since then, thousands of papers have been published in the fields of PD and DBS, and clinicians and researchers have paid attention to the issue of patient selection in order to ensure a good outcome [3-9].

4

Towards New Therapies for Parkinson's Disease

In 2009, Australia offered a referral guideline for neurologists to establish methods for enrolling ideal PD candidates for DBS. In 2010, consensus was reached for DBS in PD. With respect to patient selection, these experts stated that, “...Best results have been reported in patients with advanced PD and (1) levodopa response, (2) younger age, (3) no or few axial non–LD-responsive motor symptoms, (4) no or very mild cognitive impairment, and (5) absence of or well controlled psychiatric disease” [10]. The ideal candidate has all of the above components; however, even with these guidelines, pitfalls and controversy still exist. Diagnosis It is important to differentiate PD from atypical parkinsonism to ensure a good long-term outcome of STN-DBS, but it can be hard to discriminate between them because they share clinical features such as bradykinesia, rigidity and tremor. It is especially difficult when the disease is in its early stage and l-dopa responsiveness is moderate. Poor prognostic factors for STN-DBS can be the following: a poor response to l-dopa, the additional presence of pyramidal or cerebellar signs (e.g., ataxia), an early presentation of posture instability and autonomic failure (e.g., hypotension), within 5 years of onset, a nontremor dominant presentation, and persistent unilateral disease [11-12]. The UK Brain Bank Diagnostic Criteria for PD is recommended for assessing all surgical candidates, although it should be noted that the early symptoms of PD, such as hyposmia, REM sleep behavioral disorders, constipation and depression may precede the obvious motor symptoms and are not included on the list [13]. The use of Hoehn and Yahr (H&Y) staging and the Unified Parkinson’s Disease Rating Scale (UPDRS) is a basic requirement for evaluating patients before starting any PD intervention. In 2007, the revising process for the UPDRS was started by a task force of the Movement Disorder Society (MDS), which is aimed at incorporating more detail on non-motor symptoms, but it has not yet been published [14-17]. Age at time of surgery Age is a confounding factor and has a negative correlation with STN-DBS outcome. A trend for greater long-term STN-DBS improvements on the UPDRS part II and part III measures in younger patients has been shown; however, it is also effective in elderly patients, though the benefits may persist for only a short period of time [18]. Most studies also have shown a negative correlation with motor outcome, non-motor outcome (e.g., apathy and depression) and quality of life upon long-term follow-up [18-22]. While the cut-off age proposed by most studies is 70 years old, the benefits and risks of surgery should be weighed to meet the expectations of the patient and the care giver. Disease duration and severity Advanced PD patients with obvious medication side effects of motor fluctuation and/or dyskinesia would be good candidates for DBS. However, an H&Y Stage 1 patient with tremor dominant symptoms who is within 5 years of onset can also be a good candidate for DBS and show a substantial benefit, as can a bed-ridden Stage 5 patient. Because there have been no proven neuroprotective effects of DBS, the recommendation for an earlier intervention is based on quality of life, which will improve substantially in domains related to movement disorders and general health [23]. Though some authors postulate that disease severity may be correlated with STN-DBS outcome, a study of ours found that the outcome was not correlated with H&Y staging or disease duration [18].

Controversial Issues in Deep Brain Stimulation in Parkinson's Disease

5

Levodopa (LD) responsiveness LD responsiveness, as measured by the UPDRS part III, may predict the motor outcome of STN-DBS in a PD patient with disabling motor fluctuations and dyskinesia. In fact, this is true for all cardinal symptoms (except LD refractory tremor) that can be well controlled by STN-DBS. Pre-operative LD responsiveness may only lead to consistent UPDRS part III improvement from STN-DBS at 3 months, and its predictive value may not be valid for long-term follow-up due to co-morbid non-motor symptoms. The pre-operative LD responsiveness of tremor and axial symptoms are stable predictors for the long-term effect of DBS [18]. Cognitive, psychiatric, and other non-motor symptoms Non-motor symptoms in PD patients are a significant source of disability and impairment in the performance of activities of daily living. The non-motor symptoms of PD include dementia, sleep disorders, and dysautonomia along with neuropsychiatric and sensory complaints. Most centers exclude PD patients with dementia and neuropsychiatric symptoms from STN-DBS. As for sleep disorders and sensory complaints, some reports have shown improvement after treatment when these symptoms are present. More generally, normal pre-operative cognitive functioning is positively correlated with postoperative improvement in UPDRS part III at a long-term follow-up [18]. STN-DBS may still lead to a decline in cognitive and executive function even with strict inclusion criteria [24]; however, it has been suggested that sub-optimal contact stimulation (caused by the small volume of STN) is more strongly correlated with post-operative psychiatric events. Although there are still debates about post-operative psychiatric events, the possibility of increased depression and suicide risk prompts us to evaluate the patient’s psychological function in detail prior to the operation.

3. STN-DBS versus GPi-DBS: Which target is better for PD patients? STN-DBS is the current gold-standard surgical treatment in PD, but a high occurrence of adverse effects and neuropsychological problems following STN-DBS stimulation cause some centers to study alternative surgical targets, such as the GPi. The issues to consider when choosing a target for DBS include the following: a different set of patient selection criteria, the amount of levodopa being used, the extent of levodopa-related dyskinesia, battery life and surgeon preference. In randomized trials, DBS has been demonstrated to be superior to the best knownmedical treatment for advanced PD. Under most circumstances, STN is the chosen target rather than GPi. Although several reports have shown that the efficacy of pallidal stimulation decreases over the long-term follow up [25], others have demonstrated a persistent benefit from pallidal stimulation for up to 3 years [26]. In 2005, the first randomized trial was published by Anderson and colleagues, and their patients showed a similar improvement in motor function from subthalamic and pallidal stimulation [27]. Still, deciding which target is best is a topic still subject to debate, and several points of view need to be considered. The effect of target on motor function PD is characterized by disabling motor symptoms. Previous reports seem to have concluded that STN-DBS improves more than GPi-DBS in UPDRS part III (motor) [26-28]. However, a

6


recent large randomized trial showed a similar improvement from either STN or GPi stimulation [29]. It should be noted that the follow-up duration in this study was only 24 months and GPi might show less of a benefit after a longer period of time [25, 30]. The effect of target on non-motor symptoms Non-motor symptoms of PD have received more attention in recent years and seem to play a pivotal role in the change in quality of life caused by the amelioration of motor disabilities through medical or surgical treatment [31]. An increased percentage of post-stimulation behavioral and cognitive complications is still a major concern for STN-DBS [27, 32-33] as it is not conclusively known whether DBS causes a change in these non-motor symptoms. Although a recent randomized trial comparing PD patients undergoing STN stimulation to those who only received the best medication-based treatment showed no significant differences [34], a second study comparing STN stimulation with GPi did show that depression was worse in those who received STN-DBS [29]. This finding reminds us that non-motor symptoms should be considered during target selection for patients who plan to receive electrode implantation. The effect of target on reducing medication dosages One of the main reasons that pallidal stimulation has not become popular may be that it limits the amount one can decrease medication dosages. Most studies have shown that patients who undergo STN stimulation require a lower dose of dopaminergic medication than those who undergo GPi stimulation [28-29]. This effect is probably due to different mechanisms of action underlying the STN and GPi response to electrical current. It has been suggested that STN stimulation reverses the sensitization phenomenon that underpins levodopa induced dyskinesia (LID) [35]. In fact, STN stimulation per se cannot ameliorate LID without decreasing dopaminergic medication[36]. Contrary to this, GPi stimulation may itself decrease the severity of LID [37]. The interaction between STN and GPi activity has been suggested to play a major role in the pathogenesis of dyskinesia, and the amelioration of stimulation-related dyskinesia through proximal contact (i.e., stimulating pallido-subthalamic fibers) shown in previous reports and our own young onset PD (YOPD) patients suggests a more beneficial effect of GPi than STN in ameliorating treatment-related dyskinesia. Overall, most comparative studies showed that the daily dosage of levodopa can be reduced only in an STN-DBS group [26]. The effect of target on battery life The stimulation amplitude within the implantable pulse generator (IPG) is one significant determinant of battery life. In a multicenter study, Rodriguez-Oroz and colleagues found a similar amplitude for patients undergoing STN and GPi stimulation for 3 to 4 years [26]. However, most studies (including one large randomized trial) have shown that STN stimulation requires significantly less electrical power around 0.7~0.8 V and a pulse width of 20 μsec [38]. These parameters allow patients to receive STN stimulation for a longer period of time between pulse-generator replacements as compared to GPi stimulation. Most cost-effectiveness studies also have confirmed this benefit of STN stimulation over solely medication-based treatment for advanced PD. For countries where DBS devices are not reimbursed by health insurance, such as Taiwan, the replacement of the IPG will be a large burden for most patients. Larger amplitudes and pulse widths for GPi stimulation may lead to more frequent battery replacement and more device-related complications [30]. Improving future IPG technology may alleviate this economic consideration.


