Mechanisms in Parkinson's Disease - Mdls., Trtmts.

604 Pages·2012·25.19 MB·English

by  J. Dushanova

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
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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 [email protected]

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 123I-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