i STUDIES OF CELL DEATH IN PARKINSON’S DISEASE USING ORGANOTYPIC CELL CULTURES TUYET TB TRAN B.Sc (Hons) Discipline of Health Sciences, School of Medical Sciences The University of Adelaide September 2008 A thesis submitted to the University of Adelaide in fulfillment of the requirements for the degree of Doctor of Philosophy
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i
STUDIES OF CELL DEATH IN PARKINSON’S
DISEASE USING ORGANOTYPIC CELL
CULTURES
TUYET TB TRAN
B.Sc (Hons)
Discipline of Health Sciences, School of Medical Sciences
The University of Adelaide
September 2008
A thesis submitted to the University of Adelaide in fulfillment of the requirements for the
degree of Doctor of Philosophy
ii
DECLARATION
This work contains no material which has been accepted for the award of any other
degree or diploma in any university or other tertiary institution and that, to the best of my
knowledge and belief, the thesis contains no material previously published or written by
another person, except where due references has been made in the text.
I give consent to this copy of my thesis, when deposited in the University library, being
made available for photocopying and loan
Tuyet Tran
Date:
iii
PUBLICATIONS AND PRESENTATIONS
The following articles have been published or accepted for publication or presentation
during the period of my PhD candidature, and sections of these articles are included in
the present thesis.
Publications under review:
Tuyet T.B Tran, Peter C. Blumbergs and James A. Temlett (2008)
The effects of MPTP and rotenone on Dopaminergic neurons in Organotypic cell culture.
Journal of Neurotoxicology
Abstracts:
Tuyet T.B Tran, Peter C. Blumbergs and James A. Temlett (2007)
The Effects of MPTP and rotenone on Dopaminergic neuronal growth in Organotypic
Cell Culture. Abstracts of the 8th International Conference AD/PD 2007, Salzburg,
Austria. March 14 – 18, p327
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ACKNOWLEDGEMENTS
I wish to convey my gratitude and appreciation to the following people.
Professor James Temlett, my primary supervisor, thank you for providing me the
opportunity to undertake my PhD.
Professor Peter Blumbergs, my co-supervisor, for your time and helpful critique of my
thesis and the never-ending support.
Renee Turner and Emma Thornton, for your friendship and support. Through the good
and bad times you guys were there for me, I will cherish our friendship (especially all the
baking and Friday lunches) whether you are near or far. Wish you guys all the best for
the future and research careers.
James Donkin and Islam Hassan, for your friendship and sharing your PhD and masters
experience with me. I wish you guys the best for the future.
The Eye-boys: John Wood, Glyn Chidlow and Michael Schober, for your support and
helpful tips in thesis writing, culturing, and immunostaining. Also providing me an
opportunity to work and gain experience for my research career.
v
Ghafar Sarvestani, for your confocal expertise and taking your time teaching me how to
use the expensive equipment.
The Neuroscience Lab- Jim Manavis, for your immunohistochemistry expertise, your
jokes and support, Kathryn, Yvonne, Sven, Cathy, Bernice, Sophie and Felicity, for you
assistance when needed and friendship, I’ll miss our international days in the tea room.
My family and friends for your support, encouragement and understanding through the
never-ending years of studying.
Finally, very special thanks to a particular person who put up with all my whinging and
complaining during the few remaining years of my PhD, Luke Francis, for your
8.3.1 GDNF at varying doses did not induce a significant increase in TH-ir
cells……………………………………………………………………………..254
8.3.2 GDNF treatment promotes increase in cell size and branching……….…254
8.3.3 Post GDNF treatment following MPTP and rotenone exposure………....254
8.3.4 Pre-treatment with GDNF followed by MPTP and rotenone
exposure…………………………………………………………………….…..255
8.4 DISCUSSION………………………………………………………………...……270
8.4.1 The neurotrophic effects of GDNF on DAergic neurons survival and
development………………………………………………………………….…270
8.4.2 Neuroprotection and regeneration of DAergic neurons by GDNF…….....271
8.4.3 GDNF neuroprotection against neurotoxins in slice cultures…………….272
CHAPTER 9: ………………………………………………………………………….273
GENERAL DISCUSSION…………………………………………………………….273
9.1 INTRODUCTION………………………………………………………………...274
9.2 ORGANOTYPIC SLICE CULTURE OF VM & ST…………………………..274
9.2.1 The advantages of using organotypic slice cultures……………………...274
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9.2.2 Disadvantages of using organotypic slice cultures………………….……275
9.2.2 Summary of experimental findings…………………………………….…275
9.3 THE EFFECTS OF MPTP AND ROTENONE ON VM AND ST SLICE
CULTURES………………………………………………………………….………...278
9.3.1 MPTP and rotenone………………………………………………………278
9.3.2 Summary of experimental findings……………………………………….278
9.4 THE NEUROTROPHIC ROLE OF GDNF ON TH-ir NEURONS IN SLICE
CULTURES……………………………………………………………………….…...282
9.4.1 GDNF and DAergic neurons……………………………………………..282
9.4.2 Summary of experimental findings……………………………………….283
9.5 Summary…………………………………………………………………………...288
9.6 Conclusion ………………………………………………………………………...289
REFERENCES……………………………………………………………………...…290
APPENDICES………………………………………………………………………....400
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LIST OF FIGURES AND TABLES
Figure 1.1: Diagrammatic representation of the age predilections for typical, sporadic Parkinson’s disease and genetically determined Parkinsonism.…………………………13 Figure 1.2: Action sites of pharmacological therapies currently available for PD………32 Figure 1.3: The current model of the basal ganglia………………………………..…47-48 Figure 1.4: Stages of MDN development……………………………………………..…57 Figure 1.5: Signaling cascades in the MDN development………………………...……..58 Figure 2.1: Schematic Representation of MPTP Metabolism………………………..….77 Figure 2.2: Schematic representation of MPP+ intracellular pathways………………….87 Figure 2.3: Pathways implicated in MPTP-mediated toxicity………………………..93-94 Figure. 2.4: Chemical structure of rotenone, paraquat, MPP+, and maneb…………….111 Figure 5.1: Schematic illustration of the preparation protocol of slice cultures from 4 to 5-day-old rats………………………………………………………………………...163-164 Figure 5.2: Schematic diagram of the culturing process………………………………..165 Figure 5.3: Schematic representation of the biotin-avidin peroxidase procedure for the identification of TH-ir neurons…………………………………………………….166-167 Figure 5.4: LDH ELISA…………………………………………………………...168-169 Figure 6.1: Dopaminergic (TH-ir) controls………………………………………...…..175 Figure 6.2: Dopaminergic (TH-ir) neuronal growth in VM & ST co-cultures…………176 Figure 6.3: Dopaminergic (TH-ir) neuronal growth in VM and ST co-cultures……….177 Figure 6.4: TH-ir cell growth in co-cultures vs single cultures (SVM)………………...178 Figure 6.5: Dopaminergic (TH-ir) neuronal growth in single VM cultures (SVM)……179 Figure 6.6: Dopaminergic (TH-ir) neuronal growth in co-cultures vs SVM…………...180 Figure 6.7: GFAP growths in co-cultures vs single cultures……………………….......181
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Figure 6.8: Glial fibrillary acidic protein (GFAP-ir) growth in VM & ST co-cultures………………………………………………………………………………….182 Figure 6.9: Glial fibrillary acidic protein (GFAP-ir) growth in single VM (SVM) cultures………………………………………………………………………………….183 Figure 6.10: Dopaminergic (TH-ir) & Glial fibrillary acidic protein (GFAP-ir) growth in VM & ST co-cultures. ………………………………………………………………….184 Figure 6.11: Glial fibrillary acidic protein (GFAP-ir) growth in VM & ST co-cultures and SVM…………………………………………………………………………………….185 Figure 7.1: Schematical diagram of the experiments………………………...…………201 Figure 7.2: MPTP treated co-cultures at 7 days……………………………………….203 Figure 7.3.1: Dopaminergic (TH-ir) neuronal growth following 1 week post MPTP treatment of 7 day co-cultures…………………………………………………………..204 Figure 7.3.2: Dopaminergic (TH-ir) neuronal growth following 2 week post MPTP treatment of 7 day co-cultures…………………………………………………………..205 . Figure 7.3.3: Dopaminergic (TH-ir) neuronal growth following 3 week post MPTP treatment of 7 day co-cultures…………………………………………………………..206 Figure 7.4: MPTP treated co-cultures at 14 days……………………………………...207 Figure 7.5.1: Dopaminergic (TH-ir) neuronal growth following 1 week post MPTP treatment of 14 day co-cultures………………………………………………………....208 Figure 7.5.2: Dopaminergic (TH-ir) neuronal growth following 2 week post MPTP treatment of 14 day co-cultures………………………………………………………....209 Figure 7.5.3: Dopaminergic (TH-ir) neuronal growth following 3 week post MPTP treatment of 14 day co-cultures………………………………………………...……….210 Figure 7.5.4: Dopaminergic (TH-ir) neuronal growth following 1 week post MPTP & MPP+ treatment of 14 day co-cultures………………………………………………….211 Figure 7.6: 7 day & 14 day old co-cultures MPTP treated………………….……212-213 Figure 7.7: Rotenone treated co-cultures at 7 days………………………………….…217 Figure 7.8.1: Dopaminergic (TH-ir) neuronal growth following 1 week post rotenone treatment of 7 day co-cultures…………………………………………………….…….218