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Adverse effects of target Adverse effects of stimulation in general include cognitive decline, verbal fluency deterioration, gait disorders and mood instability (in the form of compulsiveness or depression). Most studies show that the adverse effects of stimulation are more common in STN-DBS [27, 29]. In the COMPARE trial, which was a prospective randomized trial, it was shown that under optimal conditions there was no significant difference in the incidence of mood or cognitive alteration following DBS implantation. However, a sub-scale analysis of the Visual Analogue Mood Scale showed that there was more “anger” after STN-DBS. Another randomized trial also has suggested that depression may be worse after subthalamic stimulation but improved after pallidal stimulation. The volume of the STN (~158 mm3) is much smaller than the GPi (~478 mm3) nucleus. Moreover, the sub-territory within the STN nucleus and surrounding fibers involve motor, associative and limbic circuitry that are more compact and close together. Therefore, a suboptimal electrode placement or electrical-current perturbation is more often going to be associated with STN stimulation, which may lead to mood changes and verbal fluency dysfunction. Although a randomized control trial has shown a comparable benefit for GPi stimulation compared to STN stimulation, longer follow-up studies are needed to decide which target is preferable for each patient. We have made a comparison of the targets in Table 1. Clinical trials are ongoing for alternative targets in the pedunculopontine nucleus, radiation prelemniscalis, and caudal zona incerta, and stimulation on these targets may improve symptoms that are currently unresponsive to treatment with either levodopa or STN stimulation. STN stimulation

GPi stimulation

Motor improvement

50~60%, coherent [29, 34]

27~50%, variable in long-term [29, 72]

Mood effect

higher, esp. suboptimal contact

seems unchanged

LEDD reduction

greater reduction (31.5%)

less reduction (17.8%)

Battery life

lower amplitude

higher amplitude

General adverse effect 56%

51%

Table 1. Comparison of STN and GPi stimulation

4. Targeting methods in DBS: MRI alone versus CT scan fused with MRI and/or ventriculography There are a number of targeting methods used in DBS. Which method is used depends on the facilities of the institution and the familiarity of the surgeon with a given procedure. Most practicing centers use magnetic resonance imaging (MRI) as the only tool for targeting, but others use image fusion techniques to co-register MRI and computed tomography (CT) images, or intra-operative ventriculography, which is the traditional targeting method, for determining targeting accuracy. Below we compare these methods on acquisition time, procedure complexity, and ultimate accuracy.

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The size of the STN is extremely small and it has an ovoid shape and oblique orientation [39]. The accuracy of DBS targeting may be one of the most important factor in surgical outcome because the position of the electrode determines the area across which the electrical current diffuses. Given that there are very few evidence-based studies that have directly compared the safety and effectiveness of the various imaging techniques, the best targeting method remains under debate. The methods include MRI, CT, ventriculography and various combinations thereof. Stereotactic targeting with ventriculography is the traditional method for stereotactic functional neurosurgery that has been in use for decades. While it is still used by some teams, there are concerns over its invasiveness and serious complications, such as CSF leakage and intracranial hemorrhage, which are major obstacles for most functional neurosurgeons [40]. The method involves injecting a contrast medium into the right frontal horn and acquiring representative images to determine the location of the anterior commissure and posterior commissure, which then can be used to calculate various target coordinates [41]. Compared with targeting methods that may have higher accuracy (e.g., ventriculography), targeting with MRI can be affected by the anterior displacement of the anterior commissure (AC), which elongates anterior commissure - posterior commissure (AC-PC) length [40]. A magnetic field can cause this nonlinear distortion, especially in the anterior-posterior and medial-lateral axis. Most centers only use MRI for targeting while others use image fusion techniques to coregister MRI and CT scans. MRI-directed targeting for STN-DBS has proven to be a simple yet accurate method in most DBS practicing centers; it has been a standard procedure in our hospital since 2002 [42]. The advantages of MRI includes better demarcation of deep nuclei (e.g., the red and subthalamic nucleus) as references for targeting, better visualization of critical structures that can prevent inadvertent injury (e.g., lateral ventricles and vasculatures within sulci) and a clear delineation of simulating trajectory for electrode. There are three current strategies to localize the coordinates of targets on stereotactic MRI. In direct targeting, the STN is located on MRI without any references, which is inherently prone to errors. The vague configuration of the STN makes determining the STN boundaries on a T2-weighted MR image rely on the subjective visual impression of the neurosurgeon. An indirect method of targeting uses the AC and PC as reference points, thereby avoiding bias when differentiating the border between the STN and substantia nigra, which has been shown to be more accurate than direct targeting. Targeting based on the red nucleus (RN) has not only the same accuracy as indirect targeting but also less variance, which indicates greater precision across subjects (Fig. 1) [43]. Although MRI-based targeting is becoming more popular, the potential distortion of the STN that a nonlinear magnetic field can induce is still a major concern. To counter this, some groups still use ventriculography which reliably identifies the AC-PC for indirect targeting methods using intraventricular landmarks. Although the AC-PC and the target itself (e.g., the STN) are poorly visualized on CT, MRI fused to stereotactic CT are believed to combine the advantages of both modalities, thereby increasing the spatial validity of the image and ensuring a more accurate localization, which continues to improve as fusion technology improves [44]. In our experience, stereotactic CT fused to MRI during DBS surgery can allow for a longer microelectrode recording length of STN and fewer recording tracts (Fig. 2). This indirectly demonstrates that stereotactic CT may have a better pre-operative targeting ability leading to the stimulation of optimal anatomical sites. It should be noted that it may be difficult for advanced PD patients to


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Fig. 1. Direct targeting using MR images is depicted. The target coordinates for the tip of the permanent implantable electrode are at the intersection of the perpendicular lines. The horizontal line is located along the anterior border of the red nucleus. The longitudinal lines are at 2-mm intervals from the lateral border of the red nucleus. Axial section taken at the level of the superior colliculus, just below the lowest border of the STN (4.5 mm below the mid–commissural point). 1= red nucleus; 2=substantia nigra reticulata; 3=crus cerebri. undergo MRI with a stereotactic frame, especially in an un-medicated state where obvious tremors or severe stoop posture will be present. There is a risk for these patients when sedated in the MRI suite in an attempt to quell the severe tremor because the scanning time for MRI may take more than 20 minutes. For this reason, some centers use a specific protocol for direct visualization of the STN in stereotactic MRI, which saves time [45]. At our institution, a stereotactic CT scan takes about 3 minutes, which is far below the average MRI acquisition time of 20-25 minutes for most protocols. With advances in imaging technology, we may be able to define the border of the STN directly using MRI in the future and eliminate the inherent error of nonlinear MRI distortion.

10


Fig. 2. (A) Stereotactic axial computed tomography (CT) images for fiducial registration. (B) Nonfused axial magnetic resonance image (MRI) T1 images and stereotactic CT images. (C) Co-registered Schaltenbran-Wahren atlas for red nucleus and subthalamic nucleus (STN) target planning simulation. (D) Fused axial MRI T2 and CT images, spyglass with visualization of red nucleus (thin arrow) and STN (thick arrow).


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5. The necessity of microelectrode recording in STN-DBS surgery Precise results in DBS surgery are traditionally achieved by MRI targeting followed by electrophysiological confirmation with microelectrode recording (MER) [46]. MRI scans are not always of sufficient quality to identify the target structure and are always susceptible to image distortion. MER can localize the target with more precision when MRI targeting is not precise enough. MER is used in DBS surgery to identify the target’s structural border, the subdivisions of the targeted structure and the outlines of its three-dimensional shape. MRI and MER are complementary in DBS surgery [47]; however, there are disadvantages of MER in DBS surgery, including the following: 1) it is time consuming, 2) it may increase the risk of a hemorrhage complication and 3) it is not always useful, for example when the target is located in white matter or has a large and distinct boundary that can be easily visualized with MRI. Here we will focus on whether MER is necessary in STN-DBS surgery for treating PD. Direct MRI targeting without MER is possible in STN-DBS surgery with the recent advances in high-resolution MRI (field strength of 3-Tesla or more) and advanced image processing techniques. However, there is a paucity of publications that report on the use of stereotactic MRI for direct visualization in STN-DBS surgery without MER [48]. Recently, a large series of STN-DBS without MER has been published by Foltynie et al. [49]. We compared their results with those of Krack et al [50], who performed STN-DBS with MER which recruited from a single center. Table 2 compares the demographic data of the studies’ patients, effect of DBS and complications of surgery. The baseline data of the patients are comparable except that Krack’s sample size is less than Foltynie’s. However, we should note that Krack’s report is designed for long term follow-up (5 years later) and they recruited the first 49 STNDBS patients from their center. The effect of STN-DBS at a one-year follow-up was similar in the two studies. The DBS effect is better in Krack’s study but not significantly so. In terms of surgery-related adverse events, Krack showed greater transient confusion and intracerebral hemorrhage in their patients. Foltynie showed less transient confusion and no hemorrhage events. The risk of intracerebral hemorrhage inevitably increases with a greater number of micro- or DBS electrode penetration events [51-52]. Post-operative transient confusion in DBS surgery is common. The incidence of transient confusion in STN-DBS surgery is 15.6% [53]. This phenomenon is often attributed to a mild pneumocephalus that occurs during surgery. It is not a precisely understood phenomenon, but it occurs more frequently in older and cognitively disabled patients. The risk for and volume of pneumocephalus positively correlates with the amount of time the skull is open during surgery. MER may therefore increase the risk of pneumocephalus because it is time consuming. Based on the above comparison, the same therapeutic effect for patients can be achieved in STN-DBS with and without MER, but MER has more surgery-related adverse events. Others have reported that the use of MER improves the outcome of STN-DBS [42]. With the advancement of MRI technology and imaging processing, MRI-guided STN-DBS without MER may be an alternative surgical method for advanced PD patients. The reports of MRIguided STN-DBS are sparse; therefore, we cannot conclude that this surgical method is better than STN-DBS with MER. Overall, the necessity of MER in STN-DBS surgery remains controversial.

