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

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INTRODUCTION Transition metals: the example of iron 40 Iron is a redox-active metal able to generate O2 ●─ from its interaction with molecular oxygen by auto-oxidating (Reaction 4). The reverse reaction is also possible. As a result of the Fenton reaction (Reaction 5), Fe 2+ may also be oxidized in the presence of H2O2 and generate ● OH and Fe 3+ which provokes lipid oxidation through its reaction with hydroperoxides normally present in the biological systems. In biological environment, other reactions as the Haber-Weiss reaction also occurs and requires the catalytic contribution of redox metal ions (Reaction 7). Reaction 4 Fe 2+ + O2 → Fe 3+ + O2 ●─ ●─ + 2 O2 + 4H → 2H2O2 Reaction 5 Fe 2+ + H2O2 → Fe 3+ + ● OH + OH ─ (Fenton reaction) Reaction 6 Fe 3+ + O2 ●─ → Fe 2+ + O2 Reaction 7 O2 ●─ + H2O2 → O2 + ● OH + OH ─ (Haber Weiss reaction) In PD, iron content of the SNpc is elevated with an increase of the Fe 3+ /Fe 2+ ratio from 2:1 to almost 1:2 (Riederer et al. 1988, 1989, Sofic et al. 1988, Dexter et al. 1993). These levels of iron increase the conversion of H2O2 to ● OH via the Fenton reaction and promote a greater turnover in the Haber-Weiss reaction, leading to an amplification of oxidative stress (Riederer and Youdim 1993). Alternatively, oxidative stress may increase the levels of free iron (Halliwell and Gutteridge 2003) which may interact with α-synuclein promoting its aggregation (Schipper et al. 1998, Hochstrasser et al. 2004).
DA metabolism as a source of ROS INTRODUCTION The selective neurodegeneration of SNpc DAergic in PD seems to suggest that these neurons are more vulnerable to oxidative stress, but the reason behind this is not completely understood. One potential explaination was based, at least in part, on DA metabolism either by autoxidation or catalyzed by MAO. Actually, this neurotransmitter can react with molecular oxygen generating peroxides, active quinones, � OH and other ROS that, along with those created from the respiratory chain failure, may lead to both modifications of proteins and depletion of GSH generating a highly oxidative intracellular environment. The MAO catalyzed oxidation of DA to 3,4-dihydroxyphenylacetaldehyde (DOPAL) leads to H2O2 formation, which is normally cleared by GSH. As GSH levels are decreased in SN of PD patients (Sian et al. 1994) H2O2 may be converted into � OH which may trigger lipid peroxidation causing the death of DAergic neurons. Furthermore, DA autoxidation results in the formation of the semiquinone radical which can be directly toxic (Stokes et al. 1999, Danielson and Andersen 2008) or which can lead to the formation of ROS (Olanow 1990). O2 ●─ is either metabolized into H2O2 or reacts with NO, generating the strongly reactive ONOO ●─ . After a complex process of polymerization, this autoxidation pathway leads finally to the generation of the dark- coloured, insoluble pigment called neuromelanin (Graham 1978). This compound was implicated in the vulnerability and susceptibility of DAergic neurons to neurodegeneration (Abou-Sleiman et al. 2006) but its precise mechanism remains uncertain. Several hypotheses tried to explain its contribution to the DAergic neurons death, through a macromolecule crowding effect or as an intraneuronal toxic reservoir by binding transition metals like iron or neurotoxic coumpounds like MPP + (Chung et al. 2001). 41
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Universidade de Santiago de Compost
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Don Ramón Soto Otero y Doña Estef
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Acknowledgements The work of this t
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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 and 46: INTRODUCTION characterized as are l
Page 47 and 48: INTRODUCTION (Olanow et al. 2004).
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: INTRODUCTION Oxidative damage happe
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
Page 99 and 100: AIMS OF THE PRESENT THESIS The main
Page 101: OBJETIVOS
Page 104 and 105: OBJETIVOS 3) Evaluar de forma preci
Page 107: CHAPTER 1 Time-course of brain oxid
Page 110 and 111: CHAPTER 1 INTRODUCTION 86 6-OHDA (2
Page 112 and 113: 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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