Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

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INTRODUCTION other brain areas and in the peripheral autonomic nervous system as the disease progresses (Forno et al. 1996, Wakabayashi and Takahashi 1997, Spillantini et al. 1998, Braak et al. 2003, Wakabayashi et al. 2007). The extensive distribution of LB could account for a variety of motor and non-motor symptoms of PD. Interestingly it has been proposed that LB appear first in both the olfactory bulb and lower brain stem, following then a foreseeable progression which contributes to explain the loss of olfaction which might precede motor symptoms. Figure 12: LB and LN in PD patients (A, B: Wakabayashi and Takahashi 2007, C: Braak and Del Tredici 2008) and localization of LB and LN (D: Braak et al. 2003) 22 A B C D The presence of LB is not specific for PD as they occur also in AD, dementia with LB (DLB) and in healthy people of advanced age at a greater frequency than the prevalence of PD (Gibb and Lees 1988). The role of LB in neuronal cell death is controversial and under debate: LB may be toxic by interfering with normal cellular processes and/or by sequestering important proteins for cell survival or on the other hand, they could be cytoprotective as they may sequester and degrade the toxic proteins
INTRODUCTION (Olanow et al. 2004). Most likely, LB seem to be symptomatic in PD pathogenesis, not causative (Wakabayashi et al. 2007). The six-stage system: a novel neuropathological concept of neurodegeneration Recently, Braak and colleagues established a staging procedure based on the distribution of LB and LN (Braak et al. 2003, Braak et al. 2006). According to the pathological changes observed during the cross-sectional study originally performed on autopsy cases, the authors proposed that the formation of proteinaceous intraneuronal LB and LN follows a topographically predictable sequence in six stages with ascending progression from medullary and olfactory nuclei to the cortex (Figure 13). In early stages 1 and 2, patients are pre-symptomatic. LB pathology first appears in the dorsal motor nucleus of the vagal nerve and is confined to the medulla oblongata, pontine tegmentum and anterior olfactory structures. As the disease advances, in stages 3 and 4, pathological changes appear in the SN and in other areas of the basal midbrain and forebrain. Motor symptoms become clinically manifest during this phase. Finally the final stages 5 and 6 are frequently associated with cognitive impairment as the neocortex becomes involved (Figure 14). Many groups give strong support to this neuropathological concept which states that neurodegeneration in PD starts in non-DAergic areas, notably the enteric nervous system and then rises via spinal cord and brainstem to nigral and subsequent cortical neurons (Abbott et al. 2001, Przuntek et al. 2004, Abbotth et al 2005, Ross et al. 2005, Ross et al. 2006). Nevertheless, it has also been brought into question as some neuropathological studies showed brains with important neurodegeneration and α- synuclein pathology in the SNpc and higher brain structures but lacking medullary involvement (Parkinnen et al. 2003, Jellinger 2004, Parkinnen et al. 2005, Attems and Jellinger 2008, Dickson et al. 2008, Kalaitzakis et al. 2008a, 2008b, Parkinnen et al. 2008). 23
Page 1: Universidade de Santiago de Compost
Page 5: Don Ramón Soto Otero y Doña Estef
Page 9 and 10: Acknowledgements The work of this t
Page 11 and 12: Abbreviations AA ascorbic acid AD A
Page 13: Abbreviations (continuation) PCC pr
Page 16 and 17: List of figures (continuation) Chap
Page 19 and 20: TABLE OF CONTENTS INTRODUCTION ....