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With MER (Krack et al)

Without MER (Foltynie et al)

Demographic data

Mean

± SD

Mean

Sex (no. of patients)

24 men

/ 25 women

49 men / 30 women

Age at surgery

55.0

± 7.5 (34-68)

57.3

± 7.7 (34.5-70.2)

Duration of disease

14.6

± 5.0

13.4

± 7.0

L-dopa equivalent dose

1409.0

± 605.0

1620.0

± 641.0

UPDRS III motor scores Baseline off-medication

55.7

± 11.9

51.5

± 14.9

UPDRS III motor scores One year after operation on-stimulation, off-medication

19.0

± 11.1

23.8

± 11.2

UPDRS III motor scores One year after operation on-stimulation, on-medication

11.4

± 8.9

14.5

± 8.3

± SD

Effect of STN DBS

Adverse events related to procedure Intracerebral hemorrhage

2

0

Transient confusion

12

7

Seizures

2

2

Table 2. Comparison between DBS with and without MER

6. Anesthetic considerations in DBS: Awake versus general anesthesia Traditionally, DBS is an awake surgical procedure in order to allow electrophysiological mapping and stimulation testing to assess motor responses and potential side effects. However, PD patients with obvious “off-medication” symptoms of anxiety, painful dystonia, and respiratory distress may not be good candidates for the lengthy tolerating the surgical procedures while awake [54-57]. In this section, we will report our own experience with general anesthesia during DBS surgery with MER and compare it with data from awake procedures (see Table 3).

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Operation procedures:

Awake DBS

General Anesthetic DBS

Patient’s condition

communicative and cooperative; Can tolerate severe off-symptoms

Anxious; Cannot tolerate severe off-symptoms, such as: pain, dystonia and/or respiratory difficulties

Anesthetic agents

None

Desflurane (Patient intubated under regular induction and muscle relaxant, keep Mac around 0.8~1.0) [54]

Sedative agents

propofol / remifentanil (intermittent use, e.g. during trephination)

None

MER signals

Yes

Yes

Passive movement-related MER signals

Yes

Yes

Test stimulation

Yes

No

Motor outcome

Good

Good

Surgical complication

Comparable

Comparable

Stimulation side effect

Lower

May be higher

Risk period

During surgery

Induction and extubation

Patient monitoring by anesthesiologist Yes

Yes

Mac: minimum alveolar concentration

Table 3. Comparison between awake DBS and general anesthetic DBS procedures Awake DBS procedures Most DBS centers prefer that their PD patients receive electrode implantation procedures in an awake state in order to retrieve sound electrophysiological signals from MER and to perform test stimulation. Time is crucial for a patient to tolerate the procedure while awake. Patel et al tried an MRI direct-targeting method with macro-stimulation alone. They conclude that without MER the procedure is more efficient and safe but still has a good outcome [58-59]. In the awake state, macro-stimulation is beneficial because it excludes the side effect from electrode stimulation [59]. Sedative agents are inevitable during awake procedures, especially during trephination. Propofol is popular during DBS procedures as a brief general anesthetic agent, but it may require full-time surveillance of the patient’s

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airway and vital signs by an anesthesiologist. The function of the patient’s airway can be a severe problem in an advanced PD patient’s “off” state. MER has been shown to perform properly and without affecting the surgical outcome only when remifentanil was completely stopped and the dose of propofol was carefully monitored [52, 58, 60-61]. Duque et al reported a case with these same anesthetic agents using Bispectral Analysis of the Electroencephalogram (BIS) to monitor cortical activity in order to titrate the hypnotics, which may interfere with MER procedures. While this technique may be useful, it is not convenient [62]. General anesthetic DBS procedures A detailed MER mapping within the STN may lead to an optimal placement of DBS electrodes, but the drawbacks are the length of the procedure and that the patient must be kept awake during the procedure. Some patients with severe “off-medication” PD symptoms, such as major anxiety, poorly tolerated off-medication dystonia, or respiratory difficulties may refuse DBS or may be poor candidates for DBS in an awake state [55, 57]. STN-DBS during a state of general anesthesia may be another choice for those patients with advanced PD for whom symptoms are difficult to control with medication only. In patients with advanced PD who undergo STN-DBS while awake, test stimulation after the permanent electrode is implanted is helpful to confirm the electrode position. The test stimulation verifies the maximal clinical effects intraoperatively as well as the side effects of low voltage in the case that the electrode position was sub-optimal. Test stimulation in patients receiving a general anesthetic is controversial. Hertel et al. performed test stimulation to verify possible capsular effects when using low-voltage electrode stimulation, and the voltage causing the capsular effects may be incorrectly estimated if the excitability of the capsule has been decreased by general anesthesia. In our study, we did not perform test stimulation, but no patient suffered post-operative capsular effects because our selection criteria for the trajectory of electrode implantation chose the most appropriate track [54]. The knowledge of STN topography is crucial in general anesthesia DBS surgery; therefore, MER must be used as it is the only intra-operative tool to identify the STN, map its boundaries, and map its sensorimotor component through the detection of movementrelated neuronal firing [61, 63-65]. The role of anesthesiologist in DBS surgery Most anesthesiologists are treating intubated patients under general anesthesia and in awake procedures like DBS, it can be challenging to ensure neuronal firing on the one hand and monitor patient safety the other. Avoiding medications that may interfere with MER can negatively affect patient safety, especially when the patient is agitated by a prolonged DBS procedure. However, it also is difficult to maintain a secure airway if the patient is too deeply unconscious [66-67]. In hypertensive patients, the alpha-2 agonist dexmedetomidine has been suggested as an effective sedative agent that may provide the patient comfort and good blood-pressure control and yet still allow satisfactory MER mapping by the neurophysiologist [67]. Complications may still occur during awake DBS procedures. Deoganokar reported a case of venous air embolism in an elderly PD patient with a myocardial infarction [68]. Glossop and Dobbs also report two cases of coronary artery vasospasm during electrode implantation. Though these patients recovered, the authors suggest full monitoring by an anesthesiologist throughout the surgical procedures [69].


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The effect of the anesthetic agent desflurane Desflurane (2,2,2-trifluoro-1-fluoroethyl-difluoromethyl ether) is a highly fluorinated methylethyl ether used for maintenance of a general anesthetic. It has the most rapid onset and offset of all of the volatile anesthetic drugs used for general anesthesia because of its low solubility in blood. It also is popular in neurosurgery because it can allow early extubation and facilitate early neurological evaluation [70-71]. MER also can be performed well at an anesthetic level of 0.8±0.2 minimum alveolar concentration (MAC) [54].

7. Conclusion The subthalamic nucleus plays an important role in the functional control of motor activity in the indirect dopaminergic pathway of the basal ganglia. Twenty years after the first introduction of DBS to treat PD, it remains as an important alternative treatment to l-dopa, especially in the patient with motor fluctuation and obvious l-dopa related complication. Centers performing DBS may have different protocol according to their experiences and facilities. Controversial points exist inevitably, however, through proper patient selections, cooperation between multidisciplinary teams, and refine surgical techniques we can ensure a good outcome for DBS candidate.

8. Acknowledgment This work was supported by Master Cheng Yen, President of the Tzu-Chi Foundation, and Tzu-Chi General Hospital grant TCSP 0104.

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2 Cost and Efficacy of Therapies for Advanced Parkinson's Disease Francesc Valldeoriola

Institut de Neurociències, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain 1. Introduction The economic burden of Parkinson’s disease (PD) has become a very important health topic. From the perspective of a general neurologist, health economics can appear as not prioritary; however, it is a growing topic in most modern healthcare systems; consequently health professionals should have at least a minimal understanding of how health economic information is derived. It has become important that payers and providers consider the significant impact the disease has on quality of life and how resource utilisation is directed to improve PD related clinical problems. Such measures are determinant in assessing the value of drug therapy, particularly for chronic conditions such as PD, and in determining the appropriate placement of medications on plan formularies. In the past, a comprehensive examination of a clinical condition would focus almost exclusively on areas considered relevant to patient management, such as diagnosis, etiology, treatment, and prognosis. Now, however, additional demands are being made by health policy decision makers, who can influence medical decisions through coverage and reimbursement policies. Physicians and other professional caregivers increasingly must consider the economic implications of their decisions, which has led to increased demand for disease-specific cost information.