E
*
xxvii
Figure 7.8.2: Dopaminergic (TH-ir) neuronal growth following 2 week post rotenone treatment of 7 day co-cultures…………………………………………………………..219 Figure 7.8.3: Dopaminergic (TH-ir) neuronal growth following 3 week post rotenone treatment of 7 day co-cultures………………………………………………………….220 Figure 7.9: Rotenone treated co-cultures at 14 days…………………………………..221 Figure 7.10.1: Dopaminergic (TH-ir) neuronal growth following 1 week post rotenone treatment of 14 day co-cultures…………………………………………………………222 Figure 7.10.2: Dopaminergic (TH-ir) neuronal growth following 2 week post rotenone treatment of 14 day co-cultures…………………………………………………………223 Figure 7.10.3: Dopaminergic (TH-ir) neuronal growth following 3 week post rotenone treatment of 14 day co-cultures…………………………………………………………224 Figure 7.11: 7 day & 14 day old co-cultures rotenone treated…………………….225-226 Figure 7.12: Lactate Dehydrogenase Cytotoxicity Assay (LDH) of MPTP & Rotenone treated co-cultures………………………………………………………………….228-229 Figure 7.13: MPTP & rotenone treated co-cultures 1 week post treatment- Degenerating neurons-FJC…………………………………………………………………………….230 Figure 7.14: Co-localisation of TH-ir and caspase-3 in co-cultures…………………...231 Figure 7.15: Co-localisation of TH-ir and caspase-3 in co-cultures following MPTP treatment at one week recovery period…………………………………………………232 Figure 7.16: Co-localisation of TH-ir and caspase-3 in co-cultures following rotenone treatment at one week recovery period…………………………………………………233 Figure 7.17: Co-localisation of TH-ir and caspase-3 in co-cultures following MPTP at one week recovery period…………………….………………………………………...234 Figure 7.18: Co-localisation of TH-ir and caspase-3 in co-cultures following rotenone treatment at one week recovery period………………………………………………....235 Figure 8.1: Schematical diagram of the experiments…………………………………..256 Figure 8.2: TH-ir cells in co-cultures treated with GDNF………………………...256-257 Figure 8.3: TH-ir analysis of 7 day co-cultures treated at varying doses of GDNF…………………………………………………………………………...………258
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Figure 8.4: 7 day co-cultures treated at varying doses of GDNF……………………259 Figure 8.5: The neuroprotective effects of GDNF on TH-ir cells following MPTP exposure…………………………………………………………………………….….260 Figure 8.6: The effects of GDNF post treatment following MPTP exposure…………261 Figure 8.7: The neuroprotective effects of GDNF on TH-ir cells following rotenone exposure………………………………………………………………………………...262 Figure 8.8: The effects of GDNF post treatment following rotenone exposure………………………………………………………………………………..263 Figure 8.9: LDH ELISA of GDNF post treatment following MPTP exposure……………………………………………………….……………………….264 Figure 8.10: LDH ELISA of GDNF post treatment following rotenone exposure………………………………………………………………………………...265 Figure 8.11: FJC-staining of GDNF Post-treatment on co-cultures following MPTP and
rotenone exposure………………………………………………………………………266
Figure 8.12: The neuroprotective effects of GDNF Pre-treatment on TH-ir cells following MPTP and rotenone exposure……………………………………………………….…267 Figure 8.13: The effects of GDNF Pre-treatment following MPTP exposure…………268 Figure 8.14: The effects of GDNF Pre-treatment following rotenone exposure………………………………………………………………………………...269 Table 1.1: Genes involved in Parkinsons Disease……………………...………………..11 Table 1.2: Summary of increased Oxidative stress (OS) in Idiopathic Parkinsons’s disease (IPD)……………………………………………………………………………………..15 Table 1.3: Summary of current PD treatment…………………………………………....33 Table 2.1: Characteristics of animal models of Parkinson’s disease………………….…75 Table 2.2: Relative toxicity of MPTP in different animals…………………………...….79 Table 2.3: MPTP-induced effects upon the DAergic system in different mouse strains…………………………………………………………………………………….84
xxix
Table 3 : Summary of Experimental PD In Vitro models…..…………………………..136
Table 7.1: 7 day old co-cultures treated with MPTP…………………………………...195 Table 7.2: 7 day old co-cultures treated with rotenone…………………………………196 Table 7.3: 14 day old co-cultures treated with MPTP……………………………….....197 Table 7.4: 14 day old co-cultures treated with rotenone………………………………..198 Table 7.5: 14 day old co-cultures treated with MPTP & MPP+………………………..199 Table 8.1: Dose-response of GDNF on TH-ir cells……………………………………249 Table 8.2: Post treatment of Co-cultures with GDNF following MPTP/rotenone exposure………………………………………………………………………………...251 Table 8.3: Pre-treatment of Co-cultures with GDNF prior to MPTP/rotenone exposure………………………………………………………………………………...252
xxx
ABSTRACT
In this study we aimed to investigate the effects of 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) and rotenone neurotoxins on dopaminergic (DAergic)
neuronal survival using ventral mesencephalic (VM) organotypic cell culture derived
from postnatal rat pups (P4-5) and immunocytochemistry for tyrosine hydroxylase (TH)
as a marker of DAergic cells. In addition, we examined the neuroprotective effects of
glial cell line-derived neurotrophic factor (GDNF) on TH-ir cells exposed to MPTP and
rotenone as a possible treatment for PD.
The TH-ir cells in co-cultures with striatum (ST) as a target grew better then when VM
was cultured alone and that TH-ir cells in co-cultures could be maintained without using
conditioned and trophic media. We treated 7 day and 14 day co-cultures at different
times with varying MPTP and rotenone concentrations and found 14 day old cultures
were more vulnerable than 7 day old co-cultures to the effects of either neurotoxin with
TH-ir cell numbers significantly lower in 14 day cultures compared to 7 day cultures.
Both neurotoxins induced a dose-dependent TH-ir cell reduction in the co-cultures. In
addition we compared the toxicity of MPTP and its active metabolite 1-methyl-4-
phenylpyridinium (MPP+) as the neurotoxic effects of MPTP on DAergic cells depends
on its conversion to MPP+ by astrocytes. We found no significant difference in TH-ir cell
reduction in co-cultures treated with MPTP and MPP+. Rotenone was more toxic than
MPTP with less TH-ir cell survival in the weeks post treatment. GDNF exposure
produced increased cell size and significant increases in TH-ir cell branching in co-
cultures in a dose-dependent manner. Post treatment of GDNF against MPTP and
xxxi
rotenone provided significant neuroprotection as TH-ir cell survival was at the lower
neurotoxin doses and not at the higher doses.
1
CHAPTER 1:
OVERVIEW OF PARKINSON’S DISEASE
2
1.0 INTRODUCTION
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that is
estimated to affect approximately 1% of the population older than 65 years of age (Lang
and Lozano 1998a, b). Clinically the cardinal symptoms was first described by James
Parkinson (1817) (Parkinson 2002) with most patients presenting bradykinesia, resting
tremor, rigidity, and postural instability. A number of patients also suffer from
autonomic, cognitive, and psychiatric disturbances (Aarsland et al. 2007). The major
symptoms of PD result from the profound and selective loss of dopaminergic (DAergic)
neurons in the substantia nigra pars compacta (SNc), but there is widespread
neuropathology with the SNc becoming involved later toward the middle stages of the
disease (Braak et al. 2003). The pathological hallmarks of PD are round eosinophilic
intracytoplasmic proteinaceous inclusions termed Lewy bodies (LBs) and dystrophic
neurites (Lewy neurites) present in surviving neurons (Forno 1996). PD is primarily a
sporadic disorder and its specific etiology is incompletely understood, but with the recent
insights provided through studying the genetics, epidemiology, and neuropathology of
PD, and the development of new experimental models have improved our understanding.
1.1 INCIDENCE AND PREVALENCE OF PD
PD is a common neurodegenerative disorder, characterized by neuronal cell loss in the
substantia nigra (SN) and subsequently reduced secretion of dopamine (DA). PD is the
second most common neurodegenerative disease after Alzheimer’s disease, affecting up
to 1% of the elderly population over the age of 65. Epidemiological studies have
estimated a cumulative prevalence of PD of greater than one per thousand with the
3
prevalence being limited to senior populations; this proportion increases nearly 10-fold.
