MECHANISMS IN PARKINSON’S DISEASE – MODELS AND TREATMENTS Edited by Juliana Dushanova Mechanisms in Parkinson’s Disease – Models and Treatments Edited by Juliana Dushanova Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles 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. 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 InTech Design Team First published February, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Mechanisms in Parkinson’s Disease – Models and Treatments, Edited by Juliana Dushanova p. cm. ISBN 978-953-307-876-2 Contents Preface IX Chapter 1 Update in Parkinson’s Disease 1 Fátima Carrillo and Pablo Mir Chapter 2 Timing Control in Parkinson’s Disease 39 Quincy J. Almeida Chapter 3 Free Radicals, Oxidative Stress and Oxidative Damage in Parkinson's Disease 57 Marisa G. Repetto, Raúl O. Domínguez, Enrique R. Marschoff and Jorge A. Serra Chapter 4 The Execution Step in Parkinson’s Disease – On the Vicious Cycle of Mitochondrial Complex I Inhibition, Iron Dishomeostasis and Oxidative Stress 79 Marco T. Núñez, Pamela Urrutia, Natalia Mena and Pabla Aguirre Chapter 5 Filterable Forms of Nocardia: An Infectious Focus in the Parkinsonian Midbrains 101 Shunro Kohbata, Ryoichi Hayashi, Tomokazu Tamura and Chitoshi Kadoya Chapter 6 Parkinson’s Disease and the Immune System 119 Roberta J. Ward, R.R. Crichton and D.T. Dexter Chapter 7 Cyclin-Dependent Kinase 5 – An Emerging Player in Parkinson’s Disease Pathophysiology 141 Zelda H. Cheung and Nancy Y. Ip Chapter 8 Regulation of -Synuclein Membrane Binding and Its Implications 157 Robert H.C. Chen, Sabine Wislet-Gendebien, Howard T.J. Mount and Anurag Tandon VI Contents Chapter 9 Role of FKBPs in Parkinson’s Disease 173 Souvik Chattopadhaya, Amaravadhi Harikishore and Ho Sup Yoon Chapter 10 Targeting Tyrosine Hydroxylase to Improve Bradykinesia 189 Michael F. Salvatore Chapter 11 Wading into a Theoretical Model for Parkinson's Disease 213 Diana W. Verzi Chapter 12 Successes of Modelling Parkinson Disease in Drosophila 233 Brian E. Staveley Chapter 13 Parkinson’s Disease and Parkin: Insights from Park2 Knockout Mice 251 Sarah E.M. Stephenson, Juliet M. Taylor and Paul J. Lockhart Chapter 14 Bilateral Distribution of Oxytocinase Activity in the Medial Prefrontal Cortex of Spontaneously Hypertensive Rats with Experimental Hemiparkinsonism 277 Manuel Ramírez, Inmaculada Banegas, Ana Belén Segarra, Rosemary Wangesteen, Marc de Gasparo, Raquel Durán, Francisco Vives, Antonio Martínez, Francisco Alba and Isabel Prieto Chapter 15 Dictyostelium discoideum: A Model System to Study LRRK2-Mediated Parkinson Disease 293 Arjan Kortholt, Bernd Gilsbach, and Peter J.M. van Haastert Chapter 16 Comparison of Normal and Parkinsonian Microcircuit Dynamics in the Rodent Striatum 311 O. Jaidar, L. Carrillo-Reid and J. Bargas Chapter 17 Animal Models of Parkinson’s Disease Induced by Toxins and Genetic Manipulation 323 Shin Hisahara and Shun Shimohama Chapter 18 Neuroprotective Effects of Herbal Butanol Extracts from Gynostemma pentaphyllum on the Exposure to Chronic Stress in a 6-Hydroxydopamine-Lesioned Rat Model of Parkinson's Disease Treated with or Without L-DOPA 351 Myung Koo Lee, Hyun Sook Choi, Chen Lei, Kwang Hoon Suh, Keon Sung Shin, Seung Hwan Kim, Bang Yeon Hwang and Chong Kil Lee Contents VII Chapter 19 Acetyl-L-Carnitine in Parkinson’s Disease 367 Maria Stefania Sinicropi, Nicola Rovito, Alessia Carocci and Giuseppe Genchi Chapter 20 Distribution and Regulation of the G Protein-Coupled Receptor Gpr88 in the Striatum: Relevance to Parkinson’s Disease 393 Renaud Massart, Pierre Sokoloff and Jorge Diaz Chapter 21 Human Lymphocytes and Drosophila melanogaster as Model System to Study Oxidative Stress in Parkinson's Disease 407 Marlene Jimenez-Del-Rio and Carlos Velez-Pardo Chapter 22 Inflammation in Parkinson’s Disease: Causes and Consequences 439 Louise M. Collins, André Toulouse and Yvonne M. Nolan Chapter 23 Neurotensin as Modulator of Basal Ganglia-Thalamocortical Motor Circuit – Emerging Evidence for Neurotensin NTS 1 Receptor as a Potential Target in Parkinson's Disease 471 Luca Ferraro, Tiziana Antonelli, Sarah Beggiato, Maria Cristina Tomasini, Antonio Steardo, Kjell Fuxe and Sergio Tanganelli Chapter 24 Application of Embryonic Stem Cells in Parkinson’s Disease 497 Hassan Niknejad Chapter 25 The Role of the Neuropeptide Substance P in the Pathogenesis of Parkinson’s Disease 511 Emma Thornton and Robert Vink Chapter 26 Noradrenergic Mechanisms in Parkinson’s Disease and L-DOPA-Induced Dyskinesia: Hypothesis and Evidences from Behavioural and Biochemical Studies 531 Amal Alachkar Chapter 27 Mitochondrial Haplogroups Associated with Japanese Parkinson’s Patients 557 Shigeru Takasaki Chapter 28 Role of 123 I-Metaiodobenzylguanidine Myocardial Scintigraphy in Parkinsonian Disorders 573 Masahiko Suzuki Preface Parkinson’s disease (PD) is the second most common neurodegenerative disorder that affects one to two per cent of the world’s population over the age of 65. Continued research into the pathogenesis of PD is essential as it mainly affects the elderly population. PD is characterized by a loss of dopaminergic neurons from the substantia nigra pars compacta (SNc). The