2. Economic burden of Parkinson disease PD is a progressive neurodegenerative disorder of the central nervous system with motor, cognitive, behavioural and autonomic symptoms. PD has a significant economic burden from all perspectives: society, health system, and individual patient and relatives. This is due to the high prevalence of the disease, 6.3 million people around the world (European Parkinson’s disease Association [EPDA], 2008), the nature of the symptoms and the fact that no cure exists and treatments are only aimed at relieving the effects of the disease and to improve patients’ quality of life. In Spain, taking into account a population of around 47 million people (Spanish National Institute of Statistics, 2010), and considering the different incidence and prevalence rates published (Abasolo-Osionaga et al., 2006; Benito-León et al., 2003; Bergareche et al., 2004; Claveria et al., 2002), the average incidence has been estimated at around 6,400 new cases per year, and the average prevalence at 150,000 people (European Parkinson’s Disease Association [EPDA], 2008) with PD. It is estimated that 30% of these patients are in an advanced stage of the disease (Kulisevsky, 2005). The economic impact of PD is mainly

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driven by in-patient care and nursing home costs caused by motor and non-motor symptoms that lead patients of PD to progressive disability. In addition, the cost of illness increases dramatically with severity as patients at the advanced stages are bedridden, wheelchair bound or institutionalized. According to the most recent version of the World Health Organisation (WHO) report on Global Burden of Disease, published in 2008 (Mathers et al., 2008), neuropsychiatric conditions are responsible for 22% of global disability adjusted life years (DALYs) for women aged 15–59 years, the largest cause group in all regions outside Africa. The DALY is used as a measure to quantify the burden of the disease and consists on the years of life lived in less than full health or lost from premature death. It is also important to consider that these costs will increase along with the prevalence of these diseases due to the aging of the population in Europe. Several studies have been performed to date in different countries to analyze the economic and social burden of PD. According to this literature, the main drivers of the total direct cost of PD are hospitalization and drug costs (Keranen et al., 2003; O’Brien et al., 2009) and the main drivers of total indirect cost are nursing care and productivity loss (Dengler et al., 2006; Hagell et al., 2002; O’Brien et al., 2009). In the United States, the annual economic impact of PD was estimated in 2007 at $10.78 billion, being 58% of this amount related to direct medical costs ($6.22 billion) (O’Brien et al., 2009). Nursing home care ($2.6 billion) and PD-related medications ($1.47 billion) accounted for 63% of direct medical costs. Regarding indirect costs, annual lost productivity for persons with PD was estimated at $1 billion and caregivers cost at $2.36 billion. When considering the individual economic data, annual cost per patient was $21,626 (direct cost: $12,491). Another study published in the United States (Huse et al., 2005) in 2005 quantified direct medical care costs for individual patients with PD and compared them with the costs obtained in a control group of persons without PD. Total annual direct cots were $23,101 per patient with PD versus $11,247 for controls. According to the study and based on annual data, PD patients spent approximately 2 more days in the hospital, 43 more days in longterm care institutions, and required more than 20 additional prescriptions than controls. These differences led to an increment of total annual health care costs of approximately $12,000 in PD patients. Around 50% of this excess cost was for long-term care, 24% for outpatient services, 15% for hospitalization and 14% for pharmacological treatment. The study projected the total cost of PD for the United States to be around $23 billion annually. In an Australian study (Cordato et al., 2006) the total direct health-care cost of PD for patients with Hoehn and Yahr stage 3 was found to be four times higher than that of an ageand sex-matched control group of patients without PD. The estimated annual cost was Australian $7,020 per patient. Medication was the most costly component for both groups, being significantly higher for PD patients. Within the PD group, the health care costs attributable to PD were significantly higher than health care costs not related to PD (for a 3 month period, A$1,202 versus A$553). As concerns European data, no Pan-European survey of the economic cost of PD has been performed to date. However, several studies from different countries are available in the literature. Some of the most representative ones have been considered for this chapter. A review of the literature on the economic impact of PD in UK (Findley, 2007) reported an estimated total cost of PD in the UK between £449 million and £3.3 billion annually, depending on the methodology and prevalence rate considered in each individual analysis.

Cost and Efficacy of Therapies for Advanced Parkinson's Disease

23

In another study in 2003, service use and costs for PD patients in the UK (McCrone et al., 2007) were measured. The annual costs were £13,804 per patient. Formal care costs accounted for 20% of this amount, while informal care was related to the 80% of the burden. Predictors of higher costs were identified, being male gender, level of disability and depression the more significant ones. A study published in 2003 (Zecchinelli et al., 2003) assessed health care costs associated with PD in Italy. Patients and results were classified using the Hoehn and Yahr scale. Annual direct health costs were €4,320 for mild stage (1-2), €4,748 for moderate stage (2.5-3) and €6,175 for severe stage (4-5). The average was estimated at €4,808. These results were identified as lower than the real cost, as they didn’t consider the societal perspective and neither informal care nor health care costs incurred in the private sector were included. In Germany a 3-year prospective study of the economic cost of PD (Dengler et al., 2006) was performed in 2006. The average annual cost per patient was estimated at €12,091, of which 55,9% accounted for direct costs. Drugs took up the major share of direct costs, €5,763 per year. Indirect costs accounted for €4,851 per patient per year. Within this, 76% of the costs were related to nursing care and the loss of productivity. In Sweden resource use and costs in patients with PD were collected from medical records of a cohort of 127 patients (Hagell et al., 2002) in 1996 (year 2000 costs). Direct health care costs averaged approximately €3,200 per patient per year, of which drugs were the most costly component. Non-medical direct costs were higher, €4,800 per patient per year, and costs due to lost productivity were around €5,800 per patient per year. The average total annual cost for PD was therefore estimated at €13,800 per patient. Costs of PD illness were studied in a Russian Cohort of 100 patients (year 2008 costs) (Winter et al., 2009). From the societal perspective, total annual costs per patient amounted to €5,240 per patient, with direct costs accounting for 67% and indirect costs for 33% of the total. The main drivers of the burden were informal care and drugs. Global costs for the nation were estimated at €1.1 billion per year. One of the most recent European studies, published in 2010, was performed in a cohort of 100 Czech patients with idiopathic PD to evaluate direct and indirect costs and to identify cost-driving factors (Winter et al., 2010b). Results were assessed for a 6-month period and have been projected to annual costs. Total annual costs for PD were €11,020 per patient. Direct costs accounted for 60% of the total costs and indirect for 40%. Independent costdriving factors included disease severity, motor complications, psychosis and age. The degenerative nature of PD leads to an increase of resource consumption in its advance stages. In fact, disease severity has been identified as a strong cost-predictor in several of the studies already mentioned. Motor complications (fluctuations, dyskinesias, dystonia) have been identified as factors increasing PD-related costs (Dowding et al., 2006; McCrone et al., 2007; Winter et al., 2010a; Winter et al., 2010b; Zecchinelli et al., 2003). In a 6-month observational study of PD in France, Germany and the UK, patients with different degrees of motor complications, measured using the Unified Parkinson Disease Rating Scale (UPDRS), and its effects on health care costs were examined (Péchevis et al., 2005). Dyskinesia (UPDRS part IVa) was associated with significant increases in total health care costs. Each unit increase in dyskinesia score lead to €562 additional costs per patient over a 6-month period. A 2007 published study developed in the UK (Thanvi et al., 2007) showed that Levodopa induced dyskinesia increased health care costs. Relationship between increasing cost of care and severity of the disease as measured by Hoehn and Yahr stage was proven to be

24


statistically significant. A correlation was also found between the severity of the disease, patient’s age and the use of Social Services. If we focus on advanced PD (APD) treatment costs, a systematic review of the available economic evidence of deep brain stimulation (DBS) for APD was performed in 2009 (PuigJunoy & Puig, 2009). Ten studies were identified, five of them being simple cost analyses and the other five, full economic evaluations. The cost studies included were: one description of costs of the treatment with DBS (McIntosh et al., 2003) and four comparative analyses (Charles et al., 2004; D’Ausilio et al., 2003; Fraix et al., 2006; Gerzeli et al., 2002) of DBS versus conservative pharmacological treatment. In the comparative analyses, a significant difference was observed when annual average pharmacological cost was compared between conservative treatment and DBS. The independent average cost of the DBS intervention was specified in four of the five cost studies. These results showed some variability from €20.033 (Gerzeli et al., 2002) to -€33.220 (McIntosh et al., 2003), explained mainly by differences in resources utilization, which was highly driven by surgeons’ level of experience. The intervention duration and costs decreased along with the increase of professional experience on DBS. It was also observed that pharmacological treatment costs were lower in patients after DBS intervention than in patients that remained in conservative pharmacological treatment. Regarding costs distribution, the higher resource consumption for DBS was experienced during the first year of the therapy. The comparison of DBS costs to conventional pharmacological alternative is sensitive to the inclusion of non-health related costs. When productivity loss and informal care costs were considered (Gerzeli et al., 2002), the cost of the DBS alternative was lower to the cost of the conventional pharmacological treatment.

3. Cost-effectiveness of bilateral subthalamic stimulation in advanced Parkinson’s disease Levodopa combined with adjunct medical therapy is the standard medical treatment for individuals with PD. However, prolonged use of levodopa can cause disabling motor fluctuations and dyskinesias. When medication is no longer effective or produces unacceptable side effects, surgical treatments may be a possible alternative. Ablative surgery and DBS are the main surgical treatments for advanced refractory PD. Ablative surgery includes pallidotomy, thalamotomy and subthalamotomy, which destroy the globus pallidus (GPi), thalamic nucleus and subthalamic nucleus (STN), respectively. Once the suitable target tissue has been located, it is destroyed by a radio frequency or thermocoagulation method. Expert opinion suggests nowadays that ablative procedures are rarely performed in Western countries although such procedures are still available as a treatment option for individuals in developing countries. Ablative surgery has largely been replaced by DBS, in part because DBS is potentially reversible and is perceived to be associated with improved safety and effectiveness and, in part, because ablative surgery is irreversible and regarded as having limited effectiveness and significant safety concerns. In patients with inadequate control of parkinsonian symptoms by medical treatments, bilateral subthalamic nucleus deep brain stimulation (STN-DBS) has emerged as a surgical choice for APD and has been shown to improve motor function, motor fluctuations, and health related quality of life (HRQoL) and to reduce medication usage and drug induced dyskinesia (Deuschl et al., 2006; Krack et al., 2003; Martínez-Martín et al., 2002; Rodríguez-Oroz et al., 2005; Siderowf et al., 2006; Schupbach et al., 2005; Valldeoriola et al., 2002). DBS was