A family history of risk factors is a key factor for PD development. Indeed, the estimated
genetic risk ratio for PD is approximately 1.7 (70% increased risk for PD if a sibling has
PD) for all ages, and increases over 7-fold for those under 66 years of age (Langston
1998; Rocca et al. 2005; Levy 2007). The age-adjusted prevalence rate of PD revealed
from a pilot study of at least a 42.5% increase in the disease compared to 1966 (Chan et
al. 2001). The role for genes contributing to the risk of PD is also significant. Recently,
monogenically PD as familial PD (FPD) has been identified and seven causative genes
for FPD have been identified so far. Thus, the role of genetic factors and also increasing
age play an important risk factor for the development of PD.
1.2 CLINICAL CHARACTERISTICS OF PD
Resting tremor at a frequency of 4-6 Hz occurs at rest but decreases with voluntary
movement in about 70% of Parkinson’s patients. Rigidity refers to increased resistance
(stiffness) initially occur only to trunk region but also extends to passive movement of
limbs. Bradykinesia (slowness of movement), hypokinesia (reduction in amplitude, and
akinesia (absence of normal initiation of movement) manifest as a variety symptoms,
including paucity of normal facial expression, drooling, microphagia, and decreased
stride length during walking. PD patients also develop a stooped posture and possibly
lose postural reflexes. Freezing of gait, the inability to begin a voluntary movement such
as walking is a common symptom of Parkinsonism. Impairment in different cognitive
domains such as executive functions, language, memory, and visuospatial skills occurs
frequently in PD even in the early stages of the disease (Caballol et al. 2007).
4
1.3 NEUROCHEMICAL AND NEUROPATHOLOGICAL FEATURES OF PD
1.3.1 Cell loss in PD
Idiopathic Parkinsonism (IPD) is characterized by progressive and profound loss of
neuromelanin containing DAergic neurons in the substantia nigra pars compacta (SNpc)
(Forno 1996). Moreover, slight gliosis and neuronal loss in the locus coeruleus, dorsal
vagal nucleus with variable involvement of the nucleus basalis Meynert, and other
subcortical nuclei have been reported (Chung et al. 2003). Degeneration of pigmented
neuronal systems located in the brain stem, particularly in SNpc, is the most striking
pathological feature of PD. This causes striatal DA deficiency and all the major motor
PD symptoms.
The pattern of SNpc cell loss correlates with the level of expression of DA transporter
(DAT) mRNA (Uhl et al. 1994) and is consistent with the level of DA depletion being
most pronounced in the dorsolateral putamen (Jones 1999), the main site of projection for
these neurons. At onset of symptoms, putamental DA is depleted ~80%, and ~60% of
SNpc DAergic neurons have already been lost. The mesolimbic DAergic neurons, cell
bodies of which reside adjacent to the SNpc in the ventral tegmental area (VTA), are
much less affected in PD (Horn 1979) and significantly less depletion of DA in the
amygdala (Marsden 1987), the main site of projection for these neurons.
Neuropathological studies of PD-related neurodegeneration reveal DAergic neuronal loss
to have a characteristic topology, which is distinct from the pattern seen in the aging
process. In PD, cell loss is concentrated in ventrolateral and caudal portions of SNpc,
5
whereas during normal aging the dorsomedial aspect of SNpc is affected (Marsden 1987).
The degree of terminal loss in the striatum (ST) appears to be more pronounced than that
of SNpc DAergic neuronal loss, suggesting that ST DAergic nerve terminals are the
primary target of the degenerative process. The neuropathology of PD is characterized
solely by DAergic neuron loss which correlates with the progressive motor decline.
However the neurodegeneration extends well beyond DAergic neurons (Di Monte 2003),
with many “non-DAergic” PD features. Neurodegeneration and Lewy bodies (LB)
formation are found in noradrenergic (locus ceoruleus), serotonergic (raphe), and
cholinergic (nucleus basalis of Meynert, dorsal motor nucleus of vagus) systems, as well
as in the cerebral cortex (especially cingulated and entorhinal cortices), olfactory bulb,
and autonomic nervous system. Degeneration of hippocampal structures and cholinergic
cortical inputs contribute to high rate of dementia that accompanies PD, particularly in
older patients. The clinical correlation to lesions in serotonergic and noradrenergic
pathways is not clearly characterized as DAergic systems.
In about 95% of PD cases, there is no apparent genetic linkage (referred to as “sporadic”
PD), but in the remaining cases, the disease is inherited. The symptoms worsen and prior
to the introduction of levodopa, the mortality rate among PD patients were three times
that of normal age-matched subjects. Although levodopa has dramatically improved the
quality of life for PD patients, surveys revealed that these patients continue to display
decreased longevity compared to the general population (Katzenschlager and Lees 2002;
Marinus et al. 2003; Katsarou et al. 2004; Muller and Russ 2006). Furthermore, most PD
6
patients suffer considerable motor disability after 5-10 years of disease, even after
beneficial medications.
1.3.2 Lewy Bodies in PD
Apart from the loss of melanized (Mason 1984) nigrostriatal DAergic (DAergic) neurons
another major pathological hallmark of PD includes the presence of intraneuronal
proteinacious cytoplasmic inclusions “Lewy Bodies” (LBs). This results in the classical
neuropathological finding of SNpc depigmentation where the SNpc DAergic cell bodies
project primarily to the putamen. However LBs are not specific for PD as they are also
found in Alzheimer’s disease (AD), other α-synucleinopathies such as dementia with LB
disease (DLBD), and as “an incidental” pathologic finding in people of advanced age
than the prevalence of PD (Spillantini and Goedert 2000). The role of LB in neuronal
cell death is controversial, as the reasons for their increased frequency in AD and the
relationship of incidental LB to the occurrence of PD. LBs are spherical eosinophillic
protein aggregates composed of numerous proteins, including intracytoplasmic α-
synuclein, parkin, ubiquitin, and neurofilaments, which are found in all affected brain
regions (Chung, 2003; Fahn, 2004; Marsden, 1987; De Girolami, 1999). LBs are more
than 15μm in diameter with an organized structure containing a dense hyaline core
surrounded by a clear halo. Electron microscopy reveals a dense granulovesicular core
surrounded by radiating 8-10 nm fibrils (Marsden 1987).
1.4 ETIOLOGY OF PD
1.4.1 Environmental Factors
7
The specific etiology of PD is not known. It has been proposed to be multifactorial
because of its sporadic nature. Epidemiological studies show that a number of factors
may increase the risk of developing PD (Abbott et al. 2003; Baldereschi et al. 2003).
These include the exposure to well water, pesticides, herbicide, industrial chemicals,
farming and living in rural environment (Di Monte et al. 2002; Di Monte 2003). A
number of exogenous toxins have been associated with the development of parkinsonism,
including trace metals, cyanide, carbon monoxide, and carbon disulfide. In addition, the
possible role of endogenous toxins such as tetrahydro-isoquinolines and beta-carbolines
has also been implicated (McNaught et al. 1996; Storch et al. 2000; Maruyama and Naoi
2002). However, no specific toxin has been found in the human brain of PD patients, and
also in many instances of Parkinsonism associated with toxins is not that of typical LB
PD.
A study of monozygotic and dizygotic pairs of twins was conducted to assess the genetic
versus environmental factors in the etiology of PD (Tanner et al. 1999). Results show that
the contribution of environmental factors to both early and late onset forms can never be
completely excluded; however it is more evident in late onset forms (onset beyond age
50). Human exposure to chemical compounds of synthetic origin, including pesticides,
herbicides and insecticides has been the focus of several epidemiologic studies since the
first description of Parkinson-like symptoms among individuals who had taken drugs
contaminated with 1-methyl-4-phenyl-2,3,6-tetrahydropyridine (MPTP; (Langston et al.
1999)). MPTP is converted to 1-methylphenylpyridinium (MPP+) by MAO-B in glial
cells (Nicklas et al. 1985; Schmidt and Ferger 2001), and subsequently selectively
8
concentrated in mitochondria of DAergic neurons where it interacts with elements of the
mitochondrial respiratory chain (Langston et al. 1999), leading to ATP depletion, and
eventually cell death of the DAergic neurons (Fisher A. 1986; Schmidt and Ferger 2001;
Chung et al. 2003; Di Monte 2003). Paraquat is an herbicide structurally similar to
MPTP; human exposure to paraquat has also been associated with an increased risk of PD
(McCormack et al. 2002), and studies on animal models demonstrate that paraquat
induces a selective loss of DAergic neurons (Liu et al. 2003). Conflicting results have
been produced, in recent years, in association studies between exposure to pesticides,
fungicides and herbicides and PD risk (Gorell et al. 1998; McCann et al. 1998; Baldi et
al. 2003).
Human activities related to a possible pesticide exposure, including farming, living in
rural areas and drinking water, are among risk factors associated with PD, whereas
smoking and drinking coffee are protective factors (Hernan et al. 2002). A chronic
occupational exposure to manganese is the cause of manganism, a condition
characterized by tremor, rigidity and psychosis due to the accumulation of the metal in
the basal ganglia (Mergler and Baldwin 1997). Although no changes in manganese brain
concentration has been observed in PD, exposure to manganese has been linked to the
risk of PD in some epidemiological studies (Gorell et al. 1997; Gorell et al. 1998).