SNc is part of the substantia nigra, which belongs to the group of nuclei in the midbrain, called the basal ganglia. The function of the basal ganglia requires signaling of both excitatory and inhibitory neurotransmitters to balance the two main signaling pathways, the direct and indirect pathways. These pathways remain balanced by the nigrostriatal pathway or the dopaminergic projections from the SNc to the striatum (caudate nucleus and putamen) with a basal level of striatal dopaminergic DA integral for proper function of the basal ganglia. A basal ganglia structure performs neurotransmitter-mediated operations through somatotopically organized projections to GABAergic medium spiny projection neurons (MSNs). These striatal cells are innervated by excitatory glutamatergic fibers from cortex and thalamus, and modulatory dopaminergic fibers from the midbrain and transmit neural information to the basal ganglia output structures. Neural transmission at the level of MSNs has been associated with the regulation of voluntary movement and cognitive functions. Knowledge of the new transmitter mechanisms by which such interactions take place can provide new insight into the basal ganglia physiopathology and new clues for therapy of severe motor disorders, such as Parkinson’s disease. Thus, in PD, the loss of dopamine neurons causes the subsequent loss of striatal dopamine, and the presentation of motor symptoms, such as bradykinesia, akinesia, rigidity and postural instability. The movement disorders are often associated with abnormalities in electrical activity within the substantia nigra pars reticulata. Parkinson's is a complex disorder involving alterations in brain chemistry, morphology and activity. An enhanced understanding of the interdependence of these processes will increase our understanding of this devastating disease. Accordingly, current treatment of PD involves increasing striatal dopamine content, by either direct replacement or reduction of its breakdown. Unfortunately, these treatments only provide symptomatic relief and the efficacy is somewhat limited. For example, the current “gold-standard” treatment for PD, L-DOPA, the precursor to X Preface dopamine, only alleviates symptoms for five to 10 years before debilitating side effects such as dyskinesia appears. The underlying pathogenesis of degenerating DA neurons still remains unknown. Importantly for potential PD therapeutics, the loss of neurons occurs slowly over many years, suggesting that there is a window of opportunity within which a neuroprotective therapy could be administered to slow or halt the progression of the disease. However, to date, no neuroprotective therapies are in clinical use. As this is the case, new avenues of research into the pathogenesis of PD and the discovery of possible neuroprotective agents are critical. Evidence from both clinical and experimental models of PD have elucidated a number of mechanisms that are attributed to the continuing loss of DA neurons, such as oxidative stress, mitochondrial dysfunction, and glutamate excitotoxicity. More recently, inflammatory processes, particularly the chronic activation of microglia, and blood brain barrier (BBB) dysfunction have gained much attention for their potential role in the pathogenesis of PD. There is evidence that oxidative stress participates in the neurodegeneration. Neutrophils express a primary alteration of nitric oxide release in PD patients, where reactive oxygen species and oxidative stress parameters are more probably related to the evolution of PD. Peripheral markers of oxidative stress in red blood cells of neurological patients could be a reflection of the brain condition and suggests that oxygen-free radicals are partially responsible for the damage observed in PD living patients. Other reports suggest that mitochondrial dysfunction and impairment of the respiratory complexes are associated with the neuronal loss. Substantial evidence suggests diet, in particular iron intake, and environmental risk factors, such as pesticides and heavy metals as causative of PD. However, the way genetic and environmental factors are related to the nutritional status of PD patients is still unknown. Moreover, how the nutritional status of PD patients might contribute to the development of the disorder is not yet established. Drosophila melanogaster is used as a valid model in PD research to investigate the effect of paraquat and iron alone or in combination, and polyphenols upon two different glucose feeding regimens on the life span and locomotor activity of the fly. The concept of oxidative stress is defined as an imbalance with increased oxidants or decreased antioxidants. The situations of oxidative stress, evaluated by the peripheral markers of oxidative stress in the blood of neurological patients, seem to afford a reflection of the brain condition. Brain oxidative stress, with oxygen free radicals being responsible for brain damage, provides signals to peripheral blood, at least, through the diffusible products of lipid peroxidation. The neuropeptide, substance P (SP), is widely distributed throughout both the central and peripheral nervous systems. Generally in PD, it is considered that SP expression within the SN is decreased, with such loss of SP also being attributed to symptom presentation. However, most studies have used post-mortem PD cases or experimental models of PD with maximal dopaminergic degeneration, which replicate the late stages of the disease. In these final stages, the reduction in striatal DA input has resulted in a loss of the SP/DA positive feedback mechanism and consequently the reduction in nigral SP. Indeed, it has been shown that SP content within the SN is not [...]