25

approved by the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medical Products (EMEA) for the treatment of APD, but it is still considered a relatively expensive therapy. Authorities are concerned because of the increased health expenses and are taking containment measures based on the principle that the distribution of resources must be supported by the efficiency and not exclusively by the direct clinical benefit (Greenberg et al., 1999; Weinstein et al., 2001). The DBS procedure is generally performed in two separate steps, implantation of leads followed by implantation of the neurostimulator to which the leads are connected. Patients need to be tested initially for their responsiveness to therapy. This is accomplished by implanting a lead at the relevant site using a combination of stereotactic techniques such as image-guided stereotactic localisation and physiological techniques such as microelectrode mapping or macrostimulation. The implantation procedure is generally performed under local anaesthetic. The placement of the electrode at a particular site is determined by the patient’s response to stimulation, involving physical evaluation of the lower limbs and face muscles, and interpretation of the microelectrode recording data. Once the target that elicits the best response has been localised, the testing electrodes are removed and replaced with permanent leads. Although DBS is non-ablative, the procedure may give rise to complications and side effects, some of which are neither reversible nor adaptable. The complications from DBS can arise before surgery, during surgery, in the immediate post-operative period, and after surgery. Data available on adverse events are derived from case series. Findings from these studies indicated the risk associated with DBS but did not allow quantisation of those risks compared with the Best Medical Treatment (BMT). A systematic review of case series to assess the safety and effectiveness of bilateral STN-DBS for the symptoms of PD in a total of 537 individuals has been performed (Amani et al., 2005). The authors reported the mortality rate, adverse events related to stimulation, general neurological and surgical complications and hardware-related complications. Mortality occurred at a rate of 0.4 per cent. The adverse events related to stimulation (and rates of occurrence) were: hypophonia (5.8%), eyelid apraxia (4.6%), increased libido (0.8%), sialorrhea (0.9%) and decreased memory (1.1%). Other stimulation-related adverse events included dystonia, paraesthesias, diplopia, dyskinesias and dysarthria; however these events were not reported in the studies or were underestimated. The adverse events related to general neurological and surgical complications (and rates of occurrence) were: depression (4.7%), mania/hypomania (2.0%), peri-operative confusion (13.7%), cerebrospinal fluid leak (0.1%), meningitis (0.1%), venous phlebitis (0.7%), pneumonia (0.4%), urinary tract infections (0.3%), pulmonary embolism (0.5%), seizures (0.9%), haemorrhage (2.8%). Weight gain was also considered to fall into this category, but was reported to be under-quantified in the studies. The adverse events from hardware-related complications (and rates of occurrence) were: lead problems including lead migration, breakage and repositioning (4.5%), and infections of the hardware (3.4%). The results shown n the literature review indicated that DBS allowed the maintenance of abilities to perform activities and increased motor function in the absence of effective medical treatment. In the absence of a comparator group, it is not possible to quantify the effect attributable to DBS; however, the worsening of akinesia, speech, postural stability, freezing of gait and cognitive function is consistent with the natural history of PD over time (Krack et al., 2003).

26


The effectiveness of DBS for the treatment of symptoms of PD has been assessed from one double-blind crossover and three case-control studies. DBS appears to be effective for the treatment of PD symptoms, with statistically significant changes observed between case and control participants in UPDRS and PDQ-39SI scores. These results therefore show that DBS can ameliorate the symptoms of PD (as measured by the UPDRS ADL and Motor sections) and reduce the antiparkinsonian medication required to maintain control of the symptoms of PD. Patients experienced up to a 90 per cent reduction at 24 months following surgery in the daily OFF rate. However, the assessment of the effectiveness of DBS for the treatment of symptoms is generally limited by the number of individuals analysed; significant losses to follow-up in some studies; and follow-up of the participants to a maximum of only 48 months. The reduction in antiparkinsonian medication after DBS may also significantly reduce some of the side effects of high-dose levodopa treatment over a long time (Charles et al., 2004; Mínguez-Castellanos et al., 2005; Molinuevo et al., 2000). Most of the studies on cost-effectiveness in STN-DBS have been designed in the absence of a control group of similar characteristics receiving conventional oral medication supposed to be the BMT possible. In some of the studies, the costs of expensive therapies such as apomorphine pump infusions were also considered within the concept of BMT. A cost-effectiveness study has been published with the aim of assessing the long term costeffectiveness of DBS versus BMT (Tomaszewski & Holloway, 2001) using modelling techniques to predict long term clinical and economical consequences of using DBS and BMT in advanced PD patients, showing that DBS may be an efficient therapy to treat PD patients. Such mathematical models can be useful to predict long-term cost-effectiveness, considering that long-term studies are difficult to perform in clinical practice. It is likely that such positive cost-effectiveness results would extend at least to the next two or three years after the intervention. This possibility was suggested in a survey which showed a 32% increase in total costs during the first year after surgery but a reduction of 54% for the second year, when compared to preoperative values (Charles et al., 2004). Other studies have shown similar results: a retrospective cost-effectiveness study of DBS in Germany in 46 parkinsonian patients (Meissner et al., 2005) showed an estimated Incremental Cost Effectiveness Ratio (ICER) of €979 for one point improvement of the UPDRS-III in one year; in this survey the annual pharmacological expenses were of €11,230 one year before the implantation while of only €4,449 two years after surgery. A multicentric French survey (Fraix et al., 2006) observed similar improvement of UPDRS scores and decrement of PD costs. In another survey, a prospective analysis, the incremental cost per total UPDRS unit improvement turned out to be €920 (Spottke et al., 2002). Some studies have included the cost of the battery replacement after five years of use (D’Ausilio et al., 2003; McIntosh et al., 2003; Tomaszewski & Holloway, 2001). Only a few studies considered a social perspective by showing costs derived from the losses and gains of productivity of both the patient and the caregiver before and after the intervention. Most of studies, however, are based in a retrospective design, with a short number of patients and follow-up and the absence of a control group of patients of similar clinical characteristics. Due to the absence of prospective studies comparing cost-efficacy of STN-DBS with control patients, we designed an open, prospective longitudinal study comparative of the cost, effectiveness and HRQoL between the treatment with STN-DBS and BMT in patients with


27

APD (Valldeoriola et al., 2007). Twenty-nine patients were enrolled in the study. All were included in a waiting list for STN-DBS at our centre. All participating patients signed an informed consent form. Among the patients in the waiting list for STN-DBS, the first consecutive fourteen patients were enrolled in the treatment group and the last consecutive fifteen patients were enrolled in the control group. The treatment group was assigned to STN-DBS; the control group was assigned to BMT. Both groups (STN-DBS and BMT) were largely comparable in their clinical and demographic variables including mean levodopa equivalent doses. The study estimated only direct costs. We divided them into two categories: direct medical costs, related to costs for goods and services used in the prevention, diagnosis, treatment and rehabilitation of the illness (for example costs for medical visits, hospitalization and pharmaceuticals); and direct non-medical costs, generally assumed by the patient, including expenses related to the disease (for example transportation, social services, adaptation of accommodation and any kind of special equipment, facilities or orthopaedic material). Our results showed that the ICER needed to obtain an additional improvement of one unit in the total UPDRS score was €239.8. Current management of APD includes combinations of expensive drugs and therefore savings after STN-DBS were mainly attributable to the reduction of pharmacological expenses. The incremental cost-effectiveness was of €34,389 per QALY. The quality-adjusted life year (QALY) is a measure of disease burden, including both the quality and the quantity of life lived. It is used in assessing the value for money of a medical intervention. The QALY model requires utility independent, risk neutral, and constant proportional trade-off behaviour. The QALY is based on the number of years of life that would be added by the intervention. Each year in perfect health is assigned the value of 1.0 down to a value of 0.0 for death. We also performed sensitivity analyses under different situations. When we excluded the BMT patient group patient who had a prolonged hospitalisation from the analysis, the incremental cost per QALY was of €44,078 (X1.3). In this study, two patients in the BMT group were treated with Continuous Subcutaneous Infusion of Apomorphine (CSIA), a therapy that is also considered to be expensive. Consequently we also calculated the costeffectiveness of STN-DBS when excluding these patients, obtaining a result of €62,148 per QALY (X1.8). This study showed STN-DBS anti-parkinsonian clinical efficacy and that costeffectiveness is directly related to clinical improvement in parkinsonism and to the reduction of pharmacological expenses after the intervention. As shown by others (Charles et al., 2004; Fraix et al., 2006; Meissner et al., 2005; Spottke et al., 2002), this survey in the Spanish setting showed that STN-DBS is within the adequate limits to be considered as an efficient therapy. Considering the published data available in the literature assessing DBS for APD, it can be considered safe, effective and cost-effective compared with BMT. There is sufficient evidence of safety and effectiveness, and robust information on cost-effectiveness is unlikely to emerge but the total cost is acceptable for patients in whom other therapies are insufficient. The insertion of a DBS system incurs upfront costs but may result in cost savings from its effect of controlling the motor symptoms of PD as disease progresses, allowing patients to live in more functional health states for longer periods of time with improved QoL. To date, there appears to be no evidence that DBS delays the progression of PD or affects the mortality rate, although it may be argued that mortality due to falling, for example, may

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decrease with improvements in motor skills. These savings could be realised through a reduced demand for services or a lower expenditure on certain examinations.