Copper exposure has been associated with PD, whereas iron exposure alone was not;
however exposure to combinations of iron and lead, iron and manganese and iron and
copper was associated with PD. Controversial or negative results have been obtained for
exposure to zinc, mercury and aluminium (Gorell et al. 1997; Gorell et al. 1998; Powers
9
et al. 2003). Inflammation of the brain in early life as a consequence of head injuries,
viral or bacterial infections or exposure to neurotoxicants, has been indicated as a
possible contributor to the development of PD later in life (Liu et al. 2003); moreover it
has been suggested that occupational exposure to viral (or other) respiratory infections
might be one of the risk factors for the observed increased incidence of PD cases among
teachers and healthcare workers (Tsui et al. 1999).
1.4.2 Genetic Factors
In a great majority of individuals with PD it is thought to occur sporadically, as the
family history does not indicate affected individuals in their first degree relatives.
However, a number of genetic forms of the disease have been recently discovered, and
research into these hereditary forms has helped to understand the pathophysiology of this
condition. To date, 10 loci (PARK1-10) have been mapped and found to be linked to
familial forms of PD (Riess et al. 2000; Riess et al. 2002; Steece-Collier et al. 2002;
Dawson and Dawson 2003; Fahn and Sulzer 2004; Pankratz and Foroud 2004) with
genes identified in five (see Table 1.1). They are presented either as autosomal
dominants or autosomal recessives.
The first gene discovered and mostly studied is the PARK-1 gene which encodes the
alpha synuclein (α-syn) protein (Polymeropoulos et al. 1996; Polymeropoulos 1998) and
is present in PD and dementia with LBs (DLB) but not in normal human brains. It is
normally densely accumulated within presynaptic axon terminals and beta (β)-positive
vesicles but gamma (γ)-negative are also present in the hippocampal dentate, hilar, and
10
CA2/3 regions (Galvin et al. 1999). Genetic variability in the α-syn gene has been shown
to be a risk factor for the development of PD (Conway et al. 2000; Hsu et al. 2000; Saha
et al. 2000; Lo Bianco et al. 2002; Lotharius and Brundin 2002). Immunohistochemical
studies have indicated that LBs of the brainstem and also cortical types in the brains of
PD patients with sporadic PD or DLB are strongly positive for α-syn (Hishikawa et al.
2001; Junn et al. 2003; Liani et al. 2004; Murakami et al. 2004) thus may be an important
component of LBs. α-syn knock out mice revealed a striking resistance to MPTP
induced degeneration of DA neurons and DA release. This resistance appeared to result
from the inability of the toxin to inhibit complex 1 (Dauer et al. 2002). The accumulation
of α-syn intracellulary at abnormally high quantities, in an aggregated form within the
neurons and sometimes glial cells, have been shown to contribute to the pathology of PD
and also to generate hydroxyl radicals (OH•) upon the addition of iron (Fe ii). The past
10 years has seen a shift in our etiological concepts of Parkinson's disease, moving from
a nearly exclusively environmentally mediated disease towards a complex disorder with
important genetic contributors. The identification of responsible mutations in certain
genes, particularly alpha-synuclein, Parkin, PINK1, DJ-1 and LRRK2, has increased our
understanding of the clinical and pathological changes underlying Parkinson's disease,
with implications for patient diagnosis, management and future research.
11
Table 1.1 Genes involved in Parkinsons Disease
Gene Inheritance Locus Clinical Features Histopathology α-synuclein AD PARK1/4 (4q21) Ala53Thr: early onset, rapid progression
Ala30Pro: typical parkinsonian phenotype Glu46Lys: cognitive decline, hallucinations Duplication: typical parkinsonian phenotype Triplication: early onset, rapid progression, dementia, early death
SN degeneration, Lewy body pathology in substantia nigra, cortex and hippocampus
Parkin AR PARK2 (6q25-27) Early disease onset, resembles idiopathic PD phenotype, slow disease progression, good response to levodopa, early dyskinesias, diurnal .uctuation and sleep relief
SN degeneration in the absence of Lewy bodies. Lewy body pathology reported in compound heterozygous carriers
Unknown AD PARK3 (2p13) Typical parkinsonian phenotype
Nigral Degeneration with Lewy bodies
UCH-L1 AD PARK5 (4p14) Typical parkinsonian phenotype N/A PINK1 AR PARK6 (1p35-36) Early disease onset, levodopa responsive,
slow progression, dyskinesias N/A
DJ-1 AR PARK7 (1p36) Early disease onset, levodopa responsive. Dystonia and psychiatric features reported
N/A
LRRK2 AD PARK8 (12q12) Predominantly levodopa responsive parkinsonism for all mutations. Supranuclear gaze palsy, dystonia, Supranuclear gaze palsy, dystonia, dementia and motor neuron disease is described in some individuals
All had SN degeneration. Variable additional pathology: novel ubiquitin positive inclusions and MND (Tyr1699Cys), tau pathology (Arg1441Cys), Lewy bodies (Gly2019Ser, Arg1441Cys), no additional pathology (Arg1441Cys)
activity was not significantly changed by MPTP and Epo treatment. Furthermore, Epo
stimulated astroglial GSHPx production in astroglial cell culture (Genc et al. 2002). SOD
treatment has been shown to be neuroprotective against MPP+ exposure (Gonzalez-Polo
et al. 2004), pretreatment of cultures with EUK-134 (a SOD and catalase mimetic)
completely protected DAergic neurons against MPP+-induced neurotoxicity and
prevented MPP+-induced nitration of tyrosine residues in TH (Pong et al. 2000).
Tetrahydrobiopterin, an essential cofactor for TH, may also act as an antioxidant in
DAergic neurons and protect against the toxic consequences of glutathione depletion. The
increasing intracellular tetrahydrobiopterin levels may protect against OS by complex-I
inhibition (Madsen et al. 2003). Dextromethorphan (DM), a widely used anti-tussive
agent, attenuated endotoxin-induced DAergic neurodegeneration in vitro. The
neuroprotective effect of DM in mesencephalic neuron-glia cultures significantly reduced
the MPTP-induced production of both extracellular superoxide free radicals and
intracellular ROS. More importantly, due to its proven safety record of long-term clinical
use in humans, DM may be a promising agent for the treatment of degenerative
neurological disorders such as PD (Zhang et al. 2004).
Studies have also focused on the potential of growth factors as neuroprotective and/or
neuroregenerative therapeutic agents for PD. Treatment with nerve growth factor (NGF)
promote acute cell proliferation when exposed with MPP+ via the sustained extracellular
signal-regulated kinases (ERKs) and the p38 MAPK pathway in PC12 cells (Shimoke
and Chiba 2001; Shimoke and Kudo 2002). Another growth factor that has been focused
lately is glial cell line-derived neurotrophic factor (GDNF). Exposure to MPP+ was
135
found to be also toxic for hESC-derived DAergic neurons (Human embryonic stem cells
can proliferate indefinitely yet also differentiate in vitro, allowing normal human neurons
to be generated in unlimited numbers). Treatment with (GDNF) protected TH+ve neurons
against MPP+-induced apoptotic cell death and loss of neuronal processes as well as
against the formation of intracellular ROS (Zeng et al. 2006). Moreover, we found that
the levels of glial cell line-derived neurotrophic factor (GDNF) and brain-derived
neurotrophic factor (BDNF) in the conditioned medium of mesencephalic cultures treated
with PPX and ROP were significantly increased. Blocking GDNF and BDNF with the
neutralizing antibodies, the neurotrophic effects of PPX and ROP were greatly
diminished. These results suggest that D3 dopamine receptor-preferring agonists, PPX
and ROP, exert neurotrophic effects on cultured DA neurons by modulating the
production of endogenous GDNF and BDNF, which may participate in their
neuroprotection (Du et al. 2005).
3.5.2 ROTENONE & IN VITRO STUDIES
Similar to MPP+, rotenone uptake into brain synaptosomes is similar among primates and
rodents, and hence is used in neuronal cultures. Cultures of dissociated mesencephalic
neurons from fetal rats and DA-neuron-derived cell lines such as human SH-SY5Y and
rat PC12 (see Table 3) is suitable for studying mechanisms of DAergic neuronal
degeneration and for screening new pharmacological agents. Rotenone toxicity is belived
to be a result from OS generated during DA metabolism and by mitochondrial
respiration. In addition, progressive depletion of glutathione, oxidative damage to
proteins and DNA, release of cytochrome c from mitochondria to cytosol, activation of
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caspase 3, mitochondrial depolarization, and eventually apoptosis (Greenamyre et al.
2001).