... Lewy bodies are continuously forming and disappearing in the diseased substantia nigra (Greffard et al, 2010) The brain-stem shape is a spherical 2 Mechanisms in Parkinson’s Disease – Models and Treatments structure measuring 8–3 0μm with a hyaline core surrounded by a peripheral pale-staining halo, and is composed ultrastructurally of 7–2 0-nm wide filaments with dense granular material and vesicular structures... done slowly and awkwardly, and assistance might be needed for dressing, feeding, bathing, getting out of chairs, and turning in bed Constipation, chewing and swallowing difficulties, drooling of saliva, and urge incontinence of urine are common complaints Although PD has long been considered primarily a motor disorder Nonmotor symptoms (NMS) in PD are common and were recognized by James Parkinson himself... methodologies to investigate timing control during gait in PD The results of these studies are discussed in terms of how timing deficits may be an important underlying factor contributing to many of the motor symptoms seen in PD The hypotheses described in chapter 3 are that brain oxidative stress and damage are involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases,... Speech, swallowing, and postural instability can improve initially, but axial symptoms are generally less responsive and seem to escape more readily from long-term control (Fahn et al, 2004) 10 Mechanisms in Parkinson’s Disease – Models and Treatments Levodopa exerts its symptomatic benefits through conversion to dopamine, and is routinely administered in combination with a decarboxylase inhibitor (carbidopa,... mediators and lymphocyte infiltration have also all been observed in animal models of PD, substantiating the current belief of a fundamental role of inflammation in neurodegeneration The molecular pathways underlying the pathogenesis of the disease remain poorly understood Interestingly, recent studies suggest that cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase that is predominantly active in. .. PRKN gene In fact, FBXO7 gene encodes a protein of 522 amino acids, which seems to be also involved in the system of ubiquitin-proteasome protein degradation (Di Fonzo et al, 2009; Paisán-Ruiz et al, 2010) 6 Mechanisms in Parkinson’s Disease – Models and Treatments Recently, it has been shown that patients with mutations in the gene spatacsin (SPG11) (Non PARK locus) develop a juvenile parkinsonism... (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine), underlying environmental causes remain to be discovered However, approximately 15 per cent of individuals with Parkinson’s disease have a first-degree relative who also has the disease, and five to10 per cent of Parkinson’s disease sufferers are known to have monogenic forms of the disease Furthermore, a number of the genes identified in familial Parkinson’s disease have been implicated in, and. .. Parkinson's disease Drosophila research into PD has focused on the transgenic expression of human alpha–synuclein in fly neurons and on the comprehensive investigation of two genes responsible for recessive PD, parkin and PINK1 Finally, the advantages of Drosophila as a model will continue to advance our understanding of the mechanisms that contribute to PD, and to aid in the design of therapeutic treatments. .. of levodopa (Duodopa) has been used for intraintestinal infusion of the agent and is used in more advanced stages of disease Levodopa is absorbed in the small bowel by active transport through the large neutral amino acid (LNAA) pathway, and can be impaired by alterations in gastrointestinal motility and by dietary LNAAs, such as phenylalanine, leucine, and valine, which compete with levodopa for absorption... Waters, 2006), edema (especially in the lower extremities) (Kleiner-Fisman G and Fisman, 2007) and a variety of ICDs, such as pathologic Update in Parkinson’s Disease 13 gambling, hypersexuality, and compulsive eating and shopping (Weintraub et al, 2006) Risk factors for ICDs include current use of dopamine agonists, particularly in high doses, young age of PD onset, and a premorbid or family history . MECHANISMS IN PARKINSON’S DISEASE – MODELS AND TREATMENTS Edited by Juliana Dushanova Mechanisms in Parkinson’s Disease – Models and Treatments Edited. pathogenic mechanisms of Parkinson’s disease, and studies involving primates, rodents (rat and mouse), zebrafish, nematodes and fruit flies have been instrumental in further understanding of PD. Models. Chapter 7 Cyclin-Dependent Kinase 5 – An Emerging Player in Parkinson’s Disease Pathophysiology 141 Zelda H. Cheung and Nancy Y. Ip Chapter 8 Regulation of -Synuclein Membrane Binding and Its