4. Cost analysis of DBS, CSIA and CDLCI in advanced Parkinson’s disease: The SCOPE Study For physicians in general and for neurologists in special, it becomes quite challenging to achieve an antiparkinsonian medication regimen that keeps the patient mobile while at the same time does not create side effects that outweigh the benefits of treatment, impacting patient’s quality of life (Adler, 2002). In these APD patients, refractory to pharmacological treatment, three treatments may be recommended such as DBS, Continuous Duodenal Levodopa–Carbidopa Infusion (CDLCI), and CSIA. These therapies are not recommended for all patients with APD and an adequate patient selection allows the optimization of results obtained with the three therapeutic options. Additionally, the three treatments have no clear positioning in the treatment pathway of APD patients, which leaves the decision about the eligibility of APD patients for one therapy or another to neurologists. Such decision can therefore be subjective and largely depends on the patient’s clinical status, patients’ and physicians’ preferences, as well as previous hospital experience, availability of these treatments or economic constraints. To date, as it has been described, no economic evaluation has been published comparing the costs-effectiveness profile of these three therapeutic options that exist for APD. The main reason could be the lack of published direct clinical evidence comparing at least two of the three therapies. In these cases, a modelling method can be done as a simulation of the costeffectiveness results (Stahl , 2008). A healthcare costs compqarison considering all the costs in the medium and long term (not only the acquisition costs) associated with the treatments and their consequences of chronic diseases management like PD is a valuable tool both for payers and physicians, offering useful information to support their decision making in the treatment of this patient population (Mycka et al., 2010). In order to address this evidence gap, the first cost study worldwide has already been submitted (Valldeoriola et al., 2011). The SCOPE study1 is a descriptive, quantitative and economic analysis that tried to compare the healthcare costs associated with these three alternative treatments for a 5-years, period in patients with APD in the perspective of the Spanish Healthcare System. One DBS battery replacement was included in the analysis, as the average battery life of a non-rechargeable neurostimulator has seem to oscillate between four to five years (BinMahfoodh et al., 2003; Krack et al., 2003). The costs of the devices and components of CDLCI and CSIA (infusion pump, catheters, etc.) were not included; thus it was assumed that they were provided free of charge by the supplier, and therefore their cost to the healthcare system was zero. Once all the health resources associated with the therapies were identified and quantified, its cost per unit or ‘price` was obtained from the Spanish health resources database (Spanish Cost Database, e-salud (Spanish Cost Database, e-salud, 2010). Finally, 1 SCOPE: eStudio COstes Parkinson Enfermedad. The SCOPE Study was evaluated and approved by the Ethics Committee of Clinical Research of the Hospital Clinic i Provincial, Barcelona.

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the average total cost for each of the three therapies per patient was then obtained for the 5years, period. In order to test the statistical differences of mean costs, the data analysis was carried out with the SPSS 15.0 software package for Windows and comparisons among the three therapies (non-parametric Kruskal–Wallis one-way analysis of variance by ranks multiple comparisons) and between the two therapies with the lower average total costs, DBS vs CSIA (Hollander & Wolf, 1999). Due to the higher APD costs in the first six months, when patients consume more health resources (extra visits, hospitalization, dose adjustments, etc.) (D’Ausilio at al., 2003; McIntosh et al., 2003; Tomaszewski & Holloway, 2001), it was decided to divide the HQR in four sections, or phases. In Table 1, the average cost per patient associated with the three alternative therapies in the baseline scenario for different phases are shown. Phases DBS 1. Pre-treatment period to hospitalization

1,141 ± 411

Average Costs CDLCI

CSIA

1,705 ± 357

1,231 ± 267

2. Hospitalization period to discharge (includes Procedure 27,236 ± 3,105 * or Treatment Administration)

3,165 ± 501 *

785 ± 197 *

3. Discharge from hospital to 6 4,768 ± 918 * # months post-op

25,521 ± 2,381 *

12,094 ± 2,158 * #

4. From month 6 to year 5

54,869 ± 4,190 * #

203,596 ± 8,737 *

127,284 ± 9,184 * #

Total cost per 5 years

88,014 ± 2,580 * #

233,986 ± 10,552 * 141,393 ± 9,945 * #

Average Cost per year

17,603±516 * #

46,797 ±2,110 *

28,279 ±1,989 * #

(*) Comparison of the three therapies (p EGCG > EC > (+)-C > EGC and the antiapoptotic activities appear to be structurally related to the 3gallate group (Jin, C. F. et al., 2001, Nie et al., 2002). In a related study, it was showed that EGCG protected against 6-OHDA via stimulation of PKC and modulation of cell survival/cell cycle genes such as Bax, Bad, Mdm2, Bcl-2, Bcl-w, and Bcl-x(L) and also by potent antioxidant and iron chelating actions thereby preventing nuclear translocation and activation of cell death promoting NFB (Levites et al., 2002a). Since the stability and bioavailability of EGCG are restricted, Chao et al. generated and tested a pro-drug representing a fully acetylated EGCG (pEGCG) in a PD cell model (Chao et al., 2010a). They found that pEGCG displayed improved protection compared to EGCG against 6-OHDA toxicity in SH-SY5Y neuroblastoma cells probably via activation of Akt pathway and reduced caspase-3 activity. In contrast, when Leaver et al. administered rats with EGCG for 14 days followed by exposure to 6-OHDA, they observed that EGCG produced subtle symptomatic relief in lesioned animals and could not prevent neuronal damage to a significant extent (Leaver et al., 2009). Tea extracts and EGCG have displayed therapeutic effect in other toxic models of PD. Tea extract and EGCG protected against MPTP mediated dopamine loss and neurotoxicity in vivo and this effect could be mediated by inhibition of NOS (Choi et al., 2002, Kim, J. S. et al., 2010, Li, R. et al., 2006). In a related study, it was demonstrated that green tea extract and EGCG protected against MPTP neurotoxicity via antioxidant effects and inhibition of monoamine oxidase-B (MOAB) (Levites et al. 2001). Mechanistically, green tea polyphenols can ameliorate neuronal damage via inhibitory effects on dopamine transporters (DAT), through which they block MPP+ uptake and protect dopaminergic neurons against MPP+induced injury (Pan, T. et al., 2003). Similarly, Hou et al. (2008) demonstrated that EGCG attenuated cell death in PC12 cells induced by the herbicide and PD toxin paraquat (PQ) by maintaining mitochondrial membrane potential, inhibiting caspase-3 activity and down regulating the expression of pro-apoptotic protein second mitochondrial-derived activator of caspase (SMAC) in cytosol. However, in rotenone-treated mesencephalic cultures and organotypic striatal cultures, EGCG protected striatal slices to a limited extent by counteracting NO production by rotenone but was not significantly effective against rotenone toxicity in mesencephalic cultures (Moldzio et al., 2010). Green tea could also protect against environmental toxin-induced cell injury and neuroinflammation with implications for PD. Tai and Truong (2010) reported that EGCG reduced dichlorodiphenyl-trichloroethane (DDT)-induced cell death in dopaminergic SH-

132


SY5Y cells suggesting that EGCG might activate a protective mechanism that might alleviate organochlorine pesticide-induced cell injury. Likewise, EGCG also inhibited LPS-activated microglial secretion of NO and TNF-α through the down-regulation of iNOS and TNF-α expression thereby protecting against neuroinflammation and injury in dopaminergic neurons (Li, R. et al. 2004). The antioxidant property of EGCG is also beneficial against protein aggregation in PD. Iron induces toxic aggregation of monomeric alpha synuclein leading to neurodegeneration in dopaminergic neurons. In the MPTP model, iron accumulation is also linked to NO-dependent mechanism. Mandel et al. showed that EGCG prevented the accumulation of iron and alpha-synuclein in SN thereby preventing neuronal damage (Mandel, S. et al., 2004). However, green tea and its constituent polyphenols could not protect PC12 cells against L-glutamate and MPP+ (Mazzio et al., 2001).

6. Conclusions Most of the drugs currently used in PD therapy replenish the brain dopamine and provide symptomatic relief during early PD. However, many patients develop motor complications with chronic treatment. Further, these drugs do not slowdown or prevent the progression of the disease since their ability to prevent neuronal damage has not been comprehensively validated in humans. Therefore, novel therapies with possible curative properties are being exploited for adjunctive therapy. It is well documented that neurodegeneration in PD is contributed by several interrelated disease pathways but the molecular mechanisms of their relationships and their chronology have not been completely understood. Therefore, any molecule(s) with therapeutic potential in PD should be simultaneously effective against multiple pathways. In this regard, several in vitro and in vivo studies using PD models have tested natural antioxidants and molecules for their ability to protect against neurodegeneration with implications for therapy. The most prominent are the polyphenolic antioxidants obtained from plant sources. Most of these compounds display antioxidant, anti-inflammatory and anti-cancer properties, cross the blood-brain barrier and prevent neuronal damage in neurological disorders. Recent studies strongly support the clinical application of these compounds in PD. The current chapter explores the therapeutic potential of polyphenols such as curcumin, resveratrol and tea polyphenols in PD. These three polyphenols share common biological properties including antioxidant function, low toxicity and therapeutic benefits in the brain of different PD models. The available data indeed indicate that these polyphenols could have therapeutic potential in PD. Although several studies have been carried out in the recent years, the biological properties and health benefits of these polyphenols have not been completely understood. However, the most important limiting factor for the therapeutic application of these compounds in PD is their limited bioavailability in vivo. Further, the delivery of compounds specifically to mid-brain dopaminergic neurons for maximum therapeutic effect has not been completely standardized. Apart from this, studies are also needed to test the safety and efficacy in humans to translate the experimental results for therapeutic application in PD patients.