Page 21: CHAPTER 3 Brain oxidative stress an
Page 25 and 26: INTRODUCTION PARKINSON’S DISEASE
Page 27 and 28: INTRODUCTION PD is found in all eth
Page 29 and 30: Bradykinesia INTRODUCTION Bradykine
Page 31 and 32: INTRODUCTION predate the occurrence
Page 33 and 34: Table 1: Differential diagnostic in
Page 35 and 36: INTRODUCTION Table 3: National Inst
Page 37 and 38: Figure 4: Dopamine catabolism (Mén
Page 39 and 40: The basal ganglia INTRODUCTION The
Page 41 and 42: The death of SNpc DAergic neurons I
Page 43 and 44: INTRODUCTION the dorsomedial part o
Page 45: INTRODUCTION characterized as are l
Page 49 and 50: Etiology and pathogenesis of PD INT
Page 51 and 52: Ageing INTRODUCTION Ageing remains
Page 53 and 54: INTRODUCTION The finding of MPTP to
Page 55 and 56: INTRODUCTION may clarify why many n
Page 57 and 58: Misfolding and aggregation of prote
Page 59 and 60: INTRODUCTION (E3) (Figure 18A). Los
Page 61 and 62: INTRODUCTION in connection with Par
Page 63 and 64: INTRODUCTION Oxidative damage happe
Page 65 and 66: DA metabolism as a source of ROS IN
Page 67 and 68: Contribution of oxidative and nitro
Page 69 and 70: Excitotoxicity INTRODUCTION Glutama
Page 71 and 72: INTRODUCTION al. 1996, Cicchetti et
Page 73 and 74: Experimental models of PD INTRODUCT
Page 75 and 76: INTRODUCTION induce selective DAerg
Page 77 and 78: ALUMINIUM General features INTRODUC
Page 79 and 80: INTRODUCTION Varying amounts of alu
Page 81 and 82: INTRODUCTION and antiperspirants co
Page 83 and 84: INTRODUCTION approximately 3% of al
Page 85 and 86: Excretion INTRODUCTION As insoluble
Page 87 and 88: INTRODUCTION 3.5 mg may be increase
Page 89 and 90: INTRODUCTION Oteiza 1999), non-iron
Page 91 and 92: Aluminium as a cell membrane menace
Page 93 and 94: INTRODUCTION mobilization of Ca 2+
Page 95: Aluminium impairs neurotransmission
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AIMS OF THE PRESENT THESIS The main
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OBJETIVOS
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OBJETIVOS 3) Evaluar de forma preci
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CHAPTER 1 Time-course of brain oxid
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CHAPTER 1 INTRODUCTION 86 6-OHDA (2
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CHAPTER 1 MATERIALS AND METHODS Che
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CHAPTER 1 followed by centrifugatio
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CHAPTER 1 RESULTS Effects of 6-OHDA
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CHAPTER 1 DISCUSSION 94 As shown by
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CHAPTER 1 strategies or to study th
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CHAPTER 1 Fig. 2 Changes in PCC in
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CHAPTER 2
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ABSTRACT CHAPTER 2 In the present w
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MATERIALS AND METHODS Chemicals CHA
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CHAPTER 2 atomization used were 1,5
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DISCUSSION CHAPTER 2 Aluminium ente
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Table 1. Graphite furnace programme
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CHAPTER 3 Brain oxidative stress an
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CHAPTER 3 INTRODUCTION 120 The huma
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CHAPTER 3 MATERIALS AND METHODS Che
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CHAPTER 3 1:15 for hippocampus and
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CHAPTER 3 initially incorporated to
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CHAPTER 3 RESULTS In vivo effects o
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CHAPTER 3 Effects of aluminium admi
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CHAPTER 3 DISCUSSION 132 Aluminium
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CHAPTER 3 hippocampus, showed simil
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CHAPTER 3 assume that the distinct
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CHAPTER 3 Fig. 1 Levels of TBARS (A
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CHAPTER 3 Fig. 2 Enzyme activity of
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CHAPTER 3 Fig. 3 Microphotographs s
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CHAPTER 3 Fig. 5 Levels of TBARS (A
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CHAPTER 3 Fig. 6 In vitro effects o
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SUMMARY
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SUMMARY values were attained at 48
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SUMMARY neurodegeneration in the DA
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CONCLUSIONS The results obtained in
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13) Aluminium does affect neither M
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RESUMEN RESUMEN Desde el punto de v
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RESUMEN zonas cerebrales excepto en
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CONCLUSIONES
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CONCLUSIONES Capítulo 2 4) La admi
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CONCLUSIONES 172 En base a las conc
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Publications as a direct result fro
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