Table 3 Summary of Experimental PD In Vitro models
In Vitro model
References
Primary Embryonic/ Postnatal mouse mesencephalon
(Danias et al. 1989; Lotharius and O'Malley 2001; Gao et al. 2002; Ahmadi et al. 2003; Gao et al. 2003b; Gao et al. 2003a; Gille et al. 2004; Diaz-Corrales et al. 2005; Grammatopoulos et al. 2005; Radad et al. 2006)
PC12 cell lines (Basma et al. 1992; Hartley et al. 1994; Seaton et al. 1997, 1998; Bal-Price and Brown 2000; Lamensdorf et al. 2000b; Seyfried et al. 2000; Taylor et al. 2000; Ishiguro et al. 2001; Dargusch and Schubert 2002; Zheng et al. 2002; Lee et al. 2005; Wang et al. 2005; Bal-Price et al. 2006; Hirata et al. 2006; Hirata and Kiuchi 2007; Marella et al. 2007; Tan et al. 2007; Yim et al. 2007)
Rat VM slices (Seo et al. 2002; Bywood and Johnson 2003; Sherer et al. 2003b; Sherer et al. 2003a; Tai et al. 2003; Xu et al. 2003; Gille et al. 2004; Yang et al. 2004b; Dukes et al. 2005; Hirata and Nagatsu 2005; Kress and Reynolds 2005; Liu et al. 2005; Sousa and Castilho 2005; Testa et al. 2005; Centonze et al. 2006)
Mouse MN9D cell line (Seo et al. 2002; Kweon et al. 2004; Cao et al. 2007) SH-SY-5Y cells (Seaton et al. 1997; Lamensdorf et al. 2000b; Lamensdorf et al.
2000a; Imamura et al. 2006; Klintworth et al. 2007)
Synaptosomes (Bougria et al. 1995; Fonck and Baudry 2003)
3.5.2.1 DAergic Toxicity
Rotenone treatment induces a dose- and time-dependent destruction of SNpc neuron
processes, morphologic changes, some neuronal loss, and decreased TH protein levels.
Chronic complex I inhibition also caused oxidative damage to proteins, measured by
protein carbonyl levels. This oxidative damage was blocked by the antioxidant alpha-
tocopherol (vitamin E). At the same time, alpha-tocopherol also blocked rotenone-
induced reductions in TH protein and TH immunohistochemical changes (Testa et al.
2005). The number of TH+ve neurons was shown to be reducted by 50 +/- 6%
137
[Grammatopoulos TN], along with a reduction in DA, dihydroxyphenyl acetic acid
(DOPAC) and homovanillic acid (HVA) levels in PC12 cells, DOPA formation with an
accompanying decrease in ATP and increase in lactate in rat striatal slices (Hirata and
Nagatsu 2005).
Decreases in ATP levels, changes in catechol levels, and increased DA oxidation is the
general outcome of rotenone treated neurons. Whether endogenous DA makes PC12 cells
more susceptible to rotenone is still unknown. Cells treated with the TH inhibitor alpha-
methyl-p-tyrosine (AMPT) to reduce DA levels prior to rotenone exposure revealed no
changes in rotenone-induced toxicity with or without AMPT treatment. However, a
potentiation of toxicity was observed following coexposure of PC12 cells to rotenone and
methamphetamine. PC12 cells were depleted of DA prior to methamphetamine and
rotenone cotreatment to determine whether this effect was due to DA, resulted in a large
attenuation in toxicity. These findings suggest that DA plays a role in rotenone-induced
toxicity and possibly the vulnerability of DA neurons in PD (Dukes et al. 2005).
Cell death and reduced DA release has been observed in PC12 cells induced by rotenone
(Yang et al. 2004b), this response was abolished by removal of extracellular Ca2+.
Mitochondrial inhibitors and uncouplers evoke catecholamine secretion from PC12 cells
which is wholly dependent on Ca2+ influx through voltage-gated Ca2+ channels (Taylor et
al. 2000). Rotenone also induces a rapid accumulation of DOPAL and DOPET in the
medium of cultured PC12 cells but is decreased by MPP+. 3,4-
Dihydroxyphenylacetaldehyde (DOPAL) is a toxic metabolite formed by the oxidative
138
deamination of DA. This aldehyde is mainly oxidized to 3,4-dihydroxyphenylacetic acid
(DOPAC) by aldehyde dehydrogenase (ALDH), but is also partly reduced to 3, 4-
dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase (ARs) combined
inhibition of ALDH and ARs potentiated rotenone-induced toxicity (Lamensdorf et al.
2000a).
The neurotoxic vulnerabilities between DAergic subgroups have also been studied
Rotenone induced severe dendrite loss among SN DAergic neurons, whereas
hypothalamic A11 DAergic neurons were spared. Adjacent sections that were
immunolabeled for calbindin or stained with cresyl violet also revealed a striking
dendritic degeneration of SN neurons in rotenone-exposed slices, whereas
noncatecholamine neurons, such as those in the perifornical nucleus were more resistant
(Bywood and Johnson 2003).
3.5.2.2 Oxidative Stress (OS)
One possible result of complex I inhibition is increased formation of ROS, creating
oxidative damage within the cell. Oxidative damage, rather than a bioenergetic defect, is
also seen in the in vivo rotenone model (Sherer et al. 2003b; Sherer et al. 2003a;
Bashkatova et al. 2004). PC12 cells treated with rotenone causes an apoptotic cell death
and elevated intracellular ROS and lactic acid accumulation (Lotharius and O'Malley
2001; Dargusch and Schubert 2002; Liu et al. 2005; Radad et al. 2006), the formation of
ROS and the depletion of GSH in differentiated PC12 cells (Sousa and Castilho 2005;
Kim et al. 2007).
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Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing
mitochondrial ROS production. Recently, it has been shown that fraxetin (coumarin) and
myricetin (flavonoid) have significant neuroprotective effects against apoptosis induced
by rotenone, increases the total glutathione levels in vitro, and inhibit lipid peroxidation.,
such as Mn and CuZn superoxide dismutase (MnSOD, CuZnSOD), catalase, glutathione
reductase (GR), and glutathione peroxidase (GPx) on rotenone neurotoxicity in
neuroblastoma cells. N-acetylcysteine (NAC), a potent antioxidant, was employed as a
comparative agent. SH-SY5Y-rotenone treated cells significantly increased the
expression and activity of MnSOD, GPx and catalase (endogenous antioxidant defense
system). Cells preincubated with fraxetin resulted in a decrease in the protein levels and
activity of both MnSOD and catalase, in comparison with the rotenone treatment.
Activity and expression of GPx were increased by rotenone and pre-treatment with
fraxetin did not modify those levels significantly. This suggests that rotenone-induced
neurotoxicity is partially mediated by free radical formation and OS, and that it can be
partially protected by fraxetin providing the main protection system of the cells against
oxidative injury (Molina-Jimenez et al. 2005).
The effect of the complex I-inhibitor rotenone on glutathione redox status and the
generation of reactive oxygen intermediates (ROI) in rat pheochromocytoma PC12 cells
induce a time-dependent loss of GSH, whereas treatment with lower concentrations of
rotenone increases cellular GSH. Both MPP+ and rotenone increase cellular levels of
oxidised glutathione (GSSG) and the higher concentrations of both compounds lead to an
140
elevated ratio of oxidised glutathione (GSSG) vs total glutathione (GSH + GSSG)
indicating a shift in cellular redox balance. However MPP+ or rotenone does not induce
the generation of ROI or significant elevation of intracellular levels of thiobabituric acid
reactive substances (TBARS) for up to 48 h (Seyfried et al. 2000).
3.5.2.3 αααα-Synuclein
In vitro, rotenone-induced α-synuclein aggregation (Lee et al. 2002) is correlated with
elevations in insoluble protein carbonyls (Lee et al. 2002; Sherer et al. 2002b). In
addition, in vivo rotenone infusion results in selective upregulation of α-synuclein in the
substantia nigra and the increased occurrence of higher-molecular-weight, aggregated
forms of α-synuclein (Betarbet et al. 2000; Betarbet et al. 2002a; Hoglinger et al. 2003a).
An elevation in insoluble protein carbonyls in the midbrains of rotenone-treated animals
suggests that rotenone treatment may cause oxidative modifications to α-synuclein that
make it more likely to aggregate (Giasson et al. 2000; Krishnan et al. 2003). On the other
hand, elevated α-synuclein expression can itself cause oxidative damage and render cells
more vulnerable to oxidative insults (Hsu et al. 2000; Kanda et al. 2000; Ko et al. 2000).
Aggregation of gamma-tubulin protein, which is a component of the centrosome matrix
and recently identified in LBs of PD, was observed in primary cultures of mesencephalic
cells treated with rotenone. Rotenone-treated neurons and astrocytes showed enlarged and
multiple centrosomes. These centrosomes also displayed multiple aggregates of α-
synuclein protein. Neurons with disorganized centrosomes exhibited neurite retraction
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and microtubule destabilization, and astrocytes showed disturbances of mitotic spindles
(Diaz-Corrales et al. 2005).
3.5.2.4 Complex I Inhibitor
Complex I inhibition has several potential functional consequences, including decreased
ATP production, altered calcium handling, and oxidative damage. Complex I is the first
of four multisubunit protein complexes in the mitochondrial electron transport chain
responsible for converting energy from cellular metabolism into the proton gradient used
by complex V to generate ATP. Electron transport chain dsyfunction could lead to loss of
the proton gradient, impaired ATP production, and a bioenergetic defect. However, in
dissociated culture systems, rotenone does not kill cells via ATP depletion instead
rotenone increases OS (Zhang et al. 2001; Sherer et al. 2003b).
Complex I inhibition provokes the following events: 1) activation of specific kinase
pathways; 2) release of mitochondrial proapoptotic factors, apoptosis inducing factor, and
endonuclease G. AS601245, a kinase inhibitor, exhibited significant protection against
these apoptotic events. The traditional caspase pathway does not seem to be involved
because caspase 3activation was not observed. This suggests that overproduction of ROS
caused by complex I inhibition is responsible for triggering the kinase activation
(Ishiguro et al. 2001; Lee et al. 2005; Bal-Price et al. 2006; Hirata et al. 2006; Ito et al.
2006; Radad et al. 2006; Hirata and Kiuchi 2007; Marella et al. 2007; Tan et al. 2007;
Yim et al. 2007).
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Rotenone causes the loss of mitochondrial membrane potential, released cytochrome c
into the cytosol, and reduced cytochrome c content in mitochondria addition of bHB
blocked this toxic effect and also attenuated the rotenone-induced activation of caspase-9
and caspase-3 (Imamura et al. 2006). Numerous studies also suggest that dysfunction of
mitochondrial proton-translocating NADH-ubiquinone oxidoreductase (complex I) is
associated with neurodegenerative disorders, such as PD and Huntington's disease. It was
previously shown that the single-subunit NADH dehydrogenase of Saccharomyces
cerevisiae (Ndi1P) can work as a replacement for complex I in mammalian cells such as
DAergic cell lines rat PC12 and mouse MN9D. The cells expressing the Ndi1 protein
were resistant to rotenone (Seo et al. 2002).
3.5.2.5 Inflammation
Increasing evidence suggests an important role for environmental toxins such as
pesticides in the pathogenesis of PD. Rotenone-induced DAergic neurodegeneration has
been associated with both its inhibition of neuronal mitochondrial complex I and the
enhancement of activated microglia. Previous studies with NADPH oxidase inhibitors,
diphenylene iodonium and apocynin suggest that NADPH oxidase-derived superoxide
might be a major factor in mediating the microglia-enhanced rotenone neurotoxicity.
However, because of the relatively low specificity of these inhibitors, the exact source of
superoxide induced by rotenone remains to be determined. Primary mesencephalic
cultures from NADPH oxidase--null (gp91phox-/-) or wild-type (gp91phox+/+) mice,
demonstrate the critical role for microglial NADPH oxidase in mediating microglia-
enhanced rotenone neurotoxicity. In neuron--glia cultures, DAergic neurons from
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gp91phox-/- mice were more resistant to rotenone neurotoxicity than those from
gp91phox+/+ mice. However, in neuron-enriched cultures, the neurotoxicity of rotenone
was not different between the two types of mice. These results show that the greatly
enhanced neurotoxicity of rotenone was attributed to the release of NADPH oxidase-
derived superoxide from activated microglia (Gao et al. 2003a).
Observations of rotenone and the inflammogen lipopolysaccharide (LPS) synergistically
induced DAergic neurodegeneration. The synergistic neurotoxicity of rotenone and LPS
is observed when the two agents were applied either simultaneously or in tandem.
Mechanistically, microglial NADPH oxidase-mediated generation of ROS appeared to be
a key contributor to the synergistic DAergic neurotoxicity. This conclusion is based on
the facts that inhibition of NADPH oxidase or scavenging of free radicals induced
significant neuroprotection. Finally, rotenone and LPS failed to induce the synergistic
neurotoxicity as well as the production of superoxide in cultures from NADPH oxidase-
deficient animals. This is the first demonstration that low concentrations of pesticide and
an inflammogen work in synergy to induce a selective degeneration of DAergic neurons
(Gao et al. 2003b).
Neuron-enriched and neuron/glia cultures from the rat mesencephalon, has been used to
study the role of microglia in rotenone-induced neurodegeneration. Significant and
selective DAergic neurodegeneration was observed in neuron/glia cultures 2d after
treatment with rotenone. The greatly enhanced neurodegenerative ability of rotenone was
attributed to the presence of glia, especially microglia, because the addition of microglia
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to neuron-enriched cultures markedly increased their susceptibility to rotenone.
Mechanistically, rotenone stimulated the generation of superoxide from microglia that
was attenuated by inhibitors of NADPH oxidase. Furthermore, inhibition of NADPH
oxidase or scavenging of superoxide significantly reduced the rotenone-induced
neurotoxicity (Gao et al. 2002).
3.5.2.6 Cell death via Apoptosis
Two cell models, human cultured cells HL-60 and BJAB, have shown that the exposure
of cells to rotenone induces the generation of H2O2, which leads to significant changes in
the mitochondrial membrane potential, and which is accompanied by the fragmentation
of internucleosomal DNA and the formation of DNA-ladders (Tada-Oikawa et al. 2003).
Furthermore, caspase-3 activity increases in rotenone-treated HL-60 cells in a time-
dependent manner. These apoptotic events are delayed in HP100 cells, an H2O2-resistant
clone of HL-60, confirming the involvement of H2O2 in apoptosis. In the same study, the
expression of anti-apoptotic protein, Bcl-2, in BJAB cells, was shown dramatically to
inhibit rotenone-induced changes in the mitochondrial membrane potential and the
formation of DNA ladders, confirming the involvement of mitochondrial dysfunction in
apoptosis (Tada-Oikawa et al. 2003).
Nanomolar concentrations of rotenone are also able to induce caspase-3-mediated
apoptosis in primary DA neurons in VM cultures from E15 rats (Ahmadi et al. 2003;
Hirata et al. 2006). After 11h of exposure to 30 nM rotenone, the number of DA neurons
identified by TH immunostaining decreases rapidly, and only 20% of the neurons
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survive. On the other hand, more than 70% of total neurons survive rotenone treatment,
implying that DAergic neurons (TH+-neurons) are more sensitive to rotenone (Ahmadi et
al. 2003). Rotenone significantly increases the number of apoptotic TH+-neurons
(Hartley et al. 1994; Seaton et al. 1997, 1998; Radad et al. 2006; Hirata and Kiuchi 2007;
Tan et al. 2007), which is correlated with an increase in immunoreactivity for active
caspase-3 in DAergic neurons (Seaton et al. 1997; Lee et al. 2005; Wang et al. 2005;
Hirata et al. 2006; Ito et al. 2006). Furthermore, the caspase-3 inhibitor, DEVD, rescues
a significant number of TH+-neurons from rotenone-induced death. Thus, at low
(nanomolar) concentrations, rotenone is able to induce caspase-3-mediated apoptosis in
primary DA neuron cultures, with TH+-neurons being more sensitive to rotenone-induced
toxicity than the total VM cell population (Ahmadi et al. 2003). This immediately raises
a question concerning the mechanisms involved in the selectivity of dopaminergic
neuronal death by rotenone.
Nitric oxide (NO) can also trigger either necrotic or apoptotic cell death. A 24-h
incubation of PC12 cells with NO donors or specific inhibitors of mitochondrial
respiration rotenone, in the absence of glucose, caused ATP depletion and resulted in 80-
100% necrosis. Glucose addition almost completely prevented the decrease in ATP level
and the increase in necrosis induced by the NO donors or mitochondrial inhibitors. This
suggests that the NO-induced necrosis in the absence of glucose was due to the inhibition
of mitochondrial respiration and subsequent ATP depletion. However, in the presence of
glucose, NO donors and mitochondrial inhibitors induced apoptosis of PC12 cells as
determined by nuclear morphology. The presence of apoptotic cells is prevented
146
completely by benzyloxycarbonyl-Val-Ala-fluoromethyl ketone (a nonspecific caspase
inhibitor), this shows apoptosis was mediated by caspase activation. Indeed, both NO
donors and mitochondrial inhibitors in PC12 cells caused the activation of caspase-3- and
caspase-3-processing-like proteases. Caspase-1 activity was not activated. Cyclosporin A
(an inhibitor of the mitochondrial permeability transition pore) decreased the activity of
caspase-3- and caspase-3-processing-like proteases after treatment with NO donors, but
was not effective in the case of the mitochondrial inhibitors. The activation of caspases
was accompanied by the release of cytochrome c from mitochondria into the cytosol,
which was partially prevented by cyclosporin A in the case of NO donors. These results
show that NO donors may trigger apoptosis in PC12 cells partially mediated by opening
the mitochondrial permeability transition pores, release of cytochrome c, and subsequent
caspase activation (Bal-Price and Brown 2000).
Rotenone exposure caused apoptosis in SH-SY5Y cells but not in PC12 cells. This
selective ability of paraquat and rotenone to induce apoptosis in different cell lines
correlates with their ability to activate c-Jun N-terminal protein kinase (JNK) and p38
mitogen-activated protein kinases. Furthermore, JNK and p38 are required for rotenone-
induced apoptosis in SH-SY5Y cells (Newhouse et al. 2004) as well as primary neurons
(Klintworth et al. 2007). Along with nuclear damage, the changes in the mitochondrial
membrane permeability, leading to the cytochrome c release and caspase-3 activation, the
formation of reactive oxygen species and the depletion of GSH in differentiated PC12
cells was induced by rotenone (Sousa and Castilho 2005; Kim et al. 2007).
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3.5.2.7 DA Agonists and Antioxidants
Markers of DAergic neurons are more altered than those of �-aminobutyric acid (GABA)
neurons in PD-toxin models, suggesting greater susceptibility of DAergic neurons. Thus
DA agonists are employed to replace the DA lost. Intracellular DA depletion with
reserpine significantly attenuated rotenone-induced ROS accumulation and apoptotic cell
death but not with deprenyl (Lotharius and O'Malley 2001; Dargusch and Schubert 2002;
Liu et al. 2005; Radad et al. 2006). Another DA agonist which has been shown to
possess anti-apoptotic actions is pramipexole, which also reduces caspase-3 activation,
decreases the release of cytochrome c and prevents the fall in the mitochondrial
membrane potential induced by rotenone (Schapira 2002a, b; Gu et al. 2004). The
oxidative damage and DAergic neuronal loss caused by rotenone were shown to be
blocked by alpha-tocopherol (Seyfried et al. 2000; Sherer et al. 2003b).
3.6 ORGANOTYPIC CELL CULTURE: IN VITRO MODEL FOR PD
The ability to conduct morphological assessments of ventral mesencephalic (VM) and
striatum co-cultures provides support for the use of the organotypic co-culture model of
the basal ganglia, given that DA neurons present in the VM will project axons to an
adjacent cultured striatal tissue slice (Snyder-Keller et al. 2001; Gates et al. 2004) and
form functional synapses (Tseng et al. 2007). Further analyses have shown that even the
complex patch/matrix organization of the striatal tissue is maintained when donor tissue
of VM and ST is age-appropriate (Snyder-Keller et al. 2001). These studies suggest that
it is important to use VM tissue in which the dopamine (DA) neurons have differentiated,
148
yet have not begun to project DA axons/terminals to the striatum; in this way, the likely
degeneration incurred with axotomy during tissue dissection can be limited.
PD research has utilized VM organotypic cultures, containing the DA neurons affected in
PD, in the study of tissue explants for transplantation purposes, as well as to assess
potential DA neurotoxicants. Researchers have used the VM cultured alone (Dickie et al.
1996; Hoglinger et al. 1998; Meyer et al. 2001; Shimizu et al. 2003a), the VM in co-
culture with ST (the target of VM DA neuron terminals) (Schatz et al. 1999; Katsuki et
al. 2001; Snyder-Keller et al. 2001; Kotake et al. 2003; Gates et al. 2004), and the VM,
striatum, and cortex in triple cultures to model the BG DAergic system (Plenz and Kitai
1996; Snyder-Keller et al. 2001). However, to date, studies have not adequately
described the DA development, in terms of neurochemical and protein analyses, of the
VM and striatum in co-culture (Lyng et al. 2007). Here, we have used organotypic co-
cultures of P5-6 VM and P5-6 rat ST in the roller tube system with slight modifications
(Stoppini et al. 1991; Snyder-Keller et al. 2001) to model the developing nigrostriatal DA
system.
3.6.1 MPTP application in organotypic cell cultures
Using midbrain slice cultures a few studies have demonstrated MPP+ to be a complex I
inhibitor (Madsen et al. 2003; Xu et al. 2003; Gille et al. 2004), specifically toxic to
DAergic neurons by reduction in DA levels, its metabolites and tyrosine hydroxylase-
positive cells in a dose-dependent manner (Reinhardt 1993; Madsen et al. 2003; Shimizu
et al. 2003b; Shimizu et al. 2003a; Kress and Reynolds 2005). MPP+’s toxic action was
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attenuated by NMDA inhibitor MK801 (Kress and Reynolds 2005), DA agonists such as
L-Dopa, antioxidant and bioenergetic coenzyme Q(10) (CoQ(10)) had preserving
potential on the activities of TH, complexes I and II of the respiratory chain along wit the
survival rate of DAergic neurons (Gille et al. 2004). Cell death process is believed to
occur via apoptosis evident by the loss of cell bodies and the fragmentation of processes
along with nucleus shrinkage (Kress and Reynolds 2005). This cell death was prevented
by the inhibitors of NMDA, nitric oxide synthase (NOS), cycloheximide and caspase
cascade and also rescued by L-deprenyl and dopamine D2/3 agonists (Shimizu et al.
2003b; Shimizu et al. 2003a). The influence of target tissue was also examined on co-
cultures of DAergic neurons forming dense innervation to the striatal tissue. DAergic
neurons in midbrain--striatum co-cultures were more resistant to the cytotoxic actions of
NMDA and a nitric oxide donor NOC-18, than the same neuronal population in single
midbrain cultures. On the other hand, the toxicity of MPP+ was more prominent in
midbrain-ST co-cultures than that in single midbrain cultures (Katsuki et al. 1999). The
neurotrophic factor GDNF was also examined in this in vitro model showing that pre-
treatment and post-treatment with GDNF is important to obtain maximal protection
against MPP+ toxicity (Jakobsen et al. 2005).
3.6.2 Rotenone and Organotypic Cell Culture
To a lesser extent, the use of rotenone in both animal and cell cultures is fewer than
MPP+ and has mainly been studied in primary cell cultures deriving from fetal
mesencephalon. Only a few studies have employed rotenone in this culture system.
Similar to MPP+, it is observed to be a complex I inhibitor and specific DAergic toxin
150
leading to a dose- and time-dependent destruction of SNpc neuron processes,
morphologic changes, neuronal loss, and decreased TH protein levels (Xu et al. 2003;
Kress and Reynolds 2005; Testa et al. 2005). Chronic complex I inhibition also caused
oxidative damage to proteins, measured by protein carbonyl levels. This oxidative
damage was blocked by the antioxidant alpha-tocopherol (vitamin E). At the same time,
alpha-tocopherol also blocked rotenone-induced reductions in TH protein and TH
immunohistochemical changes (Testa et al. 2005). Addition of L-Dopa, DA agonists and
antioxidants such as CoenzymeQ were able to counteract rotenone’s toxicity (Gille et al.
2004).
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4.0 AIMS OF STUDY
1) To grow and maintain the development of dopaminergic neurons in vitro using the
organotypic slice culture technique.
2) To establish a period of optimal dopaminergic neuronal growth for application of
neurotoxins.
2) To assess the effects of neurotoxins MPTP and rotenone on the survival of
dopaminergic neurons.
3) To examine the neuroprotective effects of neutrophic factor GDNF on dopaminergic
neurons with or without the toxic stress from the neurotoxins.
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CHAPTER 5:
GENERAL MATERIAL AND METHODS
153
5.1 ANIMAL CARE
5.1.1 Ethics
The experimental studies presented in this thesis were performed within the guidelines
established by the National Health and Medical Research Council (NH&MRC) and were
approved by the ethics committees of the Institue of Medical and Veterinary Science
(IMVS; 64A/04, 152A/07) and the University of Adelaide (M-64-2004) to minimize
animal suffering and to reduce the number of animals used.
5.1.2 General
Sprague-Dawley rats from postnatal day of 4 to 5 (P 4-5) were kept in a heated pad
insulated container until required.
5.2 ORGANOTYPIC SLICE CULTURES
All the culture procedures were carried out under sterile conditions, within a laminar flow
hood. Similarly, all equipment was sterilized in an oven for four hours at 180°C and
solutions were either sterile filtered or obtained pre-sterilized or autoclaved.
5.2.1 Dissection of the ventral mesencephalon and striatum
Organotypic slices were prepared from brains of pups 4-5 d of either sex according to the
procedure described by Stoppini (Gahwiler 1981; Stoppini et al. 1991) and Gahwiler
{Gahwiler, 1988 #27) with slight modifications. Briefly, pups were quickly decapitated;
small dissecting scissors were used to make a cut along the midline of the skull before the
skull was opened to expose the dorsal surface of the brain. A spatula was used to cut
154
through cranial nerves and ease the brain, dorsal surface downwards onto a sterile chilled
Petri dish. Following the rapid removal of the brain, placed on its dorsal side with the
ventral side up on a sterile glass cold Petri dish, under a dissecting microscope.
In order to dissect the striatum (ST), two cuts in the coronal plane were made; one
through the forebrain anterior to the level of the optic chiasm, the second through the
optic chiasm itself. The block was placed on its anterior cut surface and another two
horizontal cuts separated the striatum from the cerebral cortex and basal forebrain, whilst
two vertical cuts removed the septum and any remaining cortex from the striatum. Any
meninges attached to the tissue were removed with tweezers. The tissue block was
transferred to a McIlwain tissue sectioner where serial coronal sections of 300μm
thickness were cut. After transferring the ST to a petri dish containing cooled ringers
balanced salt solution (BSS; see appendices), the sections were gently teased apart. Up to
10 slices were obtained from each tissue block.
A similar procedure was used to dissect the ventral mesencephalon (VM). A coronal cut
was made through the posterior thalamus at the level of the mammilary bodies. A second
cut was made through the brain at the level of the pons in order to isolate the midbrain. A
horizontal cut removed the dorsal midbrain and cortical tissue from the ventral midbrain.
The tissue was then turned onto the dorsal cut surface and any attached meninges were
removed with fine tweezers before making a vertical midline cut to separate the two VM.
Then 200μm thick slices were cut. Up to ten cultures could be produced from each tissue
block. Finally, the sections were transferred to a solution of cooled ringers and the
155
sections were teased apart under the dissecting microscope. Petri dishes with ringer’s
solution containing either SN or ST were then transferred into another sterile Petri dish
containing chilled Gey’s balanced salt solution (GBSS; JRH biosciences) and 0.1 % D-
glucose and 0.1% potassium chloride. The Petri dishes containing either ST or SN placed
in GBSS were placed at 4°C for 90min in a fridge before mounting.
5.2.2 Mounting the slices
The slices were mounted on glass coverslips (11cm x 22cm). The coverslips were
cleaned for fifteen minutes in a 1% solution of sodium thiosulphate and potassium
hexacyano ferrate, then boiled in distilled water for two hours, immersed in ethanol for
two days and sterilised.
A plasma clot was used to mount the tissue onto the cover slips. This involved
embedding the tissue in a plasma clot which was formed by mixing a solution of chicken
plasma with thrombin. A stock solution of chicken plasma was prepared from
lyophilised chicken plasma to which 5ml of sterile purified water was added. The
solution was centrifuged at 2500 revolutions per minute (RPM) for thirty minutes and the
supernatant was sterile filtered before being frozen in 1ml aliquots. The thrombin
solution was prepared from 0.1g of bovine thrombin by addition of 5ml of sterile purified
water. The solution was centrifuged for thirty minutes at 2500 RPM and the supernatant
was sterile filtered before being frozen in 200μl aliquots.
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On the day of preparation of cultures, 150μl of the prepared thrombin solution was
diluted with 5ml of sterile GBSS. Both the chicken plasma (Sigma P-3266-5mL) and the
thrombin (Sigma T-4648-10KU) solutions were kept on ice. A 20μl drop of chicken
plasma solution was placed on one end of the pre-cleaned coverslip. A fine spatula was
then used to gently lift a section of ventral mesencephalon followed by the ST, from the
GBSS and into the drop. A 20μl drop of thrombin was then placed on the cover slip and
a spatula was used to mix the two solutions around the sections. Finally, the tissues were
carefully positioned approximately 1mm apart within the plasma clot which had formed.
5.2.3 Slice culture by the roller-tube technique
Each coverslip with the mounted cultures was placed in screw cap, diagonal bottomed
culture tube (NUNC TC tube; NC-156758, SI 110 X 6 mm) and 0.75ml of culture
medium was added to each tube. The culture medium contained 25% horse serum which
had been inactivated by heating at 56oC for thirty minutes, 50% Eagle minimum essential
medium and 25% Hanks BSS ([10 mM HEPES] IMVS; Infectious disease lab media
unit). The medium was also supplemented with d-glucose to a final concentration of
6.5mg/ml and L-glutamine to a final concentration of 0.15 mg/ml. New culture medium
was made each week. Penicillin and gentamycin were also added to the medium.
The culture tubes were placed in a roller drum which was tilted at an angle of 5o from the
horizontal axis to ensure that the cultures were immersed by the medium for about half of
the rotating cycle. The culture tubes were rotated at a rate of approximately ten
revolutions per hour. The roller drum was positioned within an incubator which kept the
157
cultures at a temperature of between 35.5 and 36.5oC. The culture medium was changed
twice a week by pouring away the old medium and adding 0.75ml fresh medium to each
tube. In order to control the number of non-neuronal cells, anti-mitotic drugs were added
to the medium for 24 hours on the third or fourth day in culture. The anti-mitotic
substances used were uridine and cytosine-β-D-arabino-furanoside, both at
concentrations of 10-3 M. Cultures were maintained for variable lengths of time, most
cases for 7 weeks.
Co-cultures included whole intact hemispheres of ventral mesencephalon containing SN
were plated 1mm apart from the ST on glass coverslips (LOMB Scientific) with 25 μl of
chicken plasma and 20 μl thrombin. Placed in a humidified chamber for 15 min to allow
the chicken plasma and thrombin to clot then into a flat-bottom culture tubes with screw
caps containing 1 ml medium [50% DMEM (IMVS; Infectious disease lab media unit),
25% Hanks balanced salt solution with 10 nM HEPES (IMVS; Infectious disease lab
media unit), 25% heat inactivated horse serum (JRH biosciences; 50120-100 M),
supplemented with glucose (1 ml 50% D-glucose to 100 ml of medium) and glutamine
(500 μl of 1 mM L-glutamine to 100 ml of medium), and 0.5% gentamycin and penicillin
(IMVS; Infectious disease lab media unit). The medium was changed twice a week.
After 4 to 6 days in vitro (DIV), co-cultures were treated with antimitotic agents 1 ml of
cytosine-β-D-arabinofuranoside (Sigma C-6645) and 1 ml of uridine (Sigma U-3750) to
100 ml of medium for 24 h to retard glial and fibroblast growth, then discarded and fresh
media was added. Cultures were maintained for variable lengths of time, most cases for 7
weeks, in a cell culture incubator at 35-36.5 °C in a roller drum at 5 revolutions per hour.
158
5.3 FIXATION OF CULTURES
Cultures were fixed at 1 week intervals with 4% paraformaldehye (pH 7.4) overnight or
minimum 4 hours at room tempertature. Then endogenous peroxidases were inactivated
with treatment with 0.5 % H2O2 (8.3 mL) plus 100% of methanol (500 mL) for 30 min.
Sections were the rinsed twice (5 min) in fresh PBS (pH 7.4) 0.3 % Triton X-100 (Sigma
T9284-500 mL).
5.3.1 Immunoperoxidase antigen retrieval
For antigen retrieval, the cultures on coverslips or 7μM sections of paraffin embedded
tissue were placed in coplin glass staining jars or slide rack (respectively) (Proscitech;
L056) containing citrate solution (see appendices) with lid screwed slightly, the coplin
jars are then placed within a kartel slide dish filled with distilled water (approximately
250 ml) and lid placed on, then microwave as follows. Place side dishes in Panasonic
microwave oven (Model NE-1037) press 0 the start button. Microwave the coverslips
until they start to boil. Once boiled remove the boiled dishes and place in a second
microwave oven (NEC). If there is 2 dishes select timer fro 10 min and power level at 2,
for 3 dishes select timer for 10 min and power level at 3. Once microwaving is complete
remove dishes from microwave take lids off and allow 30 min to cool (approximately
below 40°C). Cultures are then washed twice (5 min) fresh 0.3% Triton X-100 PBS.
5.3.2 Immunohistochemistry
Antisera: The following mono- and polyclonal antibodies were used: rabbit polyclonal
from embryonic rats or mice (Krieglstein et al. 1995b; Krieglstein et al. 1995a; Hou et al.
1996; Jordan et al. 1997; Ling et al. 1998a; Ma et al. 2000; Jakobsen et al. 2005) or
human embryonic stem cells (Zeng et al. 2006) whereas the present study has been
carried out on postnatal rat slice co-cultures. Studies of the effects of GDNF on rotenone
exposure are limited (Hirata and Kiuchi 2007; Cho et al. 2008; Yang et al. 2008).
9.5 Summary
In this study we were able to maintain the growth of DAergic neurons derived from
postnatal rat pups using the organotypic slice cultures. The importance of the trophic
target-ST in the development and survival of DAergic neurons in culture was
demonstrated by poor growth in its absence. Both neurotoxins MPTP and rotenone,
induced DAergic cell degeneration in a dose-dependent manner and TH-ir cell
vulnerability which increased with culture time. Exposure of TH-ir cells to GDNF in co-
cultures increased cell size and induced significant cell branching and lengthening despite
289
no difference in cell numbers compared to controls. TH-ir cells in co-cultures treated
with MPTP and rotenone was protected by GDNF but only at the lower doses of the
neurotoxins.
9.6 Conclusion
Thus, this study has shown the importance of using organotypic slice cultures of VM and
ST, demonstrating TH-ir cell growth and development is regulated by its trophic target-
ST. By establishing this culture system we were able to study cell death of TH-ir cells,
in addition, not only are TH-ir cells vulnerable to MPTP and rotenone treatment, but they
can be protected by GDNF. These results represent important findings in the continued
investigation of the underlying basis against PD.
290
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