7. Acknowledgements This study was financially supported by the Department of Science and Technology (No. SR/FT/L-152/2005 to MMSB). RBM is supported by an extended senior research fellowship from the Council for Scientific and Industrial Research (CSIR), India. GH is supported by a

Therapeutic Potential of Polyphenols in Parkinson’s Disease

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senior research fellowship from Indian Council for Medical Research (ICMR), India. NR is supported by a junior research fellowship from CSIR, India.

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8 Inhibition of Tau Phosphorylation as a Potential Strategy in Treatment of Parkinson’s Disease Wang Wenya

School of Pharmaceutical Sciences, Southern Medical University China 1. Introduction At present, Parkinson’s disease (PD) has become the third most common neuropathy following cerebrovascular diseases and epilepsy, and is the second most common neurodegenerative disease after Alzheimer's disease (AD). There is growing evidence that neuronal apoptosis plays a key role in the mechanism in PD, AD and other neurodegenerative diseases [Mattson, 2000; Yuan & Yankner, 2000]. Therefore, regulating neuronal apoptosis signaling pathway will provide a theoretical basis to reveal the mechanism of neuronal apoptosis; and on the basis of research, development of antineuronal apoptosis drugs to selectively interfere with critical target of apoptosis signaling pathway would be an important means in prevention of neurodegenerative diseases effectively. Although subject to intensive research, the etiology of PD is still enigmatic, which in turn has hindered the development of effective treatment. Today, PD treatment is basically symptomatic, and no neuroprotective therapies are available. The current therapy for PD mainly aims at replacing the lost neurotransmitters. The signs and symptoms of PD can be alleviated with drugs that enhance dopamine function, among which, levodopa is considered the most effective one. The most severe shortcoming of levodopa treatment is that it fails to alter the progression of PD. Patients with advanced PD may develop a variety of motor complications associated with levodopa therapy, such as switching phenomena and dyskinesia [Rylander et al., 2010]. More disappointing is the therapeutic effect of levodopa weakens after about two years (Marsden & Parkes, 1977). Therefore, there is still an urgent need of finding more beneficial treatment strategy for the disease. Here, we proposed a neuroprotective drugs to effectively control the course of PD: it can inhibit substantia nigra dopaminergic neurons from "primary" progressive loss, so as to achieve the purpose of effective treatment of Parkinson’s Disease.

2. Inhibition of tau phosphorylation as a potential strategy in treating PD Dopamine neurons have a strong ability of physiological compensation before the disease is clinically evident. Generally, the disease become clinically evident (decompensated state) when the dopamine neuron loss is sufficiently severe (greater than 75% of nigrostriatal dopamine neurons) [Lloyd, 1977]. It is well known that programmed cell death (apoptosis) plays a key role in the neurodegenerative processes in PD [Büeler, 2010; Nagatsu & Sawada,

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2007]. Several intraneuronal pathways are implicated in N-methyl-4-phenyl-1, 2, 3, 6tetrahydropyridine (MPTP) -induced neuronal apoptosis [Chung et al., 2010; Ethell & Fei, 2009; Karunakaran et al., 2008; Saporito et al., 2010]. These include c-Jun N-terminal kinases (JNK) signaling, p53 activation, cell cycle re-activation, Glycogen synthase kinase-3 (GSK3)/Tau signaling pathway, signaling through bcl-2 family proteins and so on. The neurotoxin MPTP is converted in the brain into 1-methyl-4-phenylpyridinium iodide [MPP (+)] by the enzyme monoamine oxidase B (MAO-B). MPP (+) is a selective inhibitor of mitochondrial complex I and is widely used in rodent and cell models to elicit neurochemical alterations associated with PD. We had found 10μmol/L MPP (+) activated JNK, phosphorylated c-Jun and induced neuronal apoptosis. It decreased the number of tyrosine hydroxylase (TH) immunopositive cells and reduced cytoplasmic volume. SP600125 [Bennet et al., 2001], the specific inhibitor of JNK protected dopaminergic neurons and increased the number of TH immunopositive cells via inhibiting c-Jun phosphorylation. These results indicated that SP600125 inhibited the activation of JNK and therefore protected dopaminergic mesencephalic neurons from apoptosis induced by MPP(+), which suggested that JNK might be a new target of influencing neuronal apoptosis [Wang et al., 2004]. Therefore, we had first proposed a new strategy for PD treatment, which is using a specific inhibitor of JNK. Of course, there are a great number of “targets” to interfere with nigral dopaminergic neuronal apoptosis, such as GSK-3β, also named as Tau protein kinase I (TPK I). 2.1 The tau protein Tau is a low molecular weight component of cytoskeletal structures. It is one of several types of microtubule-associated proteins (MAPs) which regulate the assembly and stability of microtubule networks. Although microtubule networks exist in all kinds of animal and plant cells, the mRNAs encoding tau proteins are expressed predominantly in neurons, where these tau proteins are localized mostly to axons [Higuchi et al., 2002]. They are abundant in neurons in the central nervous system and are less common elsewhere. This unique feature suggests that Tau may have neuron-specific functions. In a healthy person, tau protein interacts with a compound called tubulin to strengthen the neural tubes in the axons of neurons. The neural tubes essentially act like train tracks for signals to pass along the axon. Disruption in the level of tau protein can lead to instability in the neural tubes, which makes it difficult for neurons to pass signals along [Kowall & Kosik, 1987]. When tau proteins are defective, and no longer stabilize microtubules properly, they can result in dementias, such as Alzheimer's disease [Sergeant et al., 2008]. 2.2 Normal functions of tau phosphorylation Protein phosphorylation is widely used to regulate cellular processes, because it can affect binding between two proteins. Phosphorylation is a process that adds a phosphate group to a protein, particularly on the amino acid serine, threonine or tyrosine. For the Tau protein, its association with microtubules is inhibited if certain residues in its microtubule binding domain are phosphorylated [Gendron & Petrucelli, 2009]. The phosphorylation of tau plays a physiological role in regulating the affinity of tau for microtubules. Though less well studied, phosphorylation also regulates the binding of tau to signaling molecules and could thus influence tau-mediated signaling [Reynolds et al., 2008]. The kinases that phosphorylate tau can be divided into two major groups, according to motif specificity: proline-directed protein kinases (PDPK) and non-proline-directed protein kinases (non-

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PDPK). The PDPK include cyclin-dependent kinase 5 (cdk5), mitogen-activated protein kinase (MAPK), and several stress-activated protein kinases. GSK3-β is often described as a PDPK but the proline is not always required for phosphorylation by GSK3-β.The phosphorylation of tau by these kinases inhibits the ability of tau to promote microtubule assembly and facilitates the polymerization of tau into paired helical filaments (PHFs) [Evans et al., 2000]. Among the non-PDPK are cyclic AMP-dependent protein kinase (PKA), calcium- and calmodulin-dependent protein kinase II (CaMKII), and microtubule affinity regulating kinase (MARK). Unbound tau may then be hyperphosphorylated by other kinases. In fact, the phosphorylation of tau by MARK may be a prerequisite for the action of downstream kinases, including GSK-3β and Cdk5 [Nishimura et al., 2004]. Recently, Tau has received great attention because mounting evidence has indicated that hyperphosphorylation of Tau is the origin of Alzheimer's disease (AD). In an AD brain, too many residues in the Tau protein are phosphorylated [Buerger et al., 2006; Schönknecht et al., 2003 ] 2.3 Phosphorylation of tau in PD Hyperphosphorylation and accumulation of Tau in neurons and glial cells result in PHFs and is one of the main pathologic hallmarks in many neurodegenerative disorders such as AD and other Tauopathies [Sato et al., 2006]. Phospho-Tau (Ser396) has been found in synaptic-enriched fractions in AD frontal cortex at entorhinal/transentorhinal, limbic and neocortical stages [Muntané et al., 2008]. GSK-3β- immunoprecipitated sarcosyl-insoluble fractions from AD patients can phosphorylate recombinant Tau [Ferrer et al., 2005]. Densitometric studies show between 20% and 40% phospho-Tau (Ser396) in synaptic-enriched fractions of the frontal cortex in PD [Muntané et al., 2008]. Moreover, Tau- immunoreactive Lewy bodies (LBs) are detected in the medulla of 80% of individuals with sporadic PD or dementia with LBs, where Tau is often localized at the periphery of LBs [Ishizawa et al., 2003]. We also found MPP (+)/MPTP induced abnormal phosphorylation of Tau at Ser396 in nigra in PD models. To investigate whether Tau is phosphorylated in MPTP-treated dopaminergic neurons, we examined the histochemical localization of Tau (Ser396) phosphorylation level in SNc following treatment with MPTP. TH immunofluorescence was used to detect DA neurons. Three months old adult male C57 black mice were given MPTP at a dose of 30mg/kg ip. once daily for 7 days. SNc slices were prepared 6 h after the third MPTP injection, and double-labeled with antibodies against TH and phospho-Tau (Ser396). We found that in MPTP-treated mice, nearly all TH positive cells exhibited the increased levels in phopsphoTau, whereas no loss of TH positive cells was observed. Furthermore, many TH negative cells were stained with phopspho-Tau, but the levels were unchanged between MPTP-treated and untreated mice [Wang et al., 2007]. Cell counting results showed that in MPTP-treated group the percentage of phopspho-Tau stained neurons in TH positive cells was increased to 98%, while the control was just 37%. These results suggest that after MPTP treatment, Tau is selectively phosphorylated in dopaminergic neurons. Similarly, Qureshi HY found that exposure of human neuroblastoma M17 cells to MPTP enhances intracellular alpha-synuclein protein level, stimulates Tau protein phosphorylation at Ser262 and induces apoptosis [Qureshi & Paudel, 2010]. 2.4 Preventing tau phosphorylation rescued neurons A cdk5 inhibitory peptide (CIP) selectively inhibited p25/Cdk5 activity and suppressed the aberrant Tau phosphorylation and reduced apoptosis in cortical neurons [Zheng et al.,

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2005]. In SH-SY5Y-cotransfected cells expressing α-Syn and human dopamine transporter (hDAT), both LiCl and TDZD-8 blocked GSK-3β activation in a dose-dependent manner, with concomitant decreases in hyperphosphorylation of Tau and cell death [Duka & Sidhu, 2006; Duka et al., 2009]. A GSK-3beta specific inhibitor, L803-mt, attenuated Tau phosphorylation and rescued DA neurons from cell death in mesencephalic cultures [Chung et al., 2010]. We had reported that AR-A014418, a specific inhibitor of GSK-3β, reduced the levels of phospho-Tau (Ser396), protected nigral neurons from apoptosis, and restored the depletion of dopamine evoked by MPTP in C57BL/6N mice [Wang et al.,2007]. 2.5 Two anticancer drugs dephosphorylated tau and rescued dopaminergic neurons 2.5.1 Chromomycin A3 protected cultured dopaminergic neurons from apoptosis induced by MPP(+) Chromomycin A3 (Fig.1.) is a glycosidic antibiotic produced at the fermentation of a strainof Streptomyces griseus. It is also called toyomycin or aburamycin. It is not only an antibacterial antibiotic, but also an antitumor antibiotic that inhibits RNA synthesis, especially in solid tumors. Chromomycin belongs to the DNA-interactive Drugs. The compound blocks macromolecule synthesis by a specific, reversible interaction with DNA in the presence of bivalent metal ions. Binding to DNA minor groove mediates an efficient competitive inhibition of DNA gyrase and significantly affects topoisomerase II activity [Hou et al., 2008].

Fig. 1. Chemical structure of Chromomycin A3 [from sigmaaldrich] Chromomycin A3 has also been shown to be a potent inhibitor of neuronal apoptosis induced by glutathione depletion-induced oxidative stress and DNA-damaging agent Camptothecin [Chatterjee et al., 2001]. Mechanistic studies suggest that chromomycin A3 antagonizes enhanced DNA binding of the transcription factors Sp1 and Sp3 to their cognate "G-C" box, induced by oxidative stress or DNA damage [Chatterjee et al., 2001]. Furthermore, by inhibiting transcription, chromomycin A3 can inhibit protein biosynthesis.


155

Miller identified chromomycin A3 that inhibited NF-kappaB signaling in a NF-kappaB mediated beta-lactamase reporter gene assay. It induced caspase 3/7 activity and had an inhibitory effect on cervical cancer cell growth [Miller et al., 2010]. We know that oxidative stress and elevation of intracellular calcium levels are particularly important inducers of NFkappaB activation. Activation of NF-kappaB can interrupt apoptotic biochemical cascades at relatively early steps, before mitochondrial dysfunction and oxyradical production. The available data identify NF-kappaB as an important regulator of evolutionarily conserved biochemical and molecular cascades designed to prevent cell death and promote neuronal plasticity [Mattson et al., 2000]. Together, these results suggest that chromomycin A3 may be effective agents for the treatment of neurological diseases associated with aberrant activation of apoptosis and highlight the potential use of sequence-selective DNA-binding drugs as neurological therapeutics. Last year, we reported that chromomycin A3 inhibited Tau phosphorylation at Ser396 and therefore protected dopaminergic mesencephalic neurons from apoptosis induced by MPP (+) [Wang et al., 2010]. 2.5.2 Mithramycin prevented MPP(+)-induced cultured neuronal apoptosis Chromomycin A3 and mithramycin (also known as MIT and plicamycin) are two DNA binding anticancer antibiotics, acting via inhibition of replication and transcription during macromolecular biosynthesis. The clinical use of chromomycin A3 is limited because of its immuno suppressive properties and greater cytotoxic effects. But mithramycin is one of the older chemotherapy drugs, which has been in use for decades. Mithramycin (Fig.2.) selectively binds to G-C-rich DNA in the presence of Mg (2+) or Zn (2+), inhibiting RNA and DNA polymerase action [Majee & Chakrabarti, 1999]. It also inhibits c-myc expression and induces myeloid differentiation of HL-60 promyelocytic leukemia cells [Dutcher, 1997]. This drug is prescribed primarily in the treatment of malignant tumors of the testis. It is also prescribed in the treatment of hypercalcemia and hypercalciuria associated with cancer [Rosol & Capen, 1987]. It is given by intravenous route only. It was discontinued as of 2000 by the manufacturer based on decreased demand.

Fig. 2. Chemical structure of mithramycin [from sigmaaldrich]

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Renewed interest in mithramycin resulted in about 50 mithramycin related publications in the first half of 2010 alone. Most publications mentioned anti-cancer abilities of the compound, but other medical conditions were also referred, such as: Huntington's disease (HD) neurodegeneration [BirZeit P.A, on line]. Recent research shows that it is helpful in treating motor symptoms and prolonging life in a mouse model of HD [Ferrante et al., 2004].

Fig. 3. Mithramycin inhibited MPP (+)–induced apoptosis in cultured dopaminergic neurons. Dopaminergic mesencephalic neurons were obtained from 14-day-old fetal rats. At DIV5, 10 μM MPP(+) was used to induce neuronal apoptosis for 48h. Specific TH-antibody was used to detect dopaminergic neurons. (a) control, Fluorescent micrograph by fluorescence microscope showing TH positive cells visualized with FITS (green); (b) 10μM MPP(+) decreased TH positive cells and reduced cytoplasmic volume; (c) 0.2μM mithramycin, and (d) 0.5μM mithramycin rescued TH positive cells. Scale bar = 50μm. Pharmacological treatment of a transgenic mouse model of HD (R6/2) with mithramycin extended survival by 29.1%, greater than any single agent reported to date. Increased survival was accompanied by improved motor performance and markedly delayed neuropathological sequelae. Voisin screened candidate therapeutic compounds that were identified previously in cell culture/animal studies in a C. elegans HD model and found that two FDA approved drugs, lithium chloride and mithramycin, independently and in combination suppressed HD neurotoxicity [Voisine et al., 2007]. Because it is Food and Drug Administration-approved, researchers thought mithramycin is a promising drug for the


157

treatment of HD. Since mithramycin has enhanced neuronal survival and neuroprotection, it may protect dopaminergic neurons. We also use cultured dopaminergic mesencephalic neurons with MPP (+) as PD cell model.

Fig. 4. TUNEL figures of inhibitory effect of mithramycin on dopaminergic neuronal apoptosis induced by MPP (+). Dopaminergic mesencephalic neurons were obtained from 14-day-old fetal rats. At DIV5, 10 μM MPP(+) was used to induce neuronal apoptosis for 48h. Specific TH-antibody was used to detect dopaminergic neurons. (a) Positive control. Strong TUNEL labeling showed apoptotic bodies in all kinds of cells; (b) control, vehicletreated Neurons;(c) 10 μM MPP (+) induced neurons apoptosis (green) and decreased TH immunopositive cells (red). White arrow showed apoptotic dopaminergic neurons (yellow). (d) Fewer TUNEL-positive cells were shown with 1.0 μM mithramycin treatment. Scale bar = 50μm.

158


The embryos were removed at embryonic day 14 from pregnant Sprague-Dawley rats that had been anesthetized, then decerebrated. Ventral mesencephalon were dissected and collected. Cell suspensions prepared by mechanical trituration precoated overnight with 1 mg/ml polyethylenimine in borate buffer, pH 8.3. The cells were then maintained for maturation and differentiation in DMEM/F12 culture medium. Cultures were treated at DIV1 and every three days 250 µL of culture medium were replaced by medium supplemented with treatments. At DIV5, 250 µL of 500 µL medium were replaced by fresh medium supplemented or not with mithramycin at 200, 500, 1000 nM and 10 µM of MPP (+) were added. After 48 h, cells were fixed for 15 min with a 4% formaldehyde solution, washed three times with 500 µL PBS then submitted to TH immunostaining to allow analysis of DA neurons. Undoubtedly, MPP (+) induced apoptosis in cultured dopaminergic mesencephalic neurons. It decreased the number of TH positive cells and reduced cytoplasmic volume. 200, 500 and 1000 nM mithramycin rescued TH immunopositive cells from cytotoxic MPP (+) (Fig.3.). To detect DNA fragmentation, we used TUNEL. TUNEL is one of the main methods for detecting apoptotic programmed cell death. We found 1.0 μM mithramycin reduced MPP (+)-caused TUNEL-positive cells (Fig.4.) Mithramycin not only increased the number of TH immunopositive cells, but also showed protective action in a dose-dependent manner (Table 1). Interesting, mithramycin also decreased the levels of phosphorylated Tau (Fig.5).

Mithramycin (μmol/L)

Neuronal Survival ( % control)

0

32.8 ± 2.7

0.2

42.8 ± 5.2 *

0.5

57.1 ± 6.3 **

1.0

65.9 ± 7.3 **

2.0

76.3 ± 8.7 **

5.0

87.3 ± 8.4 **